Archive for the ‘Biological Networks, Gene Regulation and Evolution’ Category

Whole-Genome Sequencing Data will be Stored in Coriell’s Spin off For-Profit Entity

Posted in Biological Networks, Gene Regulation and Evolution, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged App Store, Cooper University Hospital, Fox Chase Cancer Center, Full genome sequencing, IBM, medicine, Personalized medicine on January 30, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

With IBM Help, Coriell Spins off For-Profit Entity to Store Whole-Genome Sequencing Data

Review of Coriell Institute Profile

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

http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

UPDATED on 5/16/2013

The Bank Where Doctors Can Stash Your Genome

A new company offers a “gene vault” for doctors who want to add genomics to patient care.

By Susan Young on February 19, 2013

Genomic sequencing might be more common in medicine if doctors had a simple way to send for the test and keep track of the data.That’s the hope of Coriell Life Sciences in Camden, New Jersey, a startup that grew out of a partnership between the Coriell Institute for Medical Research and IBM. The company wants to facilitate the process of ordering, storing, and interpreting whole-genome-sequence data for doctors. The company launched in January and is now working with different health-care providers to set up its service. “The intent is that the doctor would order a test like any other diagnostic test they order today,” says Scott Megill, president of Coriell Life Sciences. The company would facilitate sequencing the patient’s DNA (through existing sequencing companies such as Illumina or Ion Torrent), store it in its so-called gene vault, and act as the middleman between doctors and companies that offer interpretation services. Finally, “we will return the genetic result in the human readable form back to the electronic medical record so the doctor can read it and interpret it for the patient,” says Megill.

“You need a robust software infrastructure for storing, analyzing, and presenting information,” says Jon Hirsch, who founded Syapse, a California-based company developing software to analyze biological data sets for diagnosing patients. “Until that gets built, you can generate all the data you want, but it’s not going to have any impact outside the few major centers of genomics medicine,” he says.

The company will use a board of scientific advisors to guide them to the best interpretation programs available. “No one company is in position to interpret the entire genome for its meaning,” says Michael Christman, CEO of the Coriell Institute for Medical Research. “But by having one’s sequence in the gene vault, then the physician will be able to order interpretative engines, analogous to apps for the iPhone,” he says. Doctors could order an app to analyze a patient’s genome for DNA variants linked to poor drug response at one point, and later on, order another for variants linked to heart disease.

The cloud-based workflow could help doctors in different locations take advantage of expert interpretations anywhere, says Christman. “This would allow a doctor who’s at a community clinic in Tulsa, Oklahoma, order an interpretation of breast cancer sequences derived at Sloan Kettering,” he says.

But while the cloud offers many conveniences, it carries some potential risks. “I am a bit concerned if we really start to outsource data to the cloud without any regulation,” says Emiliano De Cristofaro, a cryptography scientist with Xerox’s PARC who is developing a genomic data storage and sharing platform. “We must not forget that the sensitivity of genomic information is quite unprecedented,” he says. “The human genome is not only a unique identifier but also contains things about ethnic heritage, predisposition to certain diseases including mental disorders, and many other traits.” Data leaks happen all the time, says Cristofaro, and while you can change your password after a security break, “there’s no way to revoke your genome.”

Keeping the genomic data secure is a key component and is the reason the group began a relationship with IBM, says Megill. The data would be stored at the company’s headquarters and would be available only to limited users—doctors and companies that offer diagnostic or other medical interpretation of the genome, he says.

If a patient changes her health-care provider, the data will remain available for her next physician. Storing the data will be free, says Christman.

http://www.technologyreview.com/news/510901/the-bank-where-doctors-can-stash-your-genome/

January 30, 2013

By Turna Ray

Originally published Jan. 29.

MOUNTAIN VIEW, Calif. – The Coriell Institute for Medical Research in partnership with IBM has launched a for-profit company that will store consumers’ whole-genome sequencing data.

The goal of the spinoff company, called Coriell Life Sciences, “is to address how will a doctor actually use whole-genome sequences in a clinical setting,” CIMR CEO Michael Christman said at a personalized medicine meeting here this week. After doctors order a whole-genome sequence, which would be provided by a sequencing service provider, Coriell Life Sciences will harmonize and store that data in a gene vault for the patient. Physicians then will be able to order certain interpretive analyses from third parties on the sequence based on the patient’s medical needs.

After planning for 18 months, Coriell and IBM launched Coriell Life Sciences a few weeks ago. Describing the company as the “expert custodians” of whole-genome data, Christman explained that patients’ information may remain in the gene vault, regardless of whether they change jobs or healthcare providers. The patient will own their data stored in the vault and will have the ability to consent to which third parties gain access to the information and for what purpose.

Coriell Life Sciences will not charge patients for storing their data. Patients can consent to allow their de-identified data to be used for research, at which point Coriell will add their information to an aggregate research database that will be used for discovery work. Alternatively, patients can remove their sequence from the vault if they choose.

Physicians that have ordered certain interpretive analysis on patients’ genome sequences will receive the results through electronic medical records. If the healthcare provider doesn’t have an EMR in place, then they can use a web portal interface through Coriell Life Sciences.

If a physician orders genomic interpretation of a patients’ data related to episodic care, however, the third-party interpretation company will have the right to the genome sequence information for performing that specific analysis. “For most collaborators, their access to patient data will be limited to only the subset of the total sequence required by their specific interpretation,” Scott Megill, CEO of the new firm, told PGx Reporter via email. “If an interpretation company has a legitimate, non-commercial research aim that could benefit from the use of large anonymized data sets, they will have an opportunity to utilize aggregate, well-consented data like any other research organization.”

Likening Coriell Life Sciences to Apple’s App Store, Megill noted that the company’s core GeneExchange product will offer a marketplace in which genome interpretation companies can charge “fair market rates” for their services. In turn for providing the sales channel, marketing, storage, data harmonization, and electronic medical records integration, Coriell Life Sciences will charge a brokerage fee for each transaction, he explained. A spokesperson for the company said that these transaction fees will be “baked into the overall cost to the payor” for each individual test.

“The data is harmonized and brokered such that it can be interpreted by a variety of clinical applications,” Christman said.

“No one company is well positioned to interpret the entire genome,” he added. “In principle what this would do is allow a doctor in Tulsa, Oklahoma, to order the cancer analysis application … that was developed at MD Anderson or Sloan Kettering.”

Coriell Life Sciences is also developing an application that will allow doctors to gauge pharmacogenomic associations in a patient’s sequence. The PGx app will be developed based on data collected by Coriell over the last five years through its Personalized Medicine Collaborative research project.

Launched in December 2007 for the lay public, the Personalized Medicine Collaborative aims to study the impact of genome-informed treatment on medical care by genotyping patients and reporting only clinically actionable genomic information. The study has so far enrolled thousands of participants and has research partnerships with Cooper University Hospital, Virtua Health, Fox Chase Cancer Center, and Helix Health (PGx Reporter 6/17/2009).

Similar to the Personalized Medicine Collaborative, the PGx app will initially enable doctors to gauge whether their patients are at risk for dozens of complex conditions and learn how they metabolize commonly prescribed drugs. “We will be expanding this offering to ultimately include several dozen drug efficacy and dosage recommendations,” Megill said.

The need for securing people’s genome data will become more acute as advanced sequencing technologies become part of mainstream medical care. Coriell Life Sciences was conceived “from a clear market need, identified in our work in the Coriell Personalized Medicine Collaborative research study, to provide the critical missing infrastructure required to enable clinical use of genome-informed medicine,” Megill said. “Doctors today have no easy way to order a genetic test, have the resulting sequence data stored in a trusted place for future use, and receive a ‘human readable’ report that can be used by doctors who haven’t been trained as geneticists.”

Coriell Life Sciences’ business model is based on an assumption that community healthcare providers will likely outsource genome sequencing and the storage of the data. “I don’t think you’re going to see the hospitals buying sequencing machines. It is rocket science and there are rocket scientists who are quite good at it,” Christman said. “So, the doctors will need the ability to collect blood and saliva and the access to FedEx. The sequence then needs to go somewhere.”

Furthermore, Coriell Life Sciences will provide doctors with options on the specific types of available data interpretation services.

“Ultimately, the sequence becomes a commodity supply to the interpretation. Doctors do not need to be educated in the value of an Illumina sequence versus a Complete Genomics sequence to order a specific interpretation,” a company spokesperson said. “Coriell Life Sciences will negotiate the best available supplier for sequence data on their behalf using stringent standards for quality and turnaround time.

“The key principle is making it easy for doctors to order tests and receive results that are ‘human readable’ – without needing to be a geneticist.”

IBM has provided technologies for Coriell Life Sciences and has invested an undisclosed amount in the company. Separate from this effort, Coriell is using IBM’s capabilities and systems to store the 1.5 gigabytes of information per person who has partaken in the Personalized Medicine Collaborative, which aims to genotype 100,000 people.

Megill, in line with other industry observers, believes that doctors are much more likely to use personalized treatment strategies if data from genomic testing were integrated into patients’ electronic medical records. In this regard, the partnership with IBM is critical, since IBM technologies are utilized in 75 percent of the world’s electronic medical record systems, he estimated.

Leveraging IBM’s integration and data interchange technologies, Coriell Life Sciences “will build bi-directional data integrations with healthcare systems so that tests can be ordered, phenotypic data can be utilized, and results can be delivered within the context of the patient record,” Megill said.

Coriell Life Sciences’ model is looking ahead to a time when having a whole genome sequence in medical care will be as commonplace as getting an annual physical exam, except one needs to get his genome sequenced only once. Several speakers at the conference in Mountain View discussed how the advent of whole genome sequencing will change patient care and the diagnostics market.

Describing a model very similar to the one being pursued by Coriell Life Sciences, Cliff Reid, CEO of sequencing firm Complete Genomics, discussed how in the future having whole genome sequence testing performed for a patient and then storing the data for future use will reduce the cost of genetic testing dramatically.

“There will be one cost up front [for whole genome sequencing]… and virtually free thereafter,” Reid said. “By storing it in a secure database, the cost of every genetic test after that is pennies and the time to get it is seconds.

“This is a radically different economic and usage profile than what we’re seeing today in the genetics industry,” he added. “This doesn’t fit very well in the current practice.”

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail Turna Ray or follow her GenomeWeb Twitter account at @PGxReporter.

In focus: Triple Negative Breast Cancer

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged breast cancer, Cancer - General, cell cycle, Chemotherapy, clonal cells, clonal heterogeneity, DNA repair, gene expression, HMEC, molecular subtyping, Myc, neoadjuvant chemotherapy, PI3K, Ras, Ras/MAPK, residual disease, SABCS, SABCS 2012, San Antonio Breast Cancer Symposium, shRNA, Therapy, TNBC, Triple-negative breast cancer on January 29, 2013| 3 Comments »

Latest research efforts reported in the San Antonio Breast Cancer Symposium, 2012

Curator: Ritu Saxena, Ph.D.

‘Triple negative breast cancer’ or TNBC, as the name suggests, is a classification of breast cancers lacking the expression of estrogen receptor (ER) and progesterone receptor expression as well as amplification of the human epidermal growth factor receptor 2 (HER2).

Unlike other breast cancer types, treating TNBC is a challenge mainly because of the absence of well-defined molecular targets and because of disease heterogeneity. Currently, neoadjuvant chemotherapies are in use to treat TNBC patients. Some, around 30%, patients respond completely to neoadjuvant chemotherapy and have good outcomes after surgery. However, if there is a residual disease after therapy, outcomes are poor.

Therefore, current focus of the field is to first understand the complexity of the disease, both at genomic and molecular level and look for targets. Also, several combination chemotherapies are currently under trial to determine the efficacy, overall response rate, progression-free survival and other relevant factors for patients suffering with different forms of TNBC.

Recently, in the San Antonio Breast Cancer Symposium (SABCS 2012), several abstarcts related to TNBC research, both clinical and pre-clinical. Here is a compilation of some of the abstracts and their relevance in the field of TNBC research:

Triple Negative Breast Cancer: Subtypes, Molecular Targets, and Therapeutic Approaches, Pietenpol JA, Vanderbilt-Ingram Cancer Center; Vanderbilt University School of Medicine (Nashville, TN), Abstract no. ES2-2.

In order to better understand the complexity of TNBC, an integrative and comprehensive genomic and molecular analysis is required. The analysis would give important cues to developing and administering effective therapeutic agents. The group has compiled an extensive number of TNBC gene expression profiles and initiated molecular subtyping of the disease. Differential GE was used to designate 25 TNBC cell line models representative of the following subtypes:

two basel-like TNBC subtypes with cell cycle and DDR gene expression signatures (BL1 and BL2);
two mesenchymal subtypes with high expression of genes involved in differentiation and growth factor pathways (M and MSL);
an immunomodulatory (IM) type;
a luminal subtype driven by androgen signaling (LAR)

The pharmacological drugs were chosen on the basis of the genetic pathways active in the cell lines with the abovementioned TNBC subtypes. It was observed that BL1 and BL2 subtype cell lines respond to cisplatin. Mesenchymal, basal, and luminal subtype lines with aberrations in PI3K signaling and have the greatest sensitivity to PI3K inhibitors.

The LAR subtype cell lines express AR and are uniquely sensitive to bicalutamide (AR antagonist). The experiment was a proof-of-concept that the best therapy could be based on TNBC subtypes.

The group has also developed a web-based subtyping tool referred to as “TNBCtype,” for candidate TNBC tumor samples using our gene expression metadata and classification methods. The approach would enable alignment of TNBC patients to appropriate targeted therapies.

The Clonal and Mutational Composition of Triple Negative Breast Cancers: Aparicio S, University of British Columbia (Vancouver, BC), Canada. Abstract no. ES2-3.

The abstract is on the same lines, TNBC heterogeneity that is. The concept of clonal heterogeneity in cancers, the spatial and temporal variation in clonal composition, is the focal point of the discussion. The group has developed next generation sequencing approaches and applied them to the understanding of mutational and clonal composition of primary TNBC. They have demonstrated that both mutational composition and clonal structure of primary TNBC is in fact a complete spectrum, a notion that is far from the previous one that stated TNBC to be a distinct disease. The authors add “clonal analysis suggests a means by which the genetic complexity might be reduced by following patient evolution over time and space.” The specific implications of the mutational and transcriptome landscapes of TNBC in relation to possible disease biologies were discussed in the symposium.

Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease:

Balko JM, etal, Vanderbilt University (Nashville, TN); Foundation Medicine, (Cambridge, MA); Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru

In the absence of hormone receptors and hence lack of targets, Neoadjuvant chemotherapy (NAC) is increasingly used in patients with TNBC. NAC can induce a pathologic complete response (pCR) in ∼30% of patients which portends a favorable prognosis. In contrast, patients with residual disease (RD) in the breast at surgical resection exhibit worse outcomes. The authors hypothesize that “profiling residual TNBC after NAC would identify molecularly targetable lesions in the chemotherapy resistant component of the tumor and that the persistent tumor cells would mirror micro-metastases which ultimately recur in such patients.” The researchers utilized targeted next generation sequencing (NGS) for 182 oncogenes and tumor suppressors in a CLIA certified lab (Foundation Medicine, Cambridge, MA) and gene expression profiling (NanoString) of the RD after NAC in 102 patients with TNBC. The RD was stained for Ki67, which has been reported to predict outcome after NAC in unselected breast cancers. Out of the 89 evaluable post-NAC tumors, 57 (64%) were basal-like; 19% HER2-enriched; 6% luminal A; 6% luminal B and 5% normal-like. Of 81 tumors evaluated by NGS, 89% demonstrated mutations in TP53, 27% were MCL1-amplified, and 21% were MYC-amplified.

Several pathways were found to be altered:

PI3K/mTOR pathway (AKT1-3, PIK3CA, PIK3R1, RAPTOR, PTEN, and TSC1)
Cell cycle genes (amplifications of CDK2, CDK4, and CDK6, CCND1-3, and CCNE1); loss of RB
DNA repair pathway (BRCA1/2, ATM)
Ras/MAPK pathway (KRAS, RAF1, NF1)
Sporadic growth factor receptor (amplifications occurred in EGFR, KIT, PDGFRA, PDGFRB, MET, FGFR1, FGFR2, and IGF1R.

NGS identified 7 patients with ERBB2 gene amplification. NGS could assist in the identification of ERBB2-overexpressing tumors misclassified at the time of diagnosis.

Amplifications of MYC were independently associated with poor recurrence-free survival (RFS) and overall survival (OS). In contrast to the earlier notion, high post-NAC Ki67 score did not predict poor RFS or OS in this predominantly TNBC cohort.

The authors concluded that “the diversity of lesions in residual TNBCs after NAC underscores the need for powerful and broad molecular approaches to identify actionable molecular alterations and, in turn, better inform personalized therapy of this aggressive disease.”

Identification of Novel Synthetic-Lethal Targets for MYC-Driven Triple-Negative Breast Cancer: Goga A, etal, UCSF (San Francisco, CA), Abstract No. S3-8

Reiterating the greatest challenge of the TNBC treatment, no targeted agents currently exist against TNBC. The group at UCSF has discovered that TNBC frequently express high levels of the MYC proto-oncogene. The discovery has led them to identify new “synthetic-lethal” strategies to selectively kill TNBC with MYC overexpression. “Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes has little effect. Using this strategy, we can take advantage of the elevated MYC signaling in TNBC to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels”

The researchers performed a shRNA synthetic-lethal screen in the human mammary epithelial cells (HMEC), to identify new molecules, such as cell cycle kinases, which when inhibited can preferentially kill TNBC cells. A high-throughput screen of ∼2000 shRNAs, that target the human kinome (∼ 600 kinases) when performed, led to the identification of 13 kinases whose inhibition by >1 shRNAs gave rise to >50% inhibition of cell growth. ARK5 and GSK3A were the two other kinases that were shown to have a synthetic-lethal interaction with MYC. Since these two kinases have been identified in other studies, it gives validity to the ability to the methods of Goga etal in identifying synthetic-lethal targets. The group is currently characterizing and validating the 11 novel targets identified in this screen, using human cancer cell lines as well as mouse cancer models to determine the impact of inhibiting these targets on triple-negative breast cancer development and proliferation.

Reference:

Dent R, etal. Triple-negative breast cancer: clinical features and patterns of recurrence (2007) Clin Cancer Res 13, 4429-4434.

Lehmann BD, etal. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies (2011) J Clin Invest. 121: 2750-67.

Chen X, etal. TNBCtype: A Subtyping Tool for Triple- Negative Breast Cancer. (2012) Cancer informatics 11, 147-156.

Abstracts presented in SABCS 2012 can be accessed here.

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Directions for Genomics in Personalized Medicine

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Genome Biology, International Global Work in Pharmaceutical, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, tagged Apoptosis, ATP, Cancer - General, cell proliferation, Cellular respiration, DNA, downregulation, driver mutations, J Craig Venter Institute, James Watson, Max Planck Society, Myc, Otto Heinrich Warburg, small molecules, suppression, TIGR, Transcriptomics, upregulation, Warburg on January 27, 2013| 8 Comments »

Directions for Genomics in Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

Word Cloud by Daniel Menzin

J. Craig Venter (Photo credit: Wikipedia)

Otto Heinrich Warburg (Photo credit: Wikipedia)

Purpose

This discussion will identify the huge expansion of genomic technology in the search for biopharmacotherapeutic targets that continue to be explored involving different levels and interacting signaling pathways. There are several methods of analyzing gene expression that will be discussed. Great primary emphasis required investigation of combinations of mutations expressed in different cancer types. James Watson has proposed a major hypothesis that expresses the need to focus on “central” “driver mutations” that correspond with the regulation of gene expression, cell proliferation, and cell metabolism eith a critical rejection of antioxiant benefits. What hasn’t been know is why drug resistance develops and whether the cellular migration and aerobic glycolysis can be redirected after cell metastasis occurs. I attempt to bring out the complexities of current efforts.

.Introduction

This discussion is a continuation of a previous discussion on the role of genomics if discovery of therapeutic targets for cancer, each somewhat different, but all related to:
The reversal of carcinoma by targeting a key driver of multiple signaling pathways that activate cell proliferation
Pinpointing a stage in a multistage process at which tumor progression links to changes in morphology from basal cells to invasive carcinoma with changes in polarity and loss of glandular architecture
Reversal of the carcinoma through using a small molecule that either is covalently bound to a nanoparticle delivery system that blocks or reverses tumor development
Synthesis of a small molecule that interacts with the translation of the genome either by substitution of a key driver molecule or by blocking at the mRNA stage of translation
Blocking more than one signaling pathway that are links to carcinogenesis and cellular proliferation and invasion

Difficulty of the problem

A problem expressed by James Watson is that the investigations that are ongoing

are following a pathway that is not driven by attacking the “primary” driver of carcinogenesis.

He uses the Myc gene as an example, as noted in the previous discussion. The problem may be more complicated than he envisions.

The most consistent problem in chemotherapy, irrespective of the design and the target has been cancer remission for a short time followed by recurrence, and then
switching to another drug, or combination chemotherapy.

It is common to “clean” the field at the time of resection using radiotherapy before chemotherapy.

But the goal is understood to be “palliation”, not cure.

This raises a serious issue in the hypothesis posed by Watson. The issue is

whether there is a core locus of genetic regulation that is common to carcinogenesis irrespective of tissue metabolic expression.
This is supported by the observation that tissue specific express is lost in cancer cells by de-differentiation.

Historical Perspective

AEROBIC GLYCOLYSIS

In 1967 Otto Warburg published his view in a paper “The prime cause and prevention of cancer”.
There are primary and secondary causes of all diseases

plague – primary: plague bacillus
plague – secondary: filth, rats, and fleas

cancer, above all diseases,

has countless seconday causes
primary – replacement of respiration of oxygen in normal body tissue by fermentation of glucose with conversion from obligate aerobic to anaerobic, as in bacterial cells

The cornerstone to understanding cancer is in study of the energetics of life

This thinking came out of decades of work in the Dahlem Institute Kaiser Wilhelm pre WWII and Max Planck Institute after WWII, supported by the Rockefeller Foundation.

The oxygen- and hydrogen-transferring enzymes were discovered and isolated.
The methods were elegant for that time, using a manometer that improved on the method used by Haldane, that did not allow the leakage of O2 or CO2.
The interest was initiated by the increased growth of Sea Urchin eggs after fertization, which turned out to be not comparable to the rapid growth of cancer cells.
Warburg used both normal and cancer tissue and measured the utilization of O2. He found
- that the normal tissue did not accumulate lactic acid.
- Cancer tissue generated lactic acid
- the rate of O2 consumption the same as normal tissue, but
- the rate of lactate formation far exceeded any tissue, except the retina.
- This was a discovery studied by “Pasteur” 60 years earlier (facultative aerobes), which he called the Pasteur effect.
- Hematopoietic cells of bone marrow develop aerobic glycolysis when exposed to a low oxygen condition.

He then followed on an observation by Otto Meyerhoff (Embden-Myerhoff cycle) that in muscle

the consumption of one molecule of oxygen generates two molecules of lactate, but in aerobic glycolysis, the relationship disappears.
He expressed the effectiveness of respiration by the ‘Meyerhoff quotient’.
He found that cancer cells didn’t have a quotient of ‘2’

The role of the allosteric enzyme phosphofructokinase (PFK) not then known, would tie together the glycolytic and gluconeogenic pathways.
He used a heavy metal ion chelator ethylcarbylamine to

sever the link and turn on aerobic glycolysis.

The explanation for this was provided years later by the work fleshed out by Lynen, Bucher, Lowry, Racker, and Sols.

The rate-limiting enzyme, PFK is regulated by the concentrations of ATP, ADP, and inorganic phosphate. The ethylcarbylamide was an ‘uncoupler’ of oxidative phosphorylation.

Warburg understood that when normal cells switched to aerobic glycolysis

it is a re-orientation of normal cell expression.
this provides the basis for the inference that neoplastic cells become more like each other than their cell of origin.
embryonic cells can be transformed into cancer cells under hypoxic conditions
re-exposure to higher oxygen did not cause reversion back to normal cells.

Warburg publically expressed the rejected view in 1954 (at age 83) that restriction of chemical wastes, food additives, and air pollution would substantially reduce cancer rates.

His emphasis on the impairment of respiration was inadequate.

the prevailing view today is loss of controlled growth of normal cells in cancer cells.

Otto Warburg: Cell Physiologist, Biochemist, and Eccentric. Hans Krebs, in collaboration with Roswitha Schmid. Clarendon Press, Oxford. 1991.ISBN 0-19-858171-8.

The Human Genome Project

The Human Genome Project, driven by Francis Collins at NIH, and by Craig Venter at the Institute for Genome Research (TIGR) had parallel projects to map the human chromosome, completed in 2003. It originally aimed to map the nucleotides contained in a human haploid reference genome (more than three billion). TIGR was the first complete genomic sequencing of a free living organism, Haemophilus influenzae, in 1995. This used a shotgun sequencing technique pioneered earlier, but which had never been used for a whole bacterium.
Venter broke away from the HGP and started Celera in 1998 because of resistance to the shotgun sequency method, and his team completed the genome sequence in three years – seven years’ less time than the HGP timetable (using the gene of Dr. Venter). TIGR eventually sequenced and analyzed more than 50 microbial genomes. Its bioinformatics group developed

pioneering software algorithms that were used to analyze these genomes,
including the automatic gene finder GLIMMER and
the sequence alignment program MUMmer.

In 2002, Venter created and personally funded the J. Craig Venter Institute (JCVI) Joint Technology Center (JTC), which specialized in high throughput sequencing. The JTC, in the top ranks of scientific institutions worldwide, sequenced nearly 100 million base pairs of DNA per day for its affiliated institutions (JCVI) .

He received his his Ph.D. degree in physiology and pharmacology from the University of California, San Diego in 1975 under biochemist Nathan O. Kaplan. A full professor at the State University of New York at Buffalo, he joined the National Institutes of Health in 1984. There he learned of a technique for rapidly identifying all of the mRNAs present in a cell and began to use it to identify human brain genes. The short cDNA sequence fragments discovered by this method are called expressed sequence tags (ESTs), a name coined by Anthony Kerlavage at TIGR.
Venter believed that shotgun sequencing was the fastest and most effective way to get useful human genome data. There was a belief that shotgun sequencing was less accurate than the clone-by-clone method chosen by the HGP, but the technique became widely accepted by the scientific community and is still the de facto standard used today.

References

Shreeve, James (2004). The Genome War: How Craig Venter Tried to Capture the Code of Life and Save the World. Knopf. ISBN 0375406298.
Sulston, John (2002). The Common Thread: A Story of Science, Politics, Ethics and the Human Genome. Joseph Henry Press. ISBN 0309084091.
“The Human Genome Project Race”. Center for Biomolecular Science & Engineering, UC Santa Cruz. Retrieved 20 March 2012.
Venter, J. Craig (2007). A Life Decoded: My Genome: My Life. Viking Adult. ISBN 0670063584.

Use of a Fluorophor Probe

An article has been discussed by Dr. Tilda Barilya on use of a sensitive fluorescent probe in the near IR spectrum at > 700 nm to identify malignant ovarian cells in-vivo in abdominal exploration by tagging an overexpressed FR-α (folate-FITA)
The author makes the point that:

In ovarian cancer, the FR-α appears to constitute a good target because it is overexpressed in 90–95% of malignant tumors, especially serous carcinomas.
Targeting ligand, folate, is attractive as it is nontoxic, inexpensive and relatively easily conjugated to a fluorescent dye to create a tumor-specific fluorescent contrast agent.
The report is identified as “ the first in-human proof-of-principle of the use of intraoperative tumor-specific fluorescence imaging in staging and debulking surgery for ovarian cancer using the systemically administered targeted fluorescent agent folate-FITC.”

While this does invoke possibilities for prognosis, the decision to perform the surgery, whether laparoscopic or open, is late in the discovery process. However, it does suggest the possibility that the discovery and the treatment might be combined if the biomarker itself had the fluorescence to identify the overexpression, but it also is combined with a tag to block the overexpession. This hypothetical possibility is now expressed below.
http://pharmaceuticalintelligence.com/2013/01/19/ovarian-cancer-and-fluorescence-guided-surgery-a-report/

Gene Editing

Dr. Aviva Lev-Ari reports that a new technique developed at MIT Broad Institute and the Rockefeller University can edit DNA in precise locations taken from Science News titled “Editing Genome With High Precision: New Method to Insert Multiple Genes in Specific Locations, Delete Defective Genes”.

Using this system, scientists can alter

several genome sites simultaneously and
can achieve much greater control over where new genes are inserted

According to Feng Zhang, this is an improvement beyond splicing the gene in specific locations and insertion of complexes difficult to assemble known as transcription activator-like effector nucleases (TALENs).

The researchers create DNA-editing complexes
using naturally occurring bacterial protein-RNA systems
that recognize and snip viral DNA, including
a nuclease called Cas9 bound to short RNA sequences.
they target specific locations in the genome, and
when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to

disrupt the function of a gene or
to replace it with a new one.
To replace the gene, a DNA template for the new gene has to be copied into the genome after the DNA is cut. The method is also very precise —
if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated.

In its first iteration, it appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer.
The research team has deposited the necessary genetic components with a nonprofit called Addgene, and they have also created a website with tips and tools for using this new technique.
The above story is reprinted from materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton.
Le Cong, F. Ann Ran, David Cox, Shuailiang Lin, Robert Barretto, Naomi Habib, Patrick D. Hsu, Xuebing Wu, Wenyan Jiang, Luciano Marraffini, and Feng Zhang. Multiplex Genome Engineering Using CRISPR/Cas Systems. Science, 3 January 2013 DOI: 10.1126/science.1231143. http://Science.com. Editing genome with high precision: New method to insert multiple genes in specific locations, delete defective genes. ScienceDaily. Retrieved January 20, 2013, from http://www.sciencedaily.com /releases/2013/01/130103143205.htm?goback=%2Egde_4346921_member_205356312.

Dr. Lev-Ari also reports on a study of early detection of breast cancer in “Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment“, by Dr. Rotem Karni and PhD student Vered Ben Hur at the Institute for Medical Research Israel-Canada of the Hebrew University. http://pharmaceuticalintelligence.com/2013/01/17 /mechanism-involved-in-breast-cancer-cell-growth-function-in-early-detection-treatment/
These researchers have discovered a new mechanism by which breast cancer cells switch on their aggressive cancerous behavior. The discovery provides a valuable marker for the early diagnosis and follow-up treatment of malignant growths.
The method they use is

RNA splicing and insertion.
The information needed for the production of a mature protein is encoded in segments called exons .
In the splicing process, the non-coding segments of the RNA (introns) are spliced from the pre-mRNA and
the exons are joined together.

Alternative splicing is when a specific ”scene” (or exon) is either inserted or deleted from the movie (mRNA), thus changing its meaning.

Over 90 percent of the genes in our genome undergo alternative splicing of one or more of their exons, and
the resulting changes in the proteins encoded by these different mRNAs are required for normal function.
the normal process of alternative splicing is altered in cancer, and
”bad” protein forms are generated that aid cancer cell proliferation and survival.

The researchers reported in online Cell Reports that breast cancer cells

change the alternative splicing of an important enzyme, called S6K1, which is
a protein involved in the transmission of information into the cell.
when this happens, breast cancer cells start to produce shorter versions of this enzyme and
these shorter versions transmit signals ordering the cells to grow, proliferate, survive and invade other tissues (otherwise proliferation is suppressed)

The application to biotherapeutics would be to ”reverse” the alternative splicing of S6K1 in cancer cells back to the normal situation as a novel anti-cancer therapy.

Additional Developments:

A*STAR Scientists Pinpoint Genetic Changes that Spell Cancer: Fruit flies light the way for scientists to uncover genetic changes.

With a new approach, researchers may rapidly distinguish the range of

genetic changes that are causally linked to cancer (i.e. “driver” mutations)
versus those with limited impact on cancer progression.

This study published in the prestigious journal Genes & Development could pave the way to design more targeted treatment against different cancer types, based on the specific cancer-linked mutations present in the patient, an advance in the development of personalized medicine.

Signaling pathways involved in tumour formation are conserved from fruit flies to humans. In fact, about 75 percent of known human disease genes have a recognizable match in the genome of fruit flies.
Leveraging on their genetic similarities, Dr Hector Herranz, a post-doctorate from the Dr. Stephen Cohen’s team developed an innovative strategy to genetically screen the whole fly genome for “cooperating” cancer genes.

These genes appear to have little or no impact on cancer.
However, they cooperate with other cancer genes, so that
the combination causes aggressive cancer, which
neither would cause alone.

In this study, the team was specifically looking for genes that

could cooperate with EGFR “driver” mutation,
a genetic change commonly associated with breast and lung cancers in humans.
SOCS5 (reported in this paper) is one of the several new “cooperating” cancer genes to be identified.

Already, there are indications that levels of SOCS5 expression are

reduced in breast cancer, and
patients with low levels of SOCS5 have poor prognosis.”

The IMCB team is preparing to explore the use of SOCS5 as a biomarker in diagnosis for cancer.
http://genes&development.com

Probing What Fuels Cancer

‘Altered cellular metabolism is a hallmark of cancer,’ says Dr Patrick Pollard, in the Nuffield Department of Clinical Medicine at Oxford. Most cancer cells get the energy they need predominantly through a high rate of glycolysis, allowing cancer cells deal with the low oxygen levels that tend to be present in a tumour.

But whether dysfunctional metabolism causes cancer, as Warburg believed, or is something that happens afterwards is a different question. In the meantime, gene studies rapidly progressed and indicated that genetic changes occur in cancer.

DNA mutations spring up all the time in the body’s cells, but

most are quickly repaired.
Alternatively the cell might shut down or be killed off (apoptosis) before any damage is caused. However, the repair machinery is not perfect.
If changes occur that bypass parts of the repair machinery or sabotage it,
the cell can escape the body’s normal controls on growth and
DNA changes can begin to accumulate as the cell becomes cancerous.

Patrick believes certain changes in cells can’t always be accounted for by ‘genetics.’
He is now collaborating with Professor Tomoyoshi Soga’s large lab at Keio University in Japan, which has been at the forefront of developing the technology for metabolomics research over the past couple of decades.

The Japanese lab’s ability to

screen samples for thousands of compounds and metabolites at once, and
the access to tumour material and cell and animal models of disease
enables them to probe the metabolic changes that occur in cancer.

There is reason to believe that

dysfunctional cell metabolism is important in cancer.
genes with metabolic functions are associated with some cancers
changes in the function of a metabolic enzyme have been implicated in the development of gliomas.

These results have led to the idea that some metabolic compounds, or metabolites, when they accumulate in cells, can cause changes to metabolic processes and set cells off on a path towards cancer.

Patrick Pollard and colleagues have now published a perspective article in the journal Frontiers in Molecular and Cellular Oncology that proposes fumarate as such an ‘oncometabolite’. Fumarate is a standard compound involved in cellular metabolism.

The researchers summarize evidence that shows how

accumulation of fumarate when an enzyme goes wrong affects various biological pathways in the cell.
It shifts the balance of metabolic processes and disrupts the cell in ways that could favour development of cancer.

Patrick and colleagues write in their latest article that the shift in focus of cancer research to include cancer cell metabolism ‘has highlighted how woefully ignorant we are about the complexities and interrelationships of cellular metabolic pathways’.

http://FrontiersMolecularCellularOncology.com

Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation
(Li G, Ruan X, Auerbach RK, Sandhu KS, et al.) Cell 2012; 148(1-2): 84-98. http://cell.com

Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET),
mapped long-range chromatin interactions associated with RNA polymerase II in human cells
uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions.

These interactions further aggregated into higher-order clusters
proximal and distal genes were engaged through promoter-promoter interactions.
most genes with promoter-promoter interactions were active and transcribed cooperatively
some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls.

Comparative analyses of different cell lines showed that

cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription,
and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions.
genetically-identified disease-associated noncoding elements were spatially engaged with corresponding genes through long-range interactions.

Overall, our study provides insights into transcription regulation by

three-dimensional chromatin interactions for both housekeeping and
cell-specific genes in human cells.

New Nucleoporin: Regulator of Transcriptional Repression and Beyond.

(NJ Sarma and K Willis) Nucleus 2012; 3(6): 1–8; http://Nucleus.com © 2012 Landes Bioscience

Transcriptional regulation is a complex process that requires the integrated action of many multi-protein complexes.
The way in which a living cell coordinates the action of these complexes in time and space is still poorly understood.

nuclear pores, well known for their role in 3′ processing and export of transcripts, also participate in the control of transcriptional initiation.
nuclear pores interface with the well-described machinery that regulates initiation.

This work led to the discovery that

specific nucleoporins are required for binding of the repressor protein Mig1 to its site in target promoters.
Nuclear pores are involved in repressing, as well as activating, transcription.

Here we discuss in detail the main models explaining our result and consider what each implies about the roles that nuclear pores play in the regulation of gene expression.

Prediction of Breast Cancer Metastasis by Gene Expression Profiles: A Comparison of Metagenes and Single Genes.

(M Burton, M Thomassen, Q Tan, and TA Kruse.) Cancer Informatics 2012:11 193–217 doi: 10.4137/CIN.S10375

The popularity of a large number of microarray applications has in cancer research led to the development of predictive or prognostic gene expression profiles. However, the diversity of microarray platforms has made the full validation of such profiles and their related gene lists across studies difficult and, at the level of classification accuracies, rarely validated in multiple independent datasets. Frequently, while the individual genes between such lists may not match, genes with same function are included across such gene lists. Development of such lists does not take into account the fact that

genes can be grouped together as metagenes (MGs) based on common characteristics such as pathways, regulation, or genomic location.

In this study we compared the performance of either metagene- or single gene-based feature sets and classifiers using random forest and two support vector machines for classifier building. The performance

within the same dataset,
feature set validation performance, and
validation performance of entire classifiers in strictly independent datasets

were assessed by

10 times repeated 10-fold cross validation,
leave-one-out cross validation, and
one-fold validation, respectively.

To test the significance of the performance difference between MG- and SG-features/classifiers, we used a repeated down-sampled binomial test approach.

MG- and SG-feature sets are transferable and perform well for training and testing prediction of metastasis outcome

in strictly independent data sets, both
between different and
within similar microarray platforms, while
classifiers had a poorer performance when validated in strictly independent datasets.

The study showed that MG- and SG-feature sets perform equally well in classifying independent data. Furthermore, SG-classifiers significantly outperformed MG-classifier

when validation is conducted between datasets using similar platforms, while
no significant performance difference was found when validation was performed between different platforms.

Prediction of metastasis outcome in lymph node–negative patients by MG- and SG-classifiers showed that SG-classifiers performed significantly better than MG-classifiers when validated in independent data based on the same microarray platform as used for developing the classifier. However, the MG- and SG-classifiers had similar performance when conducting classifier validation in independent data based on a different microarray platform. The latter was also true when only validating sets of MG- and SG-features in independent datasets, both between and within similar and different platforms.

Identification and Insilico Analysis of Retinoblastoma Serum microRNA Profile and Gene Targets Towards Prediction of Novel Serum Biomarkers.

M Beta, A Venkatesan, M Vasudevan, U Vetrivel, et al. Identification and Insilico Analysis of Retinoblastoma Serum microRNA Profile and Gene Targets Towards Prediction of Novel Serum Biomarkers.

http://Bioinformatics and Biology Insights 2013:7 21–34. doi: 10.4137/BBI.S10501

This study was undertaken

to identify the differentially expressed miRNAs in the serum of children with RB in comparison with the normal age matched serum,
to analyze its concurrence with the existing RB tumor miRNA profile,
to identify its novel gene targets specific to RB, and
to study the expression of a few of the identified oncogenic miRNAs in the advanced stage primary RB patient’s serum sample.

MiRNA profiling performed on 14 pooled serum from children with advanced RB and 14 normal age matched serum samples

21 miRNAs found to be upregulated (fold change > 2.0, P < 0.05) and
24 downregulated (fold change > 2.0, P < 0.05).

Intersection of 59 significantly deregulated miRNAs identified from RB tumor profiles with that of miRNAs detected in serum profile revealed that

33 miRNAs had followed a similar deregulation pattern in RB serum.

Later we validated a few of the miRNAs (miRNA 17-92) identified by microarray in the RB patient serum samples (n = 20) by using qRT-PCR.

Expression of the oncogenic miRNAs, miR-17, miR-18a, and miR-20a by qRT-PCR was significant in the serum samples

exploring the potential of serum miRNAs identification as noninvasive diagnosis.

Moreover, from miRNA gene target prediction, key regulatory genes of

cell proliferation,
apoptosis, and
positive and negative regulatory networks

involved in RB progression were identified in the gene expression profile of RB tumors.
Therefore, these identified miRNAs and their corresponding target genes could give insights on

potential biomarkers and key events involved in the RB pathway.

Computational Design of Targeted Inhibitors of Polo-Like Kinase 1 ( lk1).

(KS Jani and DS Dalafave) Bioinformatics and Biology Insights 2012:6 23–31.doi: 10.4137/BBI.S8971.

Computational design of small molecule putative inhibitors of Polo-like kinase 1 (Plk1) is presented. Plk1, which regulates the cell cycle, is often over expressed in cancers.

Down regulation of Plk1 has been shown to inhibit tumor progression.
Most kinase inhibitors interact with the ATP binding site on Plk1, which is highly conserved.
This makes the development of Plk1-specific inhibitors challenging, since different kinases have similar ATP sites.

However, Plk1 also contains a unique region called the polo-box domain (PBD), which is absent from other kinases.

the PBD site was used as a target for designed Plk1 putative inhibitors.
Common structural features of several experimentally known Plk1 ligands were first identified.
The findings were used to design small molecules that specifically bonded Plk1.
Drug likeness and possible toxicities of the molecules were investigated.
Molecules with no implied toxicities and optimal drug likeness values were used for docking studies.
Several molecules were identified that made stable complexes only with Plk1 and LYN kinases, but not with other kinases.
One molecule was found to bind exclusively the PBD site of Plk1.

Possible utilization of the designed molecules in drugs against cancers with over expressed Plk1 is discussed.

Conclusions

The previous discussions reviewed the status of an evolving personalized medicine multicentered and worldwide enterprise. It is also clear from these reports that the search for targeted drugs matched to a cancer profile or signature has identified several approaches that show great promise.

We know considerably more about metabolic pathways and linked changes in transcription that occur in neoplastic development.
There are several methods used to do highly accurate insertions in gene sequences that are linked to specific metabolic changes, and
some may have significant implications for therapeutics, if
- the link is a change that is associated with a driver mutation
- the link can be identified by a fluorescent or other probe
- the link is tied to a mRNA or peptide product that is a biomarker measured in the circulation
We have probes to genetic links to the control of many and interacting signaling pathways.
We know more about transcription through mRNA.
We are closer to the possibility that metabolic substrates, like ‘fumarate’ (a key intermediate in the TCA cycle), may provide a means to reverse regulate the neoplastic cells.
We may also find metabolic channels that drive the cells from proliferation to apoptosis or normal activity.

Summary

This discussion identified the huge expansion of genomic technology in the investigation of biopharmacotherapeutic targets that have been identified involving different levels and interacting signaling pathways. There are several methods of analyzing gene expression, and a primary emphasis is given to combinations of mutations expressed in different cancer types. There is a major hypothesis that expresses the need to focus on “central” “driver mutations” that correspond with the regulation of gene expression, cell proliferation, and cell metabolism. What hasn’t been know is why drug resistance develops and whether the cellular migration and aerobic glycolysis can be redirected after cell metastasis occurs.

A slight mutation in the matched nucleotides can lead to chromosomal aberrations and unintentional genetic rearrangement. (Photo credit: Wikipedia)

Deutsch: Regulation der Phosphofructokinase (Photo credit: Wikipedia)

Additional Related articles

Unraveling the Human Genome: 6 Molecular Milestones (livescience.com)
The Role Of Microorganisms In Cancer Is Being Ignored By The Current Sequencing Strategies (3quarksdaily.com)
Biological Functions of Noncoding DNA (tginnovations.wordpress.com)
Retrovirus in the human genome is active in pluripotent stem cells (sciencedaily.com)
Consistent Personal Epigenetic ‘Signatures’ Discovered In Prostate Cancer Patients’ Metastases (medicalnewstoday.com)
Melanomas Often Mutate in Two Specific Ways, Shows Study (webpronews.com)

Oogonial stem cells purified: a view towards the future of reproductive biology

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Medical and Population Genetics, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, Stem Cells for Regenerative Medicine, tagged germline, oocyte, Oogonia, reproduction, Stem cell on January 14, 2013| 4 Comments »

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

Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. A fluorescence-activated cell sorting-based protocol has been standardized that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1–2 weeks after xenotransplantation into immunodeficient female mice. Therefore, based on the multiple experimental lines of evidence reported it is reasonable to conclude that the rare cells with cell-surface expression of DDX4 that are present in the ovaries of reproductive-age women represent adult human OSCs. In addition to opening a new research field in human reproductive biology that was inconceivable less than 10 years ago, clear evidence for the existence of these cells in women may offer new opportunities to expand on and enhance current fertility-preservation strategies. For example, with assisted reproductive technologies involving cryopreservation of ovarian cortical tissue already in development for females with cancer, isolation and expansion of OSCs from this tissue before or after cryopreservation might be useful for new fertility applications. In fact, it has been found that these cells can be consistently obtained from cryopreserved and thawed human ovarian tissue samples, and that these cells per se can be cryopreserved and thawed months later with minimal loss for successful establishment in vitro. In addition, the availability of a detailed protocol for the purification of these newly discovered cells from human ovary tissue provides a much more physiologically relevant in-vitro model system from which to study human female germ cell development compared to the ESC-derived or induced pluripotent stem cell-derived germline cells that are currently used as models for human female gametogenesis.

Source References:

http://blogs.nature.com/spoonful/2012/02/video-stem-cell-discovery-puts-women%E2%80%99s-reproduction-on-fertile-grounds.html

http://www.nature.com/nm/journal/v18/n3/full/nm.2669.html

http://www.ncbi.nlm.nih.gov/pubmed/23024060

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

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Resident-cell-based, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, Cancer - General, DNA, DNA Sequencing, Human Genome Project, Induced pluripotent stem cell, National Institutes of Health, Personalized medicine, Single-nucleotide polymorphism, Stem cell on January 13, 2013| 10 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

http://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

http://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

Part 3:

Personalized Medicine: Institute Profile – Coriell Institute for Medical Research

Coriell Institute for Medical Research, founded in 1953 and based in Camden, New Jersey, is an independent non-profit research center dedicated to the study of the human genome. Expert staff and pioneering programs in the fields of personalized medicine, cell biology, cytogenetics, genotyping, and biobanking drive our mission.

The emerging field of personalized medicine draws upon a person’s genomic information to tailor treatments and prescription drug dosing to optimize health outcomes. The Coriell Personalized Medicine Collaborative^® (CPMC^®) research study is seeking to understand the usefulness of genetic risk and pharmacogenomics in clinical decision-making and healthcare management.

Coriell has a distinguished history in cell biology. We are building upon this expertise by playing an important role in induced pluripotent stem (iPS) cell research. Induced pluripotent stem cells are powerful cells which can be made from skin or blood cells, and they are revolutionizing the way human disease is studied and how drugs are developed. Skin cells from a patient diagnosed with heart disease are being genetically reprogrammed into stem cells, and then transformed into beating cardiac cells. Researchers can now examine the heart-diseased cells to better understand the progression of heart disease and develop treatments and cures. Drug efficacy and safety can also be tested in this laboratory environment, providing an efficient model of drug discovery that delivers drugs to patients sooner. This technology, called “disease in a dish,” offers researchers the potential to study the myriad of human diseases, including Alzheimer’s disease, muscular dystrophy, and diabetes.

In addition to pioneering cutting-edge research initiatives, Coriell offers custom research services – including cell culture, cytogenetic analyses, and molecular biology – to the scientific community. Furthermore, Coriell’s Genotyping and Microarray Center is one of the nation’s largest centers, with high-throughput DNA analysis, CLIA-certified genotyping platforms systems from Illumina and Affymetrix.

Essential to the Institute’s support of international scientific research is the Coriell Biobank. From this renowned cell bank, we manage and distribute the world’s most diverse collection of cell lines, DNA, and other biological resources. The Coriell Biobank provided support to the Human Genome Project, a worldwide program to map the entire human genome, and to the International HapMap Project, a project providing an efficient tool to identify disease-causing genes.

The Coriell Cell Repositories provide essential research reagents to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA derived from cell cultures. These collections, supported by funds from the National Institutes of Health (NIH) and several foundations, are extensively utilized by research scientists around the world.

The Business Aspects of the Institute

Personalized Medicine

DNA, Genes, and SNPs

What is the CPMC Study?

CPMC Technology

CPMC FAQs

CPMC Advisors and Partners

Stem Cells

Induced Pluripotent Stem (iPS) Cells

iPS Cell Research at Coriell

Biobank Catalog

Working with Coriell

Research Services

Genotyping & Microarray

Molecular Biology

Research Design & Expertise

Stem Cells

Quality at Coriell

BioBanking

Overview

What is a Biobank?

How Coriell Banks Cells

Biobank Technology

Biobank Catalog

Working with Coriell

http://www.coriell.org/

http://www.coriell.org/assets/pdfs/discover-winter2012.pdf

http://www.ccr.coriell.org/

http://www.coriell.org/about/coriell-faqs

What is the Coriell Institute of Medical Research?

Founded in 1953, Coriell Institute for Medical Research is an independent, non-profit research organization dedicated to the study of the human genome and to supporting national and international research by providing biomaterials from its renowned biobank.

How did the Coriell Institute start?

Lewis L. Coriell, MD, PhD, a virology researcher and pediatrician, recognized the need for scientific research that would translate into better patient care. After seeing how his research helped to bring the Salk vaccine to polio patients across our nation, Dr. Coriell founded the South Jersey Medical Research Foundation. It was renamed the Institute for Medical Research in 1966 to recognize its broader reach, and, in 1985, to honor Dr. Coriell’s retirement, his name was added. For a look at our history, visit our timeline.

http://www.coriell.org/about/our-history

About the Founder

“You set up an experiment to test the theory, and most of the time it’s not the way you thought it would be. But that’s the way you learn. You go from hypothesis to hypothesis. And it’s exciting because that’s the way we learn to treat, to diagnose, and to prevent illness.”

Lewis L. Coriell, MD, PhD Virologist and Pediatrician June 19, 1911 – June 19, 2001

Lewis L. Coriell was born in the farming community of Sciotoville, in southern Ohio. While he was still a young child, his family moved to Montana toward more promising agricultural opportunities. It has been written that “the aspects of character, personality, temperament, and intellect that marked Dr. Coriell’s exceptional professional life… can easily be traced to his Montana upbringing.”ⁱ

Education and Early Career

Beginning his academic journey at the University of Montana, Lewis Coriell completed undergraduate studies in biology and subsequently earned a master’s degree in bacteriology and immunology in 1936. That same year, he married fellow student Ester Lentz; they would remain by each other’s side for the next 60 years. The newlyweds moved to the University of Kansas so he could pursue doctoral studies in immunology. While there, Dr. Coriell published his first article on an aspect of science he would revolutionize: The storage of cells by freezing them. Lewis Coriell earned his doctorate in 1940 and was awarded his medical degree in 1942. The young researcher was drawn to the field of virology – the study of viruses as they evolve and infect. At this time, bacterial infections presented themselves most often in children. This combination led Dr. Coriell to seek out a residency in pediatrics. As none were immediately available, he chose a cardiology residency at Henry Ford Hospital in Detroit. MI. As it happens, the Coriells’ time in Detroit was brief.

By 1943, World War II was raging and Dr. Coriell was called to service with the United States Army Medical Command’s Biological Research Division at Fort Detrick, MD. It was here that his research in cell cultivation began. After the war, Dr. Coriell began his ideal pediatric residency under Dr. Joseph Stokes, Jr., physician-in-chief at Children’s Hospital of Philadelphia (CHOP). To his delight, Dr. Stokes placed great emphasis on research and was instrumental in attracting federal funds to research childhood disease at his institution. The ability to translate research into patient care inspired Dr. Coriell. He saw how research was essential to the treatment of his patients suffering the devastating effects of viruses like small pox, mumps, and polio.

Adventures in Cell Culture

By the time Dr. Coriell arrived in Philadelphia, virologists knew they had to grow viruses in cell culture to prepare purified viruses for the manufacture of vaccines. However, contamination was rife in the laboratory and proving to be a major obstacle. At CHOP, along with his colleagues, Dr. Coriell perfected the technique to culture human tissue in a sterile host that does not produce its own antibodies. The ability to sustain living human cells in culture, and keep them from being contaminated, led to a key breakthrough in polio research – it enabled scientists to grow the polio virus and work toward the first vaccine.

Moving to Camden and Taking on Polio

By the early 1950’s, an acute infectious disease called polio was spreading from person to person very quickly across the United States, striking fear into citizens, costing children their lives and crippling those who survived. In 1949, Dr. Coriell arrived in Camden, NJ, as medical director of Camden Municipal Hospital, one of the country’s last infectious disease hospitals and home to the majority of the region’s polio patients. In 1951, Dr. Coriell was appointed field director of the Polio Prevention Study and directed the successful gamma globulin field trials.

By 1954, the Salk polio vaccine could be made in large quantities and was ready for human clinical trials. Based on his success shepherding the gamma globulin field trials, Dr. Coriell was chosen by the National Poliomyelitis Foundation to evaluate the Salk polio virus vaccine clinical trials in New Jersey, Pennsylvania, Maryland, and Virginia. The success of the evaluation program led to the release of the Salk vaccine on the national level. Before the trials began in 1955, approximately 20,000 new polio cases were being reported each year. By 1960, cases were reduced to 3,000 per year. By 1979, that number was just 10 each year. Recognizing his contribution, Dr. Coriell received the 1957 International Poliomyelitis Congress Presidential Medal. Soon after, he became chairman of the Committee on the Control of Infectious Diseases of the American Academy of Pediatrics which formulated the vaccination procedures for all children in this critical period.

In 1953, Dr. Coriell initiated a campaign to build the first non-profit academic medical research institute in South Jersey. Under his guidance, the Institute for Medical Research began research in cancer, human cytogenetics, infectious diseases, and methods to improve cell culture techniques. The history of the Institute’s accomplishments included Dr. Coriell’s foresight in calling for the establishment of a central tissue culture bank and cell registry to certify and maintain cell cultures. It began with a partnership with the National Institutes of Health to create the first standardized cell repository. Today, the Institute is home to the world’s most diverse collection of cell lines and DNA samples available to researchers.

Working with his colleague, Dr. Gary McGarrity, Dr. Coriell applied infection control technology – specifically laminar flow – to create the laminar flow hood that is vital to infection control in laboratories, operating rooms, and hospital rooms around the world.

Dr. Coriell’s pioneering techniques for characterizing, freezing, and storing non-contaminated cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human genetics.

Retirement

Dr. Coriell retired in 1985. To honor the occasion, the institute he founded was renamed the Coriell Institute for Medical Research. He remained involved in several ways, as a member of the board and often speaking with groups about the Institute’s history. Following his retirement, Dr. Coriell was elected president of the prestigious College of Physicians of Philadelphia, the oldest medical society in America. Dr. Coriell is the only New Jersey physician to receive this honor.

Dr. Coriell, a pioneering researcher and physician, died on June 19, 2001, in Southern New Jersey. It was his 90th birthday.

A Legacy in Science

Dr. Coriell’s accomplishments in science are indeed many. Perhaps Dr. Coriell’s most enduring legacy was his generosity in knowledge and his ability to bring scientists together to explore research questions and collaborate on solutions. Several important names in science were drawn to join or spend time at the Institute; they included Warren W. Nichols, Ray Dutcher, Richard Mulivor, Etienne Lasfargues, Jesse Charney, Arthur Greene, Daniel Moore, and collaboration with Drs. Albert Levan and Joe Hin Tijo, who first discovered that humans have 46 chromosomes.

Dr. Coriell also created an institute that is a well-respected resident of the Greater Philadelphia region and known as a leader in research worldwide.

Coriell Today

Dr. Coriell’s vision is now our vision. Today, Coriell staff and scientists collaborate on scientific ideas and programs to improve human health.

The Coriell Personalized Medicine Collaborative® research study is studying the utility of using your genetic information to tailor treatments and medications for you. And building on Dr. Coriell’s innovations in cell biology, we are playing an important role in cutting-edge stem cell research to unlock the code of human disease, including Parkinson’s and heart disease. Coriell offers a range of custom research services that have long supported national and international science. In the field of biobanking, Coriell supports research all over the world from its renowned and diverse cell collections.

Our innovation today is a testament to Dr. Coriell’s pioneering past. More importantly, our innovation is a commitment to your future.

ⁱ O’Donnell, John. Coriell; The Coriell Institute for Medical Research and a Half Century of Science. Massachusetts: SHP, 2002.

Where is the Coriell Institute located?

Coriell is located at 403 Haddon Avenue, Camden, NJ 08103. For directions, click here We recommend that you park at 3 Cooper Plaza, a parking garage associated with the hospital, located directly across the street from Coriell. There is also a second hospital parking lot located on Benson Street, which is a block from the Institute.

For what is the Coriell Institute known?

Coriell Institute is a leader in the emerging field of personalized medicine – often called genome-informed medicine – which is the practice of using genetic information to better understand a patient’s risk for disease and response to medications. The Coriell Personalized Medicine Collaborative is a research study designed to study the utility of genetic information in clinical decision-making and patient care.

Coriell is also playing an important role in exploring the promise of induced pluripotent stem (iPS) cell biotechnologies. [Pluripotent refers to how cells can grow into many different types of cells.] We can take skin cells and reprogram them – essentially turn back time – to behave like a stem cell. These cells can then be triggered, using specific proteins, to become cardiac cells, neurons (brain cells), or insulin-producing pancreatic cells, amongst others. Over the years, Coriell has developed an extraordinary expertise in the culture of human cells, and much of the standard practices in cell culture were developed at Coriell. This includes the techniques for freezing and thawing cells, and sterile handling of cultures. As a result of our cell biology expertise, scientists from every major research center in the world draw upon the Coriell Cell Repositories, maintained in the world’s leading biobank, which contains cell lines and DNA representing approximately 650 diseases.

Who is on the Coriell Institute staff?

Coriell is home to approximately 120 scientific and operational staff. Michael Christman, PhD, is Coriell’s President and CEO; he is an expert in genomics and genetics. Joseph L. Mintzer is Coriell’s Executive Vice President and COO and manages the fiscal and operational aspect of the institute. Meet the rest of the Coriell leadership team here.

Who is on the Coriell Institute Board of Trustees?

Coriell is guided by a diverse Board of Trustees that includes corporate, medical, financial, and philanthropic leaders. Chairman of the Coriell Board is Robert P. Kiep III. Learn more about the Coriell Board of Trustees here.

How is Coriell Institute funded?

Coriell Institute has an annual operating budget of $17 million, about $11 million of which comes from federally- and state-funded grants and contracts. Private and corporate philanthropy provides the seed money to initiate new programs in science at Coriell – science that has the opportunity to advance discoveries in research which may not be occurring at other research institutes.

How can I support the research mission of Coriell Institute?

While the majority of Coriell’s operating revenue is derived from federally- and state-funded grants and contracts, the Institute also relies on private, foundation, and corporate philanthropy. Your support can advance the emerging field of personalized medicine to improve the practice of medicine. Your support also allows Coriell to pursue and support research in adult stem cell biology and genomics seeking to unlock the code of human disease.  There are many ways to give to Coriell: Outrights gifts, through your workplace giving programs, planned giving, volunteering your time and expertise, or attending or hosting a Coriell event. Visit our fund development page to learn more about how you can support scientific research.

How does Coriell Institute support international research?

The Coriell Cell Repositories offers essential research materials to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA. Since the first NIH-sponsored repository was established in 1964 – Coriell has distributed hundreds of thousands of cell lines and DNA samples to researchers in 64 countries. More than 7,000 peer-reviewed papers have been published citing almost 12,000 Coriell Repository samples.

What research services does Coriell Institute provide?  Coriell offers several best-in-class custom research services.

Coriell’s Genotyping and Microarray Center – one of the nation’s largest centers and CLIA-certified in 48 states – is a high-capacity facility with high-throughput systems from Affymetrix and Illumina.

The Coriell Institute Cytogenetics Laboratory is a state-of-the-art facility that combines conventional and molecular cytogenetic analyses with copy number and loss of heterozygosity (LOH) analyses by microarray. The laboratory is equipped with a network of five Applied Spectral Imaging work-stations that are used to perform G-banded karyotyping, and Fluorescent In Situ Hybridization (FISH).  Coriell also offers many preparative and diagnostic nucleic acid and molecular biology services, all subject to extensive quality controls.

And, the Coriell biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community.

Does Coriell Institute engage in gene therapy or stem cell clinical trials?

Coriell Institute does not pursue research using human embryonic stem cells, nor do we conduct clinical trials on stem cell technologies. If you are interested in gene therapy or stem cell-related clinical trials, please visit http://www.clinicaltrials.gov.

What education does Coriell offer?

Coriell offers a course in cell culture: Advanced biology coupled with the history, theory, and techniques of maintaining live cells in long-term culture is offered to students.

Coriell also invites a limited number of motivated students into the Institute to participate in a Summer Experience program to gain insight into the workings of an independent research institute

How can I stay informed on what is happening at Coriell Institute?

Sign up for our email updates and you’ll receive periodic research news, notable donations, and upcoming events. Visit our Media Center regularly to read the latest news articles and Coriell press releases.

How can I get a quick overview of Coriell Institute?

Read our Coriell Fast Facts for a basic introduction to the Institute. For more information, explore the About section of our website.

Are Coriell Institute scientists and staff available for speaking engagements?

As their schedules permit, Coriell’s scientific and operational staffs enjoy the opportunity to highlight the work occurring at Coriell. Many hold joint faculty appointments at our region’s universities and teach an array of topics from business management and healthcare policy to the science of cell culture and stem cell research.

Coriell also participates in several outreach programs each year, including science festivals and conferences. We also host tours of our laboratories for business and governmental leaders and middle school and high school students.  16. Is Coriell Institute affiliated with Cooper Medical School of Rowan University? Yes; Coriell is looking forward to welcoming the new medical school and will be integral in teaching genetics and genomics to the next generation of healthcare providers.

The Power of Stem Cell Science

The promise of stem cell research lays in its application in understanding the progression of human disease, the ability to cure disease and reverse injury, and to better target therapies to optimize our health outcomes. Induced pluripotent stem (iPS) cell technology has the ability to revolutionize the way human disease is studied. Creating iPS cell lines from various rare and common disease states, as well as from various populations, will open the doors for pre-clinical research studies.

Let Our Expertise Make Your Research a Success

Coriell offers a range of custom research services that have long supported national and international science. Whether you are requesting a cell line for your research studies or submitting DNA samples for genotyping analysis, Coriell is committed to providing you with flexible, innovative, and results-oriented research services. Our laboratories are built to foster scientific collaboration, and your research will benefit from this collaborative environment.

Coriell’s Biobank and Cell Culture Laboratory have established the gold standard in the cryopreservation of biomaterials and the capacity to support varied research worldwide. The diverse collections of biological specimens managed by Coriell offer the scientific community the highest quality specimens, which are necessary for successful research endeavors. Since the first repository – a National Institutes of Health collection – was established at Coriell in 1964, hundreds of thousands of cell lines and DNA samples have been distributed to researchers in 64 countries; more than 7,000 peer-reviewed papers have been published citing almost 12,000 biospecimens from the Coriell Biobank.

Making Medicine Personalized for You

Our health is determined by many factors: the genetics we inherit; our innate personal traits of race, age and gender; our individual behavior; our family and community networks; and at the macro level, our economic, cultural, and environmental conditions. These factors are different for every person and will change over their lifespan. So too is a person’s experience with disease and how they respond to drugs or other medical interventions. Personalized medicine intends to make medical treatment as individual as the biology of one’s disease.

Personalized medicine has the potential to offer patients and their doctors several advantages, including:

The ability to make better informed clinical decisions.

A higher probability of desired health outcomes by using better-targeted therapies.

The reduced probability of adverse reactions from medications and treatments.

A focus on prevention and prediction of disease, rather than reaction to it.

Earlier disease intervention.

Reduced healthcare costs.

Preserving cells today for research tomorrow

Dr. Lewis Coriell’s pioneering techniques for characterizing, freezing, and storing cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human research. Today, the Coriell Biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community. In addition to these high-quality biospecimens, Coriell also maintains tissue, plasma, serum, urine, and cerebrospinal fluid.

Few organizations have the history of innovations in repository science that have been developed and implemented at Coriell. For nearly 60 years, Coriell has set the standard in biobanking services, including the experimental design, collection, processing, distribution, cryogenic preservation, and information management of human biomaterials used in research. By developing and maintaining biorepositories as national and international resources for the study of human diseases, aging, and neurological disease, Coriell is committed to providing the scientific community with well-characterized, cell cultures and DNA preparations, annotated with rich phenotypic data.

Catalog Collections

NIGMS Human Genetic Repository  The Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, provides scientists around the world with resources for cell and genetic research. The samples include highly characterized cell lines and high quality DNA. Repository samples represent a variety of disease states, chromosomal abnormalities, apparently healthy individuals and many distinct human populations.

NINDS Human Genetics DNA and Cell Line Repository  The National Institute of Neurological Disorders and Stroke is committed to gene discovery, as a strategy for identifying the genetic causes and correlates of nervous system disorders. The NINDS Human Genetics DNA and Cell Line Repository banks samples from subjects with cerebrovascular disease, epilepsy, motor neuron disease, Parkinsonism, and Tourette Syndrome, as well as controls.

NIA Aging Cell Repository  Sponsored by the National Institute on Aging (NIA), the AGING CELL REPOSITORY, is a resource facilitating cellular and molecular research studies on the mechanisms of aging and the degenerative processes associated with it. The cells in this resource have been collected over the past three decades using strict diagnostic criteria and banked under the highest quality standards of cell culture. Scientists use the highly-characterized, viable, and contaminant-free cell cultures from this collection for research on such diseases as Alzheimer disease, progeria, Parkinsonism, Werner syndrome, and Cockayne syndrome.

NHGRI Sample Repository for Human Genetic Research  The National Human Genome Research Institute (NHGRI) led the National Institutes of Health’s (NIH) contribution to the International Human Genome Project, which had as its primary goal the sequencing of the human genome. This project was successfully completed in April 2003. Now, the NHGRI’s mission has expanded to encompass a broad range of studies aimed at understanding the structure and function of the human genome and its role in health and disease.

American Diabetes Association, GENNID Study  The purpose of the American Diabetes Association (ADA), GENNID Study (Genetics of non-insulin dependent diabetes mellitus, NIDDM) is to establish a national database and cell repository consisting of information and genetic material from families with well-documented NIDDM. The GENNID Study will provide investigators with the information and samples necessary to conduct genetic linkage studies and locate the genes for NIDDM.

The Autism Research Resource  The State of New Jersey funded the initiation of a genetic resource to support the study of autism in families where more than one child is affected or where one child is affected and one demonstrates another significant and related developmental disorder. This resource now receives continuing support from the Coriell Institute for Medical Research. An open bank of anonymously collected materials documented by a detailed clinical diagnosis forms the basis of this growing database of information about the disease.

IPBIR Repository  The purpose of the IPBIR – Integrated Primate Biomaterials and Information Resource is to assemble, characterize, and distribute high-quality DNA samples of known provenance with accompanying demographic, geographic, and behavioral information in order to stimulate and facilitate research in primate genetic diversity and evolution, comparative genomics, and population genetics.

HD Community BioRepository  HD Community BioRepository is a secure, centralized repository that stores and distributes quality-controlled, reliable research reagents. Huntingtin DNAs are now available and antibodies, antigenic peptides, cell lines, and hybridomas will be added soon.

USIDNET Repository  The USIDNET DNA and Cell Repository has been established as part of an NIH-funded program – the US Immunodeficiency Network (www.usidnet.org) – to provide a resource of DNA and functional lymphoid cells obtained from patients with various primary immunodeficiency diseases. These uncommon disorders include patients with defects in T cell, B cell and/or granulocyte function as well as patients with abnormalities in antibodies/immunoglobulins, complement and other host defense mechanisms.

CDC Cell and DNA Repository  The Genetic Testing Reference Material Coordination Program of the Centers for Disease Control and Prevention (CDC) and the Coriell Institute for Medical Research announce the availability of samples derived from transformed cell lines for use in molecular genetic testing. The DNA samples prepared from these reference cell lines are available through the Coriell Cell Repositories. Diseases include cystic fibrosis (CF), 5′ 10′ methylenetetrahydrofolate reductase deficiency (MTHFR), HFE-associated hereditary hemochromatosis, Huntington disease (HD), fragile X syndrome, Muenke syndrome, connexin 26-associated deafness, and alpha-thalassemia.

Leiomyosarcoma Cell and DNA Repository  The Leiomyosarcoma Cell and DNA Repository has been established with an award from the National Leiomyosarcoma Foundation. This foundation provides leadership in supporting research of Leiomyosarcoma, improving treatment outcomes of those affected by this disease as well as fostering awareness in the medical community and general public.

COHORT Project  The Cooperative Huntington’s Observational Trial Repository has been established as a resource for the discovery of information related to Huntington’s disease and its causes, progressioin, treatments, and possible cures. This is a growing bank for DATA and SPECIMENS to accelerate research on Huntington’s disease.

YERKES Repository  The Yerkes National Primate Research Center of Emory University is an international leader in biomedical and behavioral research. For more than seven decades, the Yerkes Research Center has been dedicated to advancing scientific understanding of primate biology, behavior, veterinary care and conservation, and to improving human health and well-being.

NEI-AREDS Genetic Repository  The Age-Related Eye Disease Study was designed to learn about macular degeneration and cataract, two leading causes of vision loss in older adults. The study looked at how these two diseases progress and what their causes may be. In addition, the study tested certain vitamins and minerals to find out if they can help to prevent or slow these diseases. Participants in the study did not have to have either disease. (Enrollment was completed in January 1998.) Eleven medical centers in the United States took part in the study, and more than 4,700 people across the country were enrolled in AREDS. The study was supported by the National Eye Institute, part of the Federal government’s National Institutes of Health. The clinical trial portion of the study also received support from Bausch & Lomb Pharmaceuticals and was completed in October 2001. Learn about the results of the clinical trial on the National Eye Institute’s website: http://www.nei.nih.gov/amd/.

The Wistar Institute  The Wistar Institute collection at Coriell contains cell lines that have been developed by Wistar scientists. These materials are offered for non-commercial research conducted by universities, government agencies and academic research centers. The Wistar Institute collection currently contains a group of hybridomas that produce monoclonal antibodies that are useful in influenza research and vaccine development. Melanoma cell lines, derived from patients with a wide range of disease ranging from mild dysplasia to advanced metastatic cancer, will be added shortly. More information on The Wistar Institute, its research and scientists can be found at www.wistar.org.

J. Craig Venter Institute Human Reference Genome (HuRef)  The Human Reference Genetic Material Repository makes available DNA from a single individual, J. Craig Venter, whose genome has been sequenced and assembled. The DNA samples are prepared from a lymphoblastoid cell line established at Coriell Cell Repositories from a sample of peripheral blood. The DNA samples are available in 50 microgram aliquots. The lymphoblastoid cell line is not available for distribution..

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

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged American Heart Association, Baylor College of Medicine, Michael E. DeBakey, Stony Brook University Medical Center, Vascular endothelial growth factor, VEGF, Weill Cornell Medical College of Cornell University on January 9, 2013| 6 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle

Article Date: 08 Jan 2013 – 0:00 PST

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect, said researchers from Weill Cornell Medical College, Baylor College of Medicine and Stony Brook University Medical Center in a report that appears online in the Journal of the American Heart Association.

“The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting,” said Dr. Todd K. Rosengart, chair of the Michael E. DeBakey Department of Surgery at BCM and the report’s corresponding author. “The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle. However, in these animal studies, we found that even the effect is enhanced when combined with the VEGF gene.”

“This experiment is a proof of principle,” said Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College and a pioneer in gene therapy, who played an important role in the research. “Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts.”

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure.

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, Rosengart and his colleagues transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material. (A transcription factor binds to specific DNA sequences and starts the process that translates the genetic information into a protein.)

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. (Ejection fraction refers to the percentage of blood that is pumped out of a filled ventricle or pumping chamber of the heart.)

The hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

Rosengart emphasizes that more work needs to be completed to show that the effect of the VEGF is real, but it has real promise as part of a new treatment for heart attack that would minimize heart damage.

“We have shown both that GMT can effect change that enhances the activity of the heart and that the VEGF gene is effective in improving heart function even more,” said Dr. Crystal.

The idea started with the notion of induced pluripotent stem cells – reprograming mature specialized cells into stem cells that are immature and can differentiate into different specific cells needed in the body. Dr. Shinya Yamanaka and Sir John B. Gurdon received the Nobel Prize in Medicine and Physiology for their work toward this goal this year.

However, use of induced pluripotent stem cells has the potential to cause tumors. To get around that, researchers in Dallas and San Francisco used the GMT cocktail to reprogram the scar cells into cardiomyocytes (cells that become heart muscle) in the living animals.

Now Rosengart and his colleagues have gone a step farther – encouraging the production of new blood vessels to provide circulation to the new cells.

REFERENCES:

Others who took part in this work include Megumi Mathison, Ronald Gersch, Ahmed Nasser, Sarit Lilo, Mallory Korman, Mitchell Fourman, Kenneth Shroyer, Jianchang Yang, Yupo Ma, all of Stony Brook University Medical Center and Neil Hackett of Weill Cornell Medical College.
Funding for this work came from the generosity of James and Lisa Cohen.
Weill Cornell Medical College

CITATIONS:

MLA

n.p. “Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle.” Medical News Today. MediLexicon, Intl., 8 Jan. 2013. Web.
9 Jan. 2013. <http://www.medicalnewstoday.com/releases/254618.php>

APA

n.p. (2013, January 8). “Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle.” Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/254618.php.

SOURCE:

http://www.medicalnewstoday.com/releases/254618.php

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Differentiation Therapy – Epigenetics Tackles Solid Tumors

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, tagged Aviva Lev-Ari, Biology, breast cancer, Cancer - General, Chemotherapy, colon cancer, Conditions and Diseases, DNA, Epigenetics, health, Histone, Histone deacetylase, Histone deacetylase inhibitor, histone modification, medicine, ovarian cancer, Prostate cancer, research, solid tumors on January 3, 2013| 18 Comments »

Differentiation Therapy – Epigenetics Tackles Solid Tumors

Author-Writer: Stephen J. Williams, Ph.D.

Updated 4/27/2021

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Word Cloud By Danielle Smolyar

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy is a chemotherapeutic strategy directed at re-activating endogenous cellular differentiation programs in a tumor cell therefore driving the cancerous cell to a state closer resembling the normal or preneoplastic cell and therefore incurring loss of the tumorigenic phenotype.

This post will deal with:

Agents such as histone deacetylase inhibitors (HDACi), retinoids, and PPARϒ agonists which have been shown to reactivate terminal differentiation programs in solid tumors
Clinical trials in solid tumors
Issues regarding the use of differentiation therapy in solid tumors

This post is a follow-up post to Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

To put the need for alternate chemotherapeutic strategies in perspective, one is referred to the National Cancer Statistics from http://www.cancer.gov show that 33% of cancer patients, treated with standard cytolytic chemotherapy, will still die within five years (i.e. one in three will die within 5 years). However the addition of the differentiation agent retinoic acid to standard chemotherapy regimen for treatment of acute promyelocytic leukemia (APML) had improved 5 year survival rates from a range of 50-80% up to near 90% complete remission rates while 75% become disease free, an astonishing success story. For a review of APML please be referred to http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia. Briefly, APML is predominantly a result of the chromosomal translocation producing a fusion gene between the promyelocytic leukemia (PML) and RARα receptor genes. The PML-RARα fusion protein recruits transcriptional repressors, histone deacetylases (HDACs), and DNA methyltransferases. Treatment with pharmacologic doses of retinoic acid dissociates the PML-RARα from HDACs and results in degradation of PML-RARα, eventually resulting in the differentiation of the myeloid cells in APML.

Dr. Igor Matushansky of Columbia University believes such differentiation therapy could be useful in soft tissue sarcomas, due to the existence of a connective tissue (mesenchymal) stem cell, in vitro methods which can differentiate these cells into mature tissues, and, from a gene clustering analysis his group had performed, correlation of expression signatures of each liposarcoma subtype throughout the adipocytic differentiation spectrum, including early differentiated to more mature differentiated cells(1). A parallel study by Riester and colleagues had been able to classify breast tumors and liposarcomas along a phylogenetic tree showing solid tumors can be reclassified based on cell of origin via expression patterns(2). In addition, other solid tumors, such as ovarian cancer are easily classified, based both on pathologic, histologic, and expression analysis into well and poorly differentiated tumors, correlating differentiation status with prognosis.

Compound Classes which have potential in

differentiation therapy for solid tumors

A. Histone Deacetylase Inhibitors (HDACi)

In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. Histone deacetylation leads to chromatin compaction and is associated with transcriptional repression of tumor suppressors, cell growth and differentiation. Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death (3). In a review by Kniptein and Gore, entinostat was found to be a well-tolerated HDACi that demonstrates promising therapeutic potential in both solid and hematologic malignancies(4). The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells (for references see (5). In fact, treatment of MCF-7 breast carcinoma cells with SAHA resulted in morphologic changes resembling epithelial mammary differentiation(6).

HDAC inhibitors

Figure. Structures of some HDACi used in clinical trials for cancer (see section below)

hdacwithsaha

Figure. HDAC with SAHA

B. Retinoids

Vitamin A and retinoids play significant roles in basic physiological processes such as vision, reproduction, growth, development, hematopoiesis and immunity (7). Retinoids are the natural derivatives and synthetic analogs of vitamin A. They have been shown to prevent mammary carcinogenesis in rodents (8), to inhibit the growth of human cancer cells in vitro (9,10) and be effective chemopreventive and chemotherapeutic agents in a variety of human epithelial and hematopoietic tumors (11-14).

Retinoids cannot be synthesized de novo by higher animals and consequently must be consumed in the diet. The two sources of retinoids are animal products that contain retinol and retinyl esters, and plant-derived carotenoids (provitamin A). b-carotene is the most potent vitamin A precursor and has been shown to be an active inhibitor of both tumor initiation and promotion (15).

A major function of retinol, relevant to cancer, is its function as an antioxidant. The antioxidant properties of vitamin A have been shown both in vitro and in vivo (16,17). Retinol deficiency causes oxidative damage to liver mitochondria in rats that can be reversed by vitamin A supplementation (18). A caveat to this is in vitro and in vivo evidence of chronic hypervitaminosis A inducing oxidative DNA damage, as well (19-21). Therefore, it is evident that maintaining the vitamin A concentration within a physiological range is critical to normal cell function because either a deficiency or an excess of vitamin A induces oxidative stress (22). Retinoic acids (RA) (all-trans, 9-cis and 13-cis) are the major biologically active retinoids and exert their effects by regulation of gene expression by binding two families of ligand-activated nuclear retinoid receptors (23). Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate the transcription of a large number of target genes that contain retinoic acid response elements (RAREs) in their promoters. Many of these genes are involved in cancer (13,24) and differentiation (24-26).

Several lines of evidence suggest involvement of defects in retinol signaling in cancer, from the observation that a vitamin A-deficient (VAD) diet leads to an increase in the number of spontaneous and chemically induced tumors in animals (27-29) to the observation that RA itself can induce differentiation and inhibit the growth of many tumor cells (30-32), as well as the identification that components of the RA signaling pathway are absent in cancer cells (33). Vitamin A and its metabolites have been proposed to have a dual effect in cancer prevention, as antioxidants (16,17,19,34) and differentiating agents (35-37). as it is well accepted that retinoid signaling is integral in maintaining the differentiated state of many cell types (13,38). Additionally, current rationale for chemoprevention with retinoids is based, in part, on the hypothesis that some tumors, may arise due to loss of normal somatic differentiation during tissue repair.

C. PPARϒ Agonists

Peroxisome proliferator-activated receptor ϒ (PPARϒ) is a member of the steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis but has increasing roles in differentiation and tumorigenesis. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity. One of the first agents, developed in the early 80’s for treatment of hyperlipidemia and hperlipoproteinemia, was clofibrate. All PPAR subtypes heterodimerize with the retinoid-x-receptor (RXR) and, upon binding of ATRA, activate target genes.

PPARϒ agonists have shown potential as a therapeutic in a variety of cancer types including bladder cancer (39), colon cancer(40), breast cancer(41), prostate cancer(42). There are numerous studies showing that PPARϒ agonists have anti-tumorigenic activity via anti-proliferative, pro-differentiation and anti-angiogenic mechanisms of action(43). For example, Papi et al. observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells(44) with concomitant upregulation of differentiation markers.

A great website for further information on PPAR is Dr. Jack Vanden Heuvel, Professor of Toxicology at Penn State University at http://ppar.cas.psu.edu/general_information.html.

D. Trabectedin

Trabectedin (ecteinascidin-743 (ET-743); Yondelis) is derived from the Caribbean tunicate Ecteinascidia turbinacta has antitumor activity by binding to the DNA minor groove thus disrupting binding of transcription factors and inhibiting DNA synthesis. However, it has also been shown, in myxoid liposarcoma (MLS) cells, to cause dissociation of transcription factor TLS-CHOP from promoter sequences resulting in downregulation of target genes such as CHOP, PTX3 and FN1 and induces an adipogenic differentiation program by enhancing activation of CAAT/enhancer binding protein (C/EBP) family of genes. In MLS, TLS-CHOP sequesters C/EBPβ resulting in block of differentiation programs while trabectedin disrupts this association freeing up C/EBPβ to act as transcriptional activator of genes related to differentiation.

Ongoing Cancer Clinical Trials with HDAC Inhibitors

The following is a listing of some clinical trials using histone deacetylase inhibitors in combination with approved chemotherapeutics in various tumors. This data was taken from the New Medicine Oncology Knowledge Base ( at http://www.nmok.net).

hdactrial1 hdactrial2

Issues and Future of Differentiation-based Therapy

In the review by Filemon Dela Cruz and Igor Matushansky(1), the authors suggest that, like days of old of cytotoxic monotherapy, differentiation therapy would not evolve as a simplistic one-size-fits –all but mirror an extremely complicated process. Therefore they suggest three theoretical mechanisms in which differentiation therapy may occur:

Cancer directed differentiation: differentiation pathways are activated without correcting the underlying oncogenic mechanisms which produced the initial differentiation block
Cancer reverted differentiation: correction of the underlying oncogenic mechanism results in restoration of endogenous differentiation pathways
Cancer diverted differentiation: cancer cell is redirected to an earlier stage of differentiation

Finally the authors suggest that “the potential for reversion of the malignant cancer phenotype to a more benign, or at the very least a lower grade of biological aggressiveness, may serve as a critical clinical and biologic transition of a uniformly fatal cancer into one more amenable to management or to treatment using conventional therapeutic approaches.”

References:

1. Cruz, F. D., and Matushansky, I. (2012) Oncotarget 3, 559-567

2. Riester, M., Stephan-Otto Attolini, C., Downey, R. J., Singer, S., and Michor, F. (2010) PLoS computational biology 6, e1000777

3. Seidel, C., Schnekenburger, M., Dicato, M., and Diederich, M. (2012) Genes & nutrition 7, 357-367

4. Knipstein, J., and Gore, L. (2011) Expert opinion on investigational drugs 20, 1455-1467

5. Marks, P. A. (2007) Oncogene 26, 1351-1356

6. Munster, P. N., Troso-Sandoval, T., Rosen, N., Rifkind, R., Marks, P. A., and Richon, V. M. (2001) Cancer research 61, 8492-8497

7. Napoli, J. L. (1999) Biochim Biophys Acta 1440, 139-162

8. Moon, R., Metha, R., and Rao, K. (1994) Retinoids and cancer in experimental animals. in The Retinoids: Biology, Chemistry, and Medicine (Sporn, M., Roberts, A., and Goodman, D. eds.), 2 Ed., Raven Press, New York. pp 573-596

9. De Luca, L. M. (1991) Faseb J 5, 2924-2933

10. Gudas, L. J. (1992) Cell Growth Differ 3, 655-662

11. Degos, L., and Parkinson, D. (1995) Retinoids in Oncology, Springer-Verlag, Berlin

12. Lotan, R. (1996) Faseb J 10, 1031-1039

13. Zhang, D., Holmes, W. F., Wu, S., Soprano, D. R., and Soprano, K. J. (2000) J Cell Physiol 185, 1-20

14. Fontana, J. A., and Rishi, A. K. (2002) Leukemia 16, 463-472

15. Suda, D., Schwartz, J., and Shklar, G. (1986) Carcinogenesis 7, 711-715

16. Ciaccio, M., Valenza, M., Tesoriere, L., Bongiorno, A., Albiero, R., and Livrea, M. A. (1993) Arch Biochem Biophys 302, 103-108

17. Palacios, A., Piergiacomi, V. A., and Catala, A. (1996) Mol Cell Biochem 154, 77-82

18. Barber, T., Borras, E., Torres, L., Garcia, C., Cabezuelo, F., Lloret, A., Pallardo, F. V., and Vina, J. R. (2000) Free Radic Biol Med 29, 1-7

19. Borras, E., Zaragoza, R., Morante, M., Garcia, C., Gimeno, A., Lopez-Rodas, G., Barber, T., Miralles, V. J., Vina, J. R., and Torres, L. (2003) Eur J Biochem 270, 1493-1501

20. Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Jr., Valanis, B., Williams, J. H., Jr., Barnhart, S., Cherniack, M. G., Brodkin, C. A., and Hammar, S. (1996) J Natl Cancer Inst 88, 1550-1559

21. Murata, M., and Kawanishi, S. (2000) J Biol Chem 275, 2003-2008

22. Schwartz, J. L. (1996) J Nutr 126, 1221S-1227S

23. Chambon, P. (1996) Faseb J 10, 940-954

24. Freemantle, S. J., Kerley, J. S., Olsen, S. L., Gross, R. H., and Spinella, M. J. (2002) Oncogene 21, 2880-2889

25. Collins, S. J., Robertson, K. A., and Mueller, L. (1990) Mol Cell Biol 10, 2154-2163

26. Grunt, T. W., Somay, C., Oeller, H., Dittrich, E., and Dittrich, C. (1992) J Cell Sci 103 ( Pt 2), 501-509

27. Lasnitzki, I. (1955) Br J Cancer 9, 434-441

28. Moore, T. (1965) Proc Nutr Soc 24, 129-135

29. Saffiotti, U., Montesano, R., Sellakumar, A. R., and Borg, S. A. (1967) Cancer 20, 857-864

30. Strickland, S., and Mahdavi, V. (1978) Cell 15, 393-403

31. Breitman, T. R., Selonick, S. E., and Collins, S. J. (1980) Proc Natl Acad Sci U S A 77, 2936-2940

32. Breitman, T. R., Collins, S. J., and Keene, B. R. (1981) Blood 57, 1000-1004

33. Niles, R. M. (2000) Nutrition 16, 573-576

34. Monagham, B., and Schmitt, F. (1932) J Biol Chem 96, 387-395

35. Miller, W. H., Jr. (1998) Cancer 83, 1471-1482

36. Miyauchi, J. (1999) Leuk Lymphoma 33, 267-280

37. Reynolds, C. P. (2000) Curr Oncol Rep 2, 511-518

38. Ortiz, M. A., Bayon, Y., Lopez-Hernandez, F. J., and Piedrafita, F. J. (2002) Drug Resist Updat 5, 162-175

39. Mansure, J. J., Nassim, R., and Kassouf, W. (2009) Cancer biology & therapy 8, 6-15

40. Osawa, E., Nakajima, A., Wada, K., Ishimine, S., Fujisawa, N., Kawamori, T., Matsuhashi, N., Kadowaki, T., Ochiai, M., Sekihara, H., and Nakagama, H. (2003) Gastroenterology 124, 361-367

41. Stoll, B. A. (2002) Eur J Cancer Prev 11, 319-325

42. Smith, M. R., and Kantoff, P. W. (2002) Investigational new drugs 20, 195-200

43. Rumi, M. A., Ishihara, S., Kazumori, H., Kadowaki, Y., and Kinoshita, Y. (2004) Current medicinal chemistry. Anti-cancer agents 4, 465-477

44. Papi, A., Guarnieri, T., Storci, G., Santini, D., Ceccarelli, C., Taffurelli, M., De Carolis, S., Avenia, N., Sanguinetti, A., Sidoni, A., Orlandi, M., and Bonafe, M. (2012) Cell death and differentiation 19, 1208-1219

Updated 4/27/2021

Epizyme’s EZH2 blocker boosts immuno-oncology response in prostate cancer models

Source: https://www.fiercebiotech.com/research/epizyme-s-ezh2-blocker-boosts-immuno-oncology-response-prostate-cancer-models

cancer cell surrounded by killer T cells

Inhibiting EZH2 either genetically or with a chemical inhibitor signaled the immune system to respond to PD-1 inhibition in prostate cancer. (NIH)

The protein EZH2 has long been known as a major driver of prostate cancer because of its ability to inactivate genes that would normally suppress tumor growth. Now, a team at Cedars-Sinai Cancer has shown in preclinical models of the disease that blocking EZH2 reduces resistance to immune-boosting checkpoint inhibitors—and they did it with the help of Epizyme, which won FDA approval for the first EZH2 blocker last year.

The Cedars-Sinai team inhibited EZH2 in preclinical prostate cancer models, activating interferon-stimulated genes in the immune system. The interferons then boosted the immune response and reversed resistance to drugs that inhibit the checkpoint PD-1, they reported in the journal Nature Cancer.

By inhibiting EZH2 either genetically or with a chemical inhibitor donated by Epizyme, the researchers used a technique called “viral mimicry” to “reopen” parts of the genome that are typically inactive, they explained in a statement. That signaled the immune system to respond to PD-1 inhibition.

Checkpoint inhibitors have been approved to treat several cancer types, but they’ve been largely disappointing in prostate cancer. Hence several research groups have been exploring combination strategies. They include the University of Texas MD Anderson Cancer Center, which published research in 2019 showing early evidence that combining checkpoint inhibition with anti-TGF-beta drug could be effective in prostate cancer.

More recently, bispecific antibodies have shown early promise in prostate cancer. Last September, Amgen presented data from a phase 1 study of AMG 160, a bispecific targeting PSMA and CD3 on T cells. The company said that 68.6% of patients experienced a decline in PSA, and eight out of 15 patients evaluated showed stable disease.

Regeneron is also developing a bispecific antibody for prostate cancer, targeting PSMA and CD28. The drug is being tested as a solo therapy and in combination with Regeneron’s PD-1 inhibitor Libtayo in a phase 1/2 clinical trial enrolling men with metastatic castration-resistant prostate cancer.

As for Epizyme’s EZH2 inhibitor, Tazverik, its path to market hasn’t been perfectly smooth. An advisory committee to the FDA questioned its efficacy and safety in its initial indication, metastatic or locally advanced epithelioid sarcoma. Still, the company got the go-ahead to market the drug in adult patients with the rare cancer last January. Then the FDA added follicular lymphoma to the label in June. The drug’s takeoff has been slower than expected, however, largely because the pandemic has prevented face-to-face interactions between the sales force and physicians.

The company is currently testing Tazverik in several other cancer types, including as a combination with standard-of-care treatments in castration-resistant prostate cancer.

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

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

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

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

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

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

Lung Cancer (NSCLC), drug administration and nanotechnology

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

Cancer Innovations from across the Web

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

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

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

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

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

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

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

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

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

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Genomic Endocrinology and its Future

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Genome Biology, Genomic Testing: Methodology for Diagnosis, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged disease, DNA, Dr. Sudipta Saha, endocrinology, Eukaryotic, gene, gene expression, genetic disorder, genetics, genome, genomics, hybridization on December 27, 2012| 3 Comments »

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

A number of novel genes have been identified in association with a variety of endocrine phenotypes over the last few years. However, although mutations in a number of genes have been described in association with disorders such as

hypogonadotropic hypogonadism,
congenital hypopituitarism,
disorders of sex development, and
congenital hyperinsulinism,

these account for a minority of patients with these conditions, suggesting that many more genes remain to be identified.

How will these novel genes be identified? Monogenic disorders can arise as a result of genomic microdeletions or microduplications, or due to single point mutations that lead to a functional change in the relevant protein. Such disorders may also result from altered expression of a gene, and hence altered dosage of the protein. Candidate genes may be identified by utilizing naturally occurring or transgenic mouse models, and this approach has been particularly informative in the elucidation of the genetic basis of a number of disorders.

Other approaches include the identification of chromosomal rearrangements using conventional karyotyping techniques, as well as novel assays such as array comparative genomic hybridization (CGH) and single nucleotide polymorphism oligonucleotide arrays (SNP arrays). These molecular methods usually result in the identification of gross abnormalities as well as submicroscopic deletions and duplications, and eventually to the discovery of single gene defects that are associated with a particular phenotype.

However, there is no doubt that the major advances in novel gene identification will be made as a result of the sequencing of the genome of affected individuals and comparison with control data that are already available. Chip techniques allow hybridization of DNA or RNA to hundreds of thousands of probes simultaneously. Microarrays are being used for mutational analysis of human disease genes.

Complete sequencing of genomes or sequencing of exons that encode proteins (exome sequencing) is now possible, and will lead to the elucidation of the etiology of a number of human diseases in the next few years. High-throughput, high-density sequencing using microarray technology potentially offers the option of obtaining rapid, accurate, and relatively inexpensive sequence of large portions of the genome. One such technique is oligo-hybridization sequencing, which relies on the differential hybridization of target DNA to an array of oligonucleotide probes. This technique is ideally suited to the analysis of DNA from patients with defined disorders, such as disorders of sex development and retinal disease, but suffers from a relatively high false positive rate and failure to detect insertions and deletions.

It is often difficult to perform studies in humans, and so the generation of animal models may be valuable in understanding the etiology and pathogenesis of disease. A number of naturally occurring mouse models have led to the identification of corresponding candidate genes in humans, with mutations subsequently detected in human patients. More frequently, genes of interest are often deleted and lead to the generation of disease models.

In general, mouse models correlate well with human disease; however species-specific defects need to be taken into account. Additionally, the transgenic models could be used to manipulate a condition, with the potential for new therapies. The advent of conditional transgenesis has led to an exponential increase in our understanding of how the mutation of a single gene impacts on a single organ. Using technology such as inducible gene expression systems, the effect of switching on or switching off a gene at a particular stage in development can be determined.

Advances in genomics will also have a major impact on therapeutics. Micro RNAs (miRNA) are small non-coding RNAs that regulate gene expression by targeting mRNAs of protein coding genes or non-coding RNA transcripts. Micro RNAs also have an important role in developmental and physiological processes and can act as tumor suppressors or oncogenes in the ontogenesis of cancers. The use of small interfering RNA (siRNA) offers promise of novel therapies in a range of conditions, such as cystic fibrosis and Type II autosomal dominant IGHD. Elucidation of the genetic basis of disease also allows more direct targeting of therapy. For instance, children with permanent neonatal-onset diabetes mellitus (PNDM) due to mutations in SUR1 or KIR6.2 were previously treated with insulin but have now been shown to respond well to sulfonylureas, thereby allowing the cessation of insulin therapy.

Finally, we are now entering the era of pharmacogenetics when the response of an individual to various therapeutic agents may be determined by their genotype. For example, a polymorphism in the GH receptor that results in deletion of exon 3 may be associated with an improved response to GH. Thus the elucidation of the genetic basis of many disorders will aid their management, and permit the tailoring of therapy in individual patients.

Source References:

http://www.frontiersin.org/Genomic_Endocrinology/10.3389/fendo.2011.00011/full

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Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Imaging-based Cancer Patient Management, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged breast cancer, gene expression, genome, Image analysis, Science Translational Medicine on December 24, 2012| 9 Comments »

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Reporter: Aviva Lev-Ari, PhD, RN

Some assays that gauge cancer-related signatures can’t factor in tissue architecture, while other assessments that are good at gauging tissue architecture, provide mostly qualitative tumor data. To reconcile these differences, researchers led by Yinyin Yuan of Cancer Research UK decided to combine histopathological and gene expression analysis to show that quantitative image analysis of the cellular environment inside tumors can bolster the ability of genomic profiling to predict survival in breast cancer patients. This approach, too, though, has its limitations.

For instance, molecular assays that gauge cancer-related signatures are challenged by their inability to factor in tissue architecture and the results are confounded by genomic information from the different types of cells inside the tumor other than cancer cells. Meanwhile, traditional histopathological assessments are good at gauging tissue architecture and differentiating cellular heterogeneity, but mostly provide qualitative tumor data and are too time consuming to be applied in large-scale studies.

Recognizing these weaknesses, researchers led by Yinyin Yuan of Cancer Research UK decided to combine histopathological and gene expression analysis to show that quantitative image analysis of the cellular environment inside tumors can bolster the ability of genomic profiling to predict survival in breast cancer patients. “All technologies have some sort of weakness. That’s why when we combined two types of assays — image and microarray — we get a more reliable readout,” Yuan says.

As they report in Science Translational Medicine, Yuan and her colleagues gathered histopathological information from hematoxylin and eosin-stained images as well as gene expression and copy-number variation data on a discovery set of 323 samples and on a validation set of 241 samples from patients with estrogen receptor-negative breast cancer. Using the discovery sample set, the investigators developed an image-processing method to differentiate the cells inside tumor samples as cancerous, lymphocytic, or stromal. They then tested this technique on the validation sample.

Once Yuan and colleagues had an accurate picture of the types of cells in the tumor samples, they used image analysis to correct copy-number data — as it is influenced by cellular heterogeneity — and developed an algorithm to determine patients’ HER2 status better than copy-number analysis can.

Using the image-processing method, the researchers stratified the discovery and validation sample sets into lymphocytic infiltration-high and lymphocytic infiltration-low groups — as past studies have suggested that high lymphocytic infiltration is linked to better patient outcomes.

When the image analysis was compared to the pathological scores of the samples, the discovery set showed no difference in patient outcomes, but the assessments disagreed with regard to the outcomes of the lymphocytic infiltration-low group in the validation cohort.

Hypothesizing that integrating the gene expression signatures and quantitative image analysis would improve survival prediction, the study investigators combined them. “The gene expression classifier had 67 percent cross-validation accuracy in predicting disease-specific deaths, the image-based classifier had 75 percent, and the integrated classifier reached 86 percent,” the study authors write.

Finally, Yuan and her colleagues applied the image analysis to develop a quantitative score that determines whether specific types of cells are tightly clustered — a high score — or are randomly scattered — a low score. In stromal cells, this approach could discern that breast cancer patients with a high or low score had a “significantly better outcome” than patients whose scores fell in the medium range.

Ultimately, Yuan and her colleagues show that their image processing avoids the biases of manual pathological assessments and accurately quantifies cellular composition and tissue architecture not accounted for by molecular tests. The researchers’ computational approach is also faster than traditional pathological techniques. “These two sets of samples can be done in a day,” Yuan says.
According to the study authors, the limitation of the image processing technique is, of course, that it requires matched molecular and image data.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Posted in Biological Networks, Gene Regulation and Evolution, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, Resident-cell-based, tagged Brigham and Women's Hospital, Cardiac muscle, Cell Biology, Harvard Medical School, Stem cell on December 23, 2012| 11 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Nature. 2012 Dec 5. doi: 10.1038/nature11682. [Epub ahead of print]

Mammalian heart renewal by pre-existing cardiomyocytes.

Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT.

Source

Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA.

Abstract

Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes. Other studies suggest that new cardiomyocytes are born at a very low rate, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse-chase approaches-genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry-that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.

PMID: 23222518

http://www.ncbi.nlm.nih.gov/pubmed/23222518

December 17, 2012

Source of New Heart Cell Growth Discovered

A study in mice suggests that new heart cells arise from pre-existing heart cells and that the renewal process slows with age. The findings may lead to improved regenerative therapy for people with heart damage.

Image of mouse heart cells with brightly colored nuclei.

Dividing heart cells in newborn mice incorporate a tracer that can be seen in the cells’ nuclei. The color scale at the bottom shows the intensity of the tracer signal, with higher intensity toward the right side. Image by Senyo et al., courtesy of Nature.

The heart’s muscle cells, called cardiomyocytes, don’t readily replenish themselves. So an injured heart isn’t easy to mend. After a heart attack, a significant number of cardiomyocytes die. This jeopardizes heart function and can lead to chronic heart failure and possibly death. To help heal damaged hearts, scientists have been searching for a group of cells in the heart that can replenish damaged tissue.

Recent research has shown that the human heart generates new cardiomyocytes throughout its lifespan, but how frequently the cells are generated and where they come from is still debated. Studying heart tissue and cell turnover rate is technically very challenging. Some research has hinted that new cells can arise from progenitor cells at a fairly high rate. Other work has suggested that pre-existing cardiomyocytes divide at a fairly low rate to give rise to new cells.

A team led by Dr. Richard T. Lee of Brigham and Women’s Hospital and Harvard Medical School applied novel technology to investigate heart cell regeneration in mice. They used a technique called multi-isotope imaging mass spectrometry (MIMS). MIMS can detect nonradioactive stable isotope tracers. In contrast to most other tracers, these don’t alter biochemical reactions and aren’t harmful to the organism.

The scientists incorporated a rare stable isotope of nitrogen, nitrogen-15 (¹⁵N), into thymidine—one of the building blocks of DNA. When cells divide, the [¹⁵N] thymidine is taken up and added to new DNA. It can then be seen in the cells’ nuclei using MIMS. The work was supported in part by several NIH institutes, including the National Institute on Aging (NIA) and National Heart, Lung and Blood Institute (NHLBI). The study appeared online on December 5, 2012, in Nature.

To study cell turnover at different ages, the scientists gave 3 groups of mice [¹⁵N] thymidine for 8 weeks starting at day 4 (newborn), 10 weeks (young adult) or 22 months (old adult). To distinguish which types of cells created new cardiomyocytes, they performed similar experiments in mice genetically engineered with fluorescent tags to mark cardiomyocytes.

The scientists found that new heart cells were generated from pre-existing cardiomyocytes rather than progenitor cells. They estimated a yearly renewal rate of less than 1% during normal, healthy conditions. The rate of cell regeneration, they found, declined with age.

The team next used MIMS to study cell turnover following a heart attack. In the 8 weeks after the damage, roughly 3% of heart cells regenerated in the area next to the injured site. However, the researchers also noted that many cells had taken up ¹⁵N but not completed cell division.

“Our data show that adult cardiomyocytes are primarily responsible for the generation of new cardiomyocytes and that as we age, we lose some capacity to form new heart cells,” Lee says. “This means that we are losing our potential to rebuild the heart in the latter half of life, just when most heart disease hits us. If we can unravel why this occurs, we may be able to unleash some heart regeneration potential.”

—by Miranda Hanson, Ph.D.

Archive for the ‘Biological Networks, Gene Regulation and Evolution’ Category

With IBM Help, Coriell Spins off For-Profit Entity to Store Whole-Genome Sequencing Data

Review of Coriell Institute Profile

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

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Directions for Genomics in Personalized Medicine

Purpose

.Introduction

Difficulty of the problem

Historical Perspective

The cornerstone to understanding cancer is in study of the energetics of life

This thinking came out of decades of work in the Dahlem Institute Kaiser Wilhelm pre WWII and Max Planck Institute after WWII, supported by the Rockefeller Foundation.

The Human Genome Project

Use of a Fluorophor Probe

Gene Editing

Additional Developments:

(NJ Sarma and K Willis) Nucleus 2012; 3(6): 1–8; http://Nucleus.com © 2012 Landes Bioscience

http://Bioinformatics and Biology Insights 2013:7 21–34. doi: 10.4137/BBI.S10501

Computational Design of Targeted Inhibitors of Polo-Like Kinase 1 ( lk1).

Conclusions

Summary

Additional Related articles

Other posts related to this discussion were published on this Open Source Online Scientific Journal from Leaders in Pharmaceutical Business Intelligence:

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Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 3:

Personalized Medicine: Institute Profile – Coriell Institute for Medical Research

The Business Aspects of the Institute

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Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle

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Differentiation Therapy – Epigenetics Tackles Solid Tumors

Updated 4/27/2021

Compound Classes which have potential in

differentiation therapy for solid tumors

Ongoing Cancer Clinical Trials with HDAC Inhibitors

Issues and Future of Differentiation-based Therapy

Updated 4/27/2021

Epizyme’s EZH2 blocker boosts immuno-oncology response in prostate cancer models

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

Search Results for ‘cancer’ on this web site

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Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Related Stories

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Mammalian heart renewal by pre-existing cardiomyocytes.

Source

Abstract

Source of New Heart Cell Growth Discovered

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