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Familial Cancer Database Online | FaCD September 4, 2008

Posted by ramunas in bio-software, cancer genetics, familial cancer, hereditary cancer, Resources, technology.

Familial Cancer Database Online is a very useful online tool for experts in cancer genetics to assist in making a genetic differential diagnosis in cancer patients as well as remind tumor spectrum associated with certain hereditary disorders.

And its dynamic cyberinfrastructure already brings the most updated content in the field of clinical cancer genetics with intention to develop further.

The content was created and is edited by dr. Rolf Sijmons (on the left – during poster presentation at ESHG meeting in Barcelona this year), clinical geneticist and associate professor clinical oncogenetics at the Dept. of Genetics of the University Medical Center Groningen (UMCG), the Netherlands. However, other experts who want to contribute to particular syndrome files are invited to contact the editor; these authors will be listed in the syndrome files they contributed to.

And I’m pleased of being included in the list of contributors for the contribution to rare hereditary disorder called Mosaic Variegated Aneuploidy syndrome, where in addition to other symtomes the risk for several cancers (leukemia, rhabdomyosarcomas and embrional kidney cancers) is increased.

FaCD is intended for free of charge use by health professionals with at least basic knowledge of clinical cancer genetics.


Technology of a year 2007 January 28, 2008

Posted by ramunas in technology.
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Yes, it is official. 2007 already was announced as a year of human genome variation. Not surprisingly, the technology of a year 2007 was elected the next generation-sequencing (by Nature Methods).

It is truly remarkable advance not only from a technological perspective, but also it marks the end of ABI monopoly in sequencing.

Congratulations to 454 (Roche), Solexa (Illumina), Solid (ABI) and some more in the frontline (for advances and reviews visit SEQanswers.com).

Happy 2008! | And Briefly About 2007 December 31, 2007

Posted by ramunas in breast cancer, BT Test, cancer genetics, DiaGenic, familial cancer, genetic testing, MammaPrint, Oncotype DX, PC Detect, prostate cancer, sporadic cancer, technology.

(artwork by Hollis Sigler, 1948-2001)

Happy New Year 2008! Especially to all people, who encountered and battled cancer. Also for those who work to help fight this disease. Lot of advances in our understanding about this condition were achieved this year. It is too naive think that we could completely eliminate cancer, but it is very realistic to think that we can (and will able) to better predict and control this disease.

2007 will be known in history as a breakthrough in understanding of our (Humans: Homo sapiens sapientis) genome variation and enormous success in genome wide association studies (GWAS) for complex disorders ) cancer included (e.g. see my post about breast cancer).

2008 will be definitely an exciting journey through a highway (yet in a desert) of personalized genomics:

(from a movie Electroma, 2007)

I believe that individual molecular profiles will soon help to improve the early detection of cancer : over 50 novel DNA methylation-based biomarkers of breast cancer (by Orion Genomics) can replace mamography in a near future.

(courtesy of Biotage)

Also 37 gene expression markers from peripheral blood (by DiaGenic) will be offered in UK by Opaldia from 2008 (also covered by EyeOnDna, GeneticsAndHealth and MedGadget).

A new BT Test (by Provista Life Sciences) is designed to complement other testing methods to aid doctors in more accurately diagnosing breast cancer in its early stages, when life-saving treatment is most effective (via). The BT Test utilizes a proprietary algorithm to evaluate the levels and relationship of multiple, cancer associated protein biomarkers in blood serum. This data is coupled with a patient’s personal medical profile to generate a comprehensive report designed to assist healthcare providers in making an earlier diagnosis of breast cancer (via).

Two gene-expression assays, Oncotype DX and MammaPrint, have been developed and extensivelly reviewed in 2007, to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer. In the future, these tests may be useful in determining the need for systemic adjuvant therapy in such patients (ref.).

Unexpectedly, some years ago alterations in mitochondrial DNA – our reminder about The Seven Daughters of Eve – have been suspected to play an important role in the development and progression of cancer. Several mutations have been identified in a wide variety of human tumors, including breast, colorectal, ovarian, gastric, hepatic and esophageal cancers, as well as hematological malignancies [ref.]. Some studies this year points to the importance of the variants in D-loop in familial breast cancer.

Genomic alterations in a new cancer marker – nucleophosmin (NPM1) (by Ipsogen) – has an enormous impact in the biological study, diagnosis, prognostic stratification, and monitoring of minimal residual disease of various lymphomas and leukemias (especially acute myeloid leukemia (AML)). The discovery of NPM1 gene alterations also represents the rationale basis for development of molecular targeted drugs.

Panacea Pharmaceuticals (hm, what a name…) has initiated manufacturing of PC Detectsm kits, the Company’s diagnostic test for prostate cancer, under GMP condition. It based on detection of Human Aspartyl (Asparaginyl) beta-Hydroxylase (HAAH), a cancer biomarker. HAAH has been established as an excellent biomarker for many types of cancer, including prostate cancer. The protein is typically undetectable in sera from cancer-free individuals, thus, an elevated serum protein level of HAAH is highly diagnostic for cancer. PC Detectsm is recommended as an adjunct to the prostate specific antigen (PSA) test and the digital rectal examination (DRE), the currently recommended prostate cancer screening methods (ref.).

A booming field in micro-RNA and cancer field is expected to blossom in forthcoming years – microRNA-10b and breast cancer metastases is a recent example in Nature. It is truly biology’s Big Bang in our 21st century – The RNA revolution.

(photo from Economist)

Tumor immunology, with cancer immunoediting concept in ahead, T regulatory cells and advances in therapeutic cancer vaccines is an important future promise. Individualized cancer immunotherapy with RNA loaded dendritic cells (DC) vaccines (by Argos Therapeutics) is one of the opportunities and new generation of choices.

BOADICEA Final Version Released December 15, 2007

Posted by ramunas in bio-software, breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, ovarian cancer, technology.
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Here is probably the most accurate breast&ovarian cancer risk/mutation probability calculation web-application released from Cambridge University Genetic Epidemiology UnitBOADICEA.

BOADICEA is a computer program that enables the user to estimate BRCA1/BRCA2 mutation carrier probabilities and breast/ovarian cancer risks based on polygenic model. The BOADICEA Web Application (BWA) has been designed in collaboration with clinical geneticists and researchers, in order to make BOADICEA risk estimations much quicker and easier.

It differs from available (BRCAPRO, Gail, Couch, Frank, Manchester model etc.), since it assumes not only high penetrance genes (eg. BRCA) for risk calculation, but also contribution of other low penetrance genes, most not yet identified (thus polygenic).

For more than a year lot of users tested beta phase (I am grateful to Alex Cunningham, the main developer and programmer, for letting to participate during this phase) and the final version was released. Excellent work, I would say!

The approach was first described by Antoniou AC et al. in 2004 and it was shown that overall familial risks of breast cancer predicted by this model were close to those observed in epidemiological studies.

Anyone can register to use the program including researchers, healthcare professionals and the public. However, if you are a member of the public and you are concerned about your family history, it is strongly advised that you seek guidance first from your general practitioner (see Advice for members of the public).

N.B. Be aware, however, that current model is based on genetic epidemiology of UK population. For other populations it may give not correct risk estimation.

P.S. I would like to apologize my readers for not posting long – I’m completely drowned in the final year of my residency and end of a year…

New Molecular Test For Postmenopausal Breast Cancer | Mammostrat September 6, 2007

Posted by ramunas in breast cancer, mammostrat, sporadic cancer, technology.

The Molecular Profiling Institute, Inc. has just announced that they are now providing Mammostrat, a new molecular-targeted breast prognostic test, to breast cancer patients, nationwide in the USA. The Mammostrat prognostic test utilizes five immunohistochemical (IHC) biomarkers a diagnostic algorithm.to classify patients into high, moderate, or low-risk categories for disease recurrence.

Acctually, it is not a true genetic test. Mammostrat is a five-antibody immunohistochemistry (IHC) prognostic test for postmenopausal, estrogen receptor-expressing, hormone receptor-treated (tamoxifen) breast cancer patients with node-negative disease who will receive hormonal therapy and are considering adjuvant chemotherapy. It utilizes standard paraffin-embedded tissue (via and via) .

The five markers are as follows:

  • p 53 , which is known to play a central role in cell cycle regulation and mutations in p53 contribute to tumor formation (aka “the Guardian of Genome”)
  • HTF9C , which is co-expressed with proteins that are involved in DNA replication, implicating HTF9C in DNA replication and cell cycle control.
  • CEACAM5 , which is normally expressed in embryonic tissue and is aberrantly expressed in some cancers.
  • NDRG1, which is expressed under conditions of hypoxia and other stresses. It may have a role in helping tumors survive under the hypoxic, stressful environment confronting aggressive tumors.
  • SLC7A5, which is involved in nutrient transport. Over-expression of SLC7A5 could help sustain the high growth rate of cancer cells by increasing a cell’s ability to consume nutrients.

Mammostrat testing is performed by staining the supplied sections and appropriate control tissue with the five Mammostrat antibodies. A trained pathologist will then score the stained slides according to established criteria. A “0” for negative staining or a “1” for positive staining for each antibody will be entered into the AGI algorithm to calculate a “Risk Index.” The Risk Index value will be used to classify the patient as low, moderate, or high likelihood of breast cancer recurrence. The ordering pathologist will receive a report similar to the sample report shown here. The Mammostrat report will list the staining result for each antibody, the Risk Index category (i.e. low, medium, or high) and an interpretation of what the score means for the patient.

Pathologists, oncologists and patients should use the Mammostrat test results in conjunction with other clinical information to help select amongst treatment options (via).

Because Mammostrat uses traditional immunohistochemistry technology, the test is expected to be significantly less expensive than existing molecular-based, prognostic tests for breast cancer and is typically covered by insurance.

“Mammostrat’s cost-effective, molecular-targeted analysis enables MPI to provide the test at a significant discount compared to our competitors. Moreover, test results will be available quickly — an average of seven business days — versus two weeks for alternative, comparable tests.” , says Todd Maney, Ph.D., Vice President of New Product Development.

The test was developed by Applied Genomics, Inc (AGI). who rigorously translated recent genomic insights in cancer into a novel immunohistochemistry test. Mammostrat test results have been validated using over a thousand patient samples in North America.

AGI also has developed PulmoType and PulmoStrat IHC based antibody tests for lung cancer.

The standard of care for most of postmenopausal women with estrogen receptor expressing, node negative breast cancer is surgery to remove tumor followed by hormone signaling targeted therapy (e.g. tamoxifen or aromatase inhibitors) (ref.).

The prognosis for this group of early stage, estrogen receptor positive breast cancer patients is considered favorable with approximately 90% or more of these patients surviving five years and longer. However, several studies have demonstrated that outcomes can be further improved by treatment with cytotoxic chemotherapy. Since it is clear that most patients will remain disease free in the absence of additional therapy it is likely that cytotoxic therapy is only important for a small subset of these early-stage cancers. Since chemotherapy comes with difficult side effects (e.g. nausea, hair loss, severe fatigue) and long term risk of cardiovascular complications and secondary tumors, the decision whether to use adjuvant chemotherapy is difficult and controversial. The potential benefit of using Mammostrat testing is to identify those patients at high risk of cancer recurrence and therefore more likely to benefit from additional chemotherapy as opposed to those patients at low risk of recurrence who may choose to forgot chemotherapy.

I think it would be of interest to include these protein encoding genes into some gene expression profiling test as well.

MRI Is Better for Early Breast Cancer Detection | Lancet study August 14, 2007

Posted by ramunas in breast cancer, cancer genetics, research, technology.
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Last week issue of medical journal the Lancet presents an important data from 5-years perspective study, which shows that MRI (magnetic resonance imaging) outperforms conventional mammography for detection of ductal carcinoma in situ (DCIS), an early pre-invasive breast cancer which arises in the milk ducts (listen to the audio podcast stream from Lancet).

“MRI is more powerful and accurate for diagnosing pre-invasive breast cancer called ductal carcinoma in situ (DCIS),” concluded lead research Dr. Christiane Kuhl, from the Department of Radiology at the University of Bonn, Germany [via].

In the study, Kuhl and colleagues collected data on more than 7,300 women over five years. In addition to mammograms, the women were also given MRIs. The researchers wanted to see if MRIs could detect DCIS. The study found that x-ray based mammograms detect only 56% of early lesions in high risk women compared with 92% when magnetic resonance imaging scans (MRI) are used.

Moreover, of the 89 women diagnosed with “high grade” DCIS — the ones most likely to develop into cancer — 98 percent were found by MRI, compared with 52 percent found by mammography. In addition, 48 percent were missed by mammography but found by MRI alone (via).

Age, menopausal status, personal or family history of breast cancer or of benign breast disease, and breast density of women with MRI-only diagnosed DCIS did not differ significantly from those of women with mammography-diagnosed DCIS, study abstract states.

Cancer screening programmes are failing to detect nearly half of the earliest cases of breast cancer according to research which suggests women’s lives could be saved if all were offered hi-tech MRI scans, the Guardian states.

“If you picked up all cases of ductal carcinoma in situ [DCIS] you would prevent virtually all cases of breast cancer. Our finding that MRI is superior to mammography in detecting it turns things upside down.”, researchers said.

High-grade DCIS almost always becomes invasive and does so after a short time, Kuhl explained. “When it becomes invasive, it is biologically aggressive — that means it kills,” she said.

In contrast, low-grade DCIS usually remains within the duct and poses no threat. In fact, women can have low-grade DCIS for a lifetime with no ill effects, Kuhl said.

Also, MRI was not associated with many false positive findings. The positive predictive value of both methods was similar — 55 percent for mammography and 59 percent for MRI, the researchers reported.

“These findings can only lead to the conclusion that MRI outperforms mammography in tumour detection and diagnosis. MRI should thus no longer be regarded as an adjunct to mammography but as a distinct method to detect breast cancer in its earliest stage.”, said experts from the Radboud University Nijmegen Medical Centre in the Netherlands.

However, despite the technology’s advantages, its cost and a lack of people skilled at reading breast MRIs means it won’t replace mammograms any time soon, experts say.

“Also, MRI is more difficult to read, and you have to use different criteria to diagnose DCIS than for invasive breast cancer.” Since MRI is used less often than mammography “the number of radiologists who are experienced in interpreting breast MRIs is far smaller than the number of radiologists who are able to accurately interpret a mammogram”.

This is the beginning of the death of mammography, but that is going to be a long death,” Kuhl predicted. (via).

The study raises new questions about the national breast cancer screening programmes, which sees all women between the ages of 50 and 70 called in for regular mammograms but not MRI scans (at two-yearly visits in my country.) Only younger women at high risk of breast cancer are offered the more expensive MRI scans, because mammography is not informative in premenopausal women due to dense breast tissue.

Anyway, the results should be interpreted with caution (ref.):

“This study says that potentially mammograms are missing half of women with DCIS. The implication is that mammograms may not be the most sensitive way of finding early breast cancer, but it is clearly saying that more research is needed. A lot of women walk around with it without it being invasive or harmful. Some clinicians argue that we are over-diagnosing and over-treating already. It doesn’t seem practical to do MRI on every woman. It’s costly and very time-consuming as well”, says consultant nurse at Breast Cancer Care.

“The programme uses mammography to screen all women in the UK aged 50 or more for breast cancer. The results in the Lancet are not representative of the screening population, and so have to be interpreted with care”, states Julietta Patnick, director of UK NHS cancer screening programmes.

Senior policy officer at Breakthrough Breast Cancer, said: “This is an interesting but complex study which gives us more information about the detection of early breast changes. However, it is important to note that the women who took part in this study had a higher chance of an abnormality being found and therefore are not representative of the general population.”

What is a connection between MRI, DCIS and cancer genetics, you may wonder? It is now well established, that BRCA1-positive breast tissue has different histopathological appearance and course – its usually G3, estrogen negative and expressing basal-like phenotype. Recently published studies from Canada, Italy, Germany (btw, by the same author), the Netherlands and UK (MARIBS study) all similarly showed, that MRI outperforms mammography in BRCA1 breast cancers and annual MRI is now included as addition to mammography for TP53, BRCA1 and BRCA2 mutation carriers screening programs, performed from 30 till 49 years in UK and other countries. Cost effectiveness of MRI is also proven.

MRI procedure is more invasive than mammography, because contrast enhancing substance must be injected intravenously and special equipment is used:

The genetics of DCIS is also interesting topic – it is only several years since it was shown, that DCIS cases actually have the same proportion of BRCA1 and BCRA2 mutation as invasive breast cancer has – mutations were found in a significant proportion of women with DCIS who presented for hereditary risk assessment [via]. DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are non-carriers, but occurs at an earlier age [via].

Virtual Cancer Information And Services | Second Life July 31, 2007

Posted by ramunas in bio-software, cancer genetics, media, technology.
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Cyberspace now become more and more widespread phenomena. A Virtual world Second Life, created by Linden Research, Inc , ScienceRoll sees as a new creative education environment. Personally, I have to do a lot in my first (real) life, before I can join a Second Life, but anyway, this environment reminds me a lot of SF’s ideas, I’d read before – William Gibson’s cyberspace, Matrix and S. Lukjanenko’s DeepTown. Interestingly, lot of corporations and real-world institutions are opening their offices in this virtual world, and American Cancer Society’s (ACS) is not an exception. Forbes announces, that on July 27 and 28, almost 2,500 people gathered online in the world of Second Life and run a virtual relay race to raise money for cancer research.

The third annual virtual “Relay for Life” marks the grand opening of the American Cancer Society’s (ACS) virtual headquarters in the Second Life community, which is a co-sponsor of the relay.

Well, I would better join a bicycle ride to raise a funds, but anyway:

The new virtual building, which opened June 1, is designed to provide the same cancer information and services to people in the virtual world as the organization provides in the real world. The building includes presentation and meeting rooms for cancer education sessions and fund-raising meetings, and will soon feature a staffed link to the group’s National Cancer Information Center. The headquarters also features green space and gardens to showcase user-created art that expresses the personal fight against cancer.

“Already, we have existing peer-to-peer Second Life cancer support groups coming to us to use the facility and our resources. We are certain that, going forward, the community will find untold uses for our office space in terms of education, advocacy, fund raising and community support,” said Moss.

It is interestingly whether they have genetic counseling room there? I think that kind of service would be great, especially if you’d implement a portable hyper-DNA-collection-USB device 🙂

Gene-expression Profiling in Cancer | A Brief Review July 24, 2007

Posted by ramunas in breast cancer, cancer genetics, GeneSearch, MammaPrint, Oncotype DX, sporadic cancer, technology.

It seems I’m getting more and more interested in gene-expression profiling (GEP) oncotests. In the Internet the information about this topic is quite messy and dispersed, so here I will try to draw some focus on this emerging technology (what will be added to a Genetic testing section later).

So, if we want to make gene-expression profiling, or in the other words, to answer an important question – what genes are expressed in a particular cell type of an organism, at a particular time, under particular conditions? [ref.]- first we need to have a sample of a tumor tissue to analyze its RNA pattern (or more precisely, messenger RNA (mRNA)). Here, unlike in mutations search, we’re not interested in DNA. RNA is quite instable molecule, so you need be quite cute and smart to manage preserve and analyse it.

A breast cancer is currently a holy grail for gene-expression profiling research to identify genes associated with breast cancer and to measure their activity in tumor cells, i.e. obtain its gene expression profiles.

Several techniques for measuring gene expression are available: a) a microarray based analysis and b) reverse transcriptase-polymerase chain reaction (RT-PCR). To measure gene expressions with a microarray you need to have a “fresh” (or “unpreserved”) tumor tissue samples. Tumor samples are frequently preserved in this way in Europe. Whereas in the United States tumor samples are more commonly preserved in formalin and embedded in paraffin blocks. Microarray analysis cannot be done on tissue that has been preserved in this way [ref.]. Since our pathologists are accredited by College of American Pathologists, they’re using paraffin blocks as well. Instead, for formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks RT-PCR can be used to measure gene expression.

Therefore its important to know, that because of this difference in common methods of tissue processing has led to the development of tests in Europe and the United States that are quite different from one another, and that are based on measurements of the activity of different sets of genes.

In Europe, using microarray analysis, researchers are studying the usefulness of at least two different groups, or “panels”, of genes in studies on early stage tumors from node negative patients. One is a 70-gene panel, and another is a 76-gene panel. 1,2 Only three genes are common to both panels, while all the others are unique to one test or the otherB. In spite of this difference, both panels have yielded results that appear to be promising,3 and a commercial test based on the 70-gene panel is already available in the United States under the name MammaPrint®. (via)

Based on 76-gene panel Johnson&Jonson’s companies Veridex research, a two genes expression The GeneSearch™ Breast Lymph Node (BLN) Assay test was recently approved dy FDA, and is based on RT-PCR (i.e. for analysis in FFPE).

Common use of FFPE and a need for gene expression profiling using RT-PCR has led researchers in the United States to investigate several other panels of genes that produce too much or too little protein in early stage, node-negative, and estrogen receptor-positive breast cancer cells. A 21-gene panel commercial Oncotype DX test is one of example, which recently was approved by TEC to inform decision making about adjuvant chemotherapy only for a women with estrogen receptor-positive, node-negative, tamoxifen-treated breast cancer.

Let’s have a closer look at these genes [ref.]:

Measurements of five of those 21 genes (Beta-actin, GAPDH, RPLPO, GUS, and TFRC ) are used as “controls” – that is, to verify that the test has not been contaminated or run improperly.

The other 16 genes, which produce their proteins at varying levels in different tumors, include:

  • genes associated with cell proliferation (Ki-67, STK15, Survivin, Cyclin B1, and MYBL2);
  • genes associated with cellular invasion (Stromolysin 3, and CathepsinL2);
  • genes associated with HER2 activity (GRB7 and HER2);
  • genes associated with estrogen activity (ER, PR, Bc12, and SCUBE2); and
  • three other genes with distinctly different activity in cancer cells (GSTM1, BAG1, and CD68).

This Oncotype DX panel has only a single gene overlap with the 70-gene MammaPrint® panel. The reason for such diversity between gene panels under investigation are because of differences in tissue preparation, differences in laboratory methodologies, and differences in measurement techniques. At present, these gene-expression profile tests have only been validated on stored sample tissue.

Whether one of the existing panels will prove to be significantly superior to others, or whether newer panels will emerge that have better predictive power remains to be seen. It is clear that additional validation studies and more clinical experience are needed to establish the reliability of gene expression profiling for predicting tumor recurrence and response to specific treatments (ref.)


Personalized DNA Analyzer | Precautions July 20, 2007

Posted by ramunas in media, technology.
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Those GreenFluorescentProtein (GFP) Bunny lovers should welcome a first personalized PCR device – Spartan DX!

When Steve Wozniak assembled a first personal computer prototype Apple-I in 1976 nobody thought that will be so widespread as is today.

I think the fiction world, desribed in William Gibson, Bruce Sterling and Paul Di Filippo novels, has already came into reality.

For “only” $14,995 U.S. dollars, you can take a Spartan DX Personal DNA Analyzer to your next family reunion and start checking for those “non-paternity events.” (via)

Or even perform a cancer predisposition test. I am convinced that predictive DNA testing can not be regarded as solely laboratory practice – it must be appropriately interpreted (before and after genetic testing) by a specialist (i.e. clinical geneticist). Otherwise you can misinterpret the data and have all the worst consequences behind that.

This research-only device is just begging for application in some sort of futuristic lab or organization. Like maybe in a Gattaca-style research center.(via)

Can you foresee an impact of these “DNA results on demand”?

Improved DNA Electrophoresis | Better Than TBE or TAE Buffer July 20, 2007

Posted by ramunas in research, technology.

When I run my electrophoresis gel I have a plenty time to update this blog :). But it seems that a significant time lag needed to run EF will shrink soon – ScienceDaily reports, that a better DNA separation electrophoresis from Johns Hopkins University allows to do it five times faster and less expensive. Buffer solutions ingredients involved in the EF process have been unchanged for 30 years, and its seems they are not the best ones: the evidence shows that the compound lithium boric acid in DNA electrophoresis is the optimal solution for this process.

“A process that normally takes around one and a half, two hours to do can be done in 10 minutes – in some instances it can be 10-fold faster,”

inventor claims. Well, I do it usually for 30-40 minutes, but anyway…

According to Dr. Brody, the finding is “not just a useful discovery for cancer research, but also for the neurosciences, developmental biology – increasingly, many fields involve DNA analysis.” The process has already been gaining acceptance and use internationally (via) .