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Dr. Roger Rosenberg, director of the Alzheimer’s Disease Center at UT Southwestern Medical Center, has been awarded the first Medal for Scientific Achievement by the World Federation of Neurology.

The federation is made up of more than 100 neurology associations internationally. It established the award, and another for service to international neurology, in 2008. The prizes are the first ever given by the federation.

“I am honored that my colleagues in the World Federation of Neurology have recognized my efforts to develop the study of molecular genetics in neurological diseases, from Machado-Joseph disease to Alzheimer’s disease,” Dr. Rosenberg said. “I also want to acknowledge my colleagues at the Alzheimer’s Disease Center for their clinical and research efforts, which have facilitated my own research.”

The award will be presented at the federation’s World Congress of Neurology in Bangkok on Oct. 26. Dr. Rosenberg, who has studied the genetic basis of neurological diseases for three decades, is also co-chair of the meeting’s scientific program and provided input on molecular genetics for previous programs of the federation.

In 1975 he and his colleagues published the first in a series of papers on the clinical and genetic basis for an inherited disease that causes degeneration in a brain region essential for balance and coordination. He named the ailment Machado-Joseph disease after two affected families.

He and his colleagues showed that this disease is caused by repeats of a small DNA coding in a single gene. Detection of this mutation and genetic counseling has eliminated the disease in affected families.

Similar repeats have been found to occur in Huntington’s disease and other disorders of coordination.

Currently, Dr. Rosenberg’s research centers on a vaccine against Alzheimer’s disease that uses DNA to create antibodies against beta-amyloid, a small protein that accumulates in the brains of people with Alzheimer’s. He recently received a patent for this approach.

Among his many publications is The Molecular and Genetic Basis of Neurological and Psychiatric Disease, the leading textbook in the field, which is now in its fourth edition.

Dr. Rosenberg attended Tufts University and received his bachelor’s degree in biochemistry and medical degree with distinction from Northwestern University. He joined the UT Southwestern faculty in 1973, served as chairman of neurology until 1991 and became director of the Alzheimer’s Disease Center in 1988.

The center, one of 32 funded by the National Institutes of Health, contains five core groups that conduct clinical research, study the neuropathology of Alzheimer’s, provide education and outreach to the community, support data management and provide administrative functions.

Dr. Rosenberg served as president of the American Academy of Neurology from 1991 to 1993. He is editor-in-chief of Archives of Neurology and a member of the editorial board of theJournal of the American Medical Association.

Source:
Aline McKenzie

UT Southwestern Medical Center Continue reading →

Besides their tremendous value in treating high cholesterol and lowering the risk of heart disease, statins have also been reported to potentially lower the risks of other diseases, such as dementia. However, a study in the October Journal of Lipid Research finds that similar statin drugs can have profoundly different effects on brain cells – both beneficial and detrimental. These findings reinforce the idea that great care should be taken when deciding on the dosage and type of statin given to individuals, particularly the elderly.

John Albers and colleagues compared the effects of two commercially used statins, simvastatin and pravastatin, on two different types of brain cells, neurons and astrocytes (support cells that help repair damage). By directly applying the drugs to cells as opposed to administering them to animals, they could eliminate differences in the drugs’ ability to cross the blood-brain barrier as a reason for any differing effects. Albers and colleagues looked at the expression of genes related to neurodegeneration, and found that indeed, despite using biologically equivalent drug concentrations, differences were seen both between cells, and between drugs; for example, simvastatin reduced the expression of the cholesterol transporter ABCA1 by approximately 80% in astrocytes, while pravastatin lowered expression by only around 50%. Another interesting difference was that while both statins decreased expression of the Tau protein – associated with Alzheimer’s disease – in astrocytes, they increased Tau expression in neurons; pravastatin also increased the expression of another Alzheimer’s hallmark, amyloid precursor protein (APP)

.
While increased levels of these two proteins may account for potential risks of disease, Albers and colleagues also note that large decreases in cholesterol proteins like ABCA1 should be considered. Brain cholesterol levels tend to be reduced in elderly people, and in such individuals the long-term effects of statin therapy could lead to transient or permanent cognitive impairment.

From the article: “Differential effects of simvastatin and pravastatin on expression of Alzheimer’s disease-related genes in human astrocytes and neuronal cells” by Weijiang Dong, Simona Vuletic and John J. Albers

Source: Nick Zagorski

American Society for Biochemistry and Molecular Biology Continue reading →

deCODE genetics
(Nasdaq: DCGN) announced the launch of deCODE MI(TM), a reference
laboratory test for variations in the genome (called SNPs) that the company
has associated with increased risk of myocardial infarction, or heart
attack. The SNPs are located on chromosome 9 and were discovered by deCODE
earlier this year. As described in the journal Science in July, deCODE
scientists found that people who carry two copies of these variants are at
double the risk of suffering an early heart attack — before the age of 50
in men and 60 in women — than are those who do not carry them. deCODE
validated the role of these variants in five groups of patients and
controls from Iceland and the United States, and other researchers have
replicated this finding in several European, US, and Canadian cohorts.

“With the launch of deCODE MI, we have taken another of our
breakthroughs in genetics and transformed it into a new tool in the fight
to prevent heart attack. While many risk factors for heart attack are
understood, the disease remains the leading cause of death in the
industrialized world and the early- onset cases often take both patients
and doctors so dangerously by surprise. deCODE MI(TM) tests for a genetic
risk factor that is independent of other risks such as cholesterol, obesity
and smoking, and therefore provides a means of identifying individuals who
may derive particular benefit from earlier and more aggressive prevention
efforts,” said Dr. Kari Stefansson, CEO of deCODE.

How to order deCODE MI(TM)

deCODE MI(TM) is performed in deCODE’s Clinical Laboratory Improvement
Amendments (CLIA) certified laboratory, and must be authorized by a
qualified physician. If you are an individual who would like more
information on deCODE MI(TM) to discuss with your doctor, or a physician
interested in learning more about deCODE MI(TM) for your patients, please
visit us at decodediagnostics.

The variants detected by deCODE MI(TM), are two SNPs (single-letter
variants in the genome) on chromosome 9p21. They were discovered by deCODE
scientists earlier this year through genome-wide SNP analysis in Iceland
and replicated in three cohorts of European descent from Philadelphia,
Atlanta and Durham, North Carolina. Of the 17,000 patients and control
subjects in the study, more than 20% of participants carried two copies of
the variant, corresponding to a more than 60% increase in risk of heart
attack, regardless of age of onset, compared to those without the variant.
In early-onset cases — men and women who suffered a heart attack before
the ages of 50 and 60, respectively — carrying two copies of the variant
corresponds to an approximate doubling of risk compared to non-carriers.
The variant is estimated to account for approximately one-fifth of the
incidence of heart attack in populations of European origin, and nearly one
third of early-onset cases, making it the one of the most significant
genetic risk factors found to date for heart attack as a public health
problem.

About deCODE

deCODE is a biopharmaceutical company applying its discoveries in human
genetics to the development of drugs and diagnostics for common diseases.
deCODE is a global leader in gene discovery — our population approach and
resources have enabled us to isolate key genes contributing to major public
health challenges from cardiovascular disease to cancer, genes that are
providing us with drug targets rooted in the basic biology of disease.
Through its CLIA-certified laboratory, deCODE is offering a growing range
of DNA-based tests for gauging risk and empowering prevention of common
diseases, including deCODE T2(TM) in type 2 diabetes; deCODE AF(TM) for
atrial fibrillation and stroke; and deCODE MI(TM) for heart attack. deCODE
is delivering on the promise of the new genetics(SM). On the web at
decode.

Any statements contained in this presentation that relate to future
plans, events or performance are forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995. These
forward-looking statements are subject to a number of risks and
uncertainties that could cause actual results to differ materially from
those described in the forward- looking statements. These risks and
uncertainties include, among others, those relating to technology and
product development, integration of acquired businesses, market acceptance,
government regulation and regulatory approval processes, intellectual
property rights and litigation, dependence on collaborative relationships,
ability to obtain financing, competitive products, industry trends and
other risks identified in deCODE’s filings with the Securities and Exchange
Commission. deCODE undertakes no obligation to update or alter these
forward-looking statements as a result of new information, future events or
otherwise.

deCODE genetics
decodediagnostics Continue reading →

In just six years, bacteria in the genus Rickettsia spread through a population of the sweet potato whitefly (Bemisia tabaci), an invasive pest of global importance. Infected insects lay more eggs, develop faster and are more likely to survive to adulthood compared to their uninfected peers.

The discoveries were made by a University of Arizona-led team of scientists and are published in the April 8 issue of the journal Science.

“It’s instant evolution,” said Molly Hunter, a professor of entomology in the UA’s College of Agriculture and Life Sciences and the study’s principal investigator. “Our lab studies suggest that these bacteria can transform an insect population over a very short time.”

“It is not uncommon to find a microbe providing some benefits to their hosts, but the magnitude of fitness benefits we found is unusual,” she added.

In addition to the observed evolutionary advantages – which biologists call fitness benefits – Hunter’s team discovered that the bacteria manipulate the sex ratio of the whiteflies’ offspring by causing more females to be born than males.

According to Hunter, the bacteria are transmitted only through the maternal lineage (from mother to offspring). Therefore, it is beneficial for them to make sure more female than male whiteflies are born.

“However, we don’t know how they’re doing that yet,” she said.

Anna Himler, a postdoctoral research associate in Hunter’s lab and the lead author on the research paper, said her team was most surprised by the speed with which the bacteria moved through the whitefly population.

In 2000, the researchers found Rickettsia in only 1 percent of the whiteflies in Arizona. In 2003, the microbes had spread through half of the population, and today, almost all whiteflies in Arizona contain the bacterium.

Whiteflies come in many different species and variants within species called biotypes. Of those, none are considered as detrimental to agriculture as the “B Biotype” of the sweet potato whitefly, which originated in the Mediterranean.

Contrary to what their name implies, whiteflies belong to an order of insects known as Hemiptera and are related to aphids and true bugs. Like their kin, they puncture their host plants and suck out the sugary sap. In addition to stripping the plant of nutrients, larvae and adults produce copious amounts of honeydew, which attracts mold and leads to damage of the leaves. Finally, whiteflies transmit plant viruses; in the case of the sweet potato whitefly, more than a hundred different kinds.

Compared to the vast majority of whiteflies, which are highly specialized and feed only on particular host plants, the sweet potato whitefly feeds on more than 600 host plants, which means it can move from one plant to another through the seasons.

“Here in Arizona, it probably starts out on weeds in the spring, and then moves on to melons, and when melons are done, it moves in big numbers onto cotton and feeds on that all summer long,” Hunter explained. “In the fall, it moves on to vegetables, and so it just keeps going.”

What whiteflies lack in body size – they are about one-sixteenth of an inch long – they make up for in numbers. Whiteflies can colonize a host plant in large numbers and blanket leaves with larvae and sticky honeydew in a short time.”

“In the late 1980s and early 1990s, when this new biotype arrived in the Southwest, the population just exploded,” Hunter said. “Sometimes you could see clouds of whiteflies in the air, gumming up windshields. With integrated pest management practices, many developed by colleagues here at the UA, their impact has decreased tremendously, but they still are the worst pest in Arizona’s cotton industry. If it wasn’t for whiteflies, farmers would be spraying cotton a lot less.”

The team is now trying to explain how Rickettsia increases whitefly fitness. In one conceivable scenario, the bacteria might turn down the plant defenses in an effort to make it easier for the whitefly to feed on the plant.

Himler said that because studies done elsewhere suggested fitness differences were not important, her team initially believed that in order for the microbes to spread so rapidly through the population, the whiteflies must pass them on through horizontal transfer (from individual to individual) rather than through vertical transfer (from mother to offspring).

“So we did this big horizontal transmission experiment but found almost nothing. At the same time, we saw these incredible differences between the Rickettsia-positive and Rickettsia-negative whitefly cultures. In evolution, fitness is the money. So I just saved a couple of leaves from my plants from the horizontal transmission experiment and thought, let’s look at the offspring. Even though I only had a few leaves, the effect was strong. We found many more offspring coming from the Rickettsia-positive plants than from the control plants.”

“Rickettsia-infected whiteflies lay more eggs, more of those eggs survive, and there is the reproductive manipulation toward producing more female than male offspring. These effects are not unheard of, but the strength that we found here is unusual.”

According to Hunter, the interaction between host and bacteria is a tug-of-war between a positive and negative effect.

“In general, taking the sex ratio control away from the host is not a good thing for the host,” she said. There is a reason why most living organisms have roughly equal proportions of sexes. If there were more females, then any individual producing more males would produce more progeny. This is one of the reasons a one-to-one sex ratio is really common in nature.”

The team believes that discovering how profoundly and how fast microbes can change a population of a pest of global importance has implications for pest management strategies.

“It would be interesting to see if by having a microbe that has this big effect in one direction, if you could make it so that it has an effect in the other direction, to help control the pest,” Hunter said. “Could we use symbionts in a way to make things less of a problem, to manage pest populations in a more sustainable way?”

Source:
Daniel Stolte
University of Arizona Continue reading →

Scientists have discovered how an unusual protein helps a cell bypass damage when making new DNA, thereby averting the cell’s self-destruction.

But they also discovered that this protein, an enzyme called Dpo4, often makes errors when copying the genomic DNA sequence that later might cause the cell to become cancerous.

The findings by researchers with Ohio State University ‘s Comprehensive Cancer Center are described in two back-to-back papers in The Journal of Biological Chemistry.

“Unrepaired DNA damage presents a big roadblock for the DNA replication machinery, which cannot go around it,” says Zucai Suo, assistant professor of biochemistry. “This damage will trigger cell death because the DNA is not replicated.

“This protein bypasses the damage and saves cells from self-destructing, but it is very error prone, which suggests that it may also play a role in cancer.”

Dpo4 is one of a family of enzymes called Y-family DNA polymerases that were first discovered about 10 years ago and are only now becoming understood.

“These enzymes provide a survival mechanism for cells,” says first author Kevin Fiala, a graduate student in Suo’s laboratory. “They allow DNA replication to continue, so the cell doesn’t die. But they don’t repair the DNA damage that exists.”

DNA damage is a routine problem for cells, Suo says. For example, every cell loses more than 10,000 DNA bases daily. Dedicated repair enzymes fix 80 percent or more of this damage, but the rest remains.

Cells use Y-family enzymes to bypass that remaining damage when making new DNA prior to cell division, thus forcing these enzymes to copy damaged DNA.

How these bypass enzymes work, however, isn’t known. The Dpo4 protein used in this research comes from a microorganism. It is relatively easy to produce in large quantities and to study, and it is similar to one of the four such enzymes found in humans.

For this research, Fiala developed a new way to sequence very short lengths of DNA. “This allowed us to pin down exactly what mistakes Dpo4 makes,” he says.

The findings reveal why the enzyme makes mistakes.

DNA resembles a spiral staircase that is made from separate halves, with half-steps protruding from each. The half-steps fit together down the center to form the complete staircase.

In DNA, the half-steps are known as the bases – the ‘A’s, ‘C’s, ‘G’s and ‘T’s – that run the length of a DNA helix. A complete step is formed by pairs of bases according to a rule: ‘A’ always pairs with ‘T,’ and ‘C’ always pairs with ‘G.’

When cells make new DNA, the two strands separate, and each old half becomes a template for a new partner. The DNA-making machinery travels along the old half, building the new half according to the bases it finds on the old half. When it meets an ‘A’ on the old half, it pairs it with a ‘T’ on the new half (and vice versa); when it meets a ‘G’ on the old half, it pairs it with a ‘C’ on the new strand. In the end, there are two complete DNA molecules instead of one, each made up of an old half and a new half.

But trouble arises during the building if one of the bases – one of the half steps – is missing. When the DNA replication machine encounters the gap, it stalls. If the standstill continues, the cell will self-destruct.

It’s at this point when Dpo4 jumps in. It adds a base opposite the gap and then leaves, allowing the DNA-making machinery to bypass the damage and continue construction.

The action averts cell suicide, but the gap – and the stop-gap base – might become a mutation that, in conjunction with later genetic damage, causes the cell to eventually become cancerous.

“The objective of this enzyme is to allow replication to continue, not to repair the damage,” says Fiala. The damage will persist, and cells might try to repair it later. But as long as DNA replication can continue, the cell survives.”

Currently, Suo’s laboratory is investigating human Y-family DNA polymerases.

Funding from a National Science Foundation Career Award Grant, an American Heart Association Predoctoral Fellowship Grant and a Herta Camerer Gross Graduate Research Fellowship supported this research.

Contact: Darrell E. Ward
Ohio State University Continue reading →

A new study in the October 31st issue of Cell, a Cell Press journal, has revealed the molecular and cellular underpinnings of one of the most common, single gene causes for learning disability in humans. The findings made in learning disabled mice offer new insight into what happens in the brain when we learn and remember.

While most previous studies have focused on the role of brain cells that excite other brain cells in the process of learning, the current results suggest that inhibitory neurons and a careful balance between excitatory and inhibitory signals may be just as essential, according to the researchers. They liken the role of those inhibitory and excitatory signals in the brain to the role of red and green stoplights in directing traffic.

” The significance of these findings is two-fold,” said Alcino Silva of the University of California, Los Angeles. “First, we have in great detail the exact mechanism for one of the most common single gene causes for learning disability known. It’s also a beachhead in our understanding of the balance between excitation and inhibition critical for learning.”

Learning disabilities are estimated to affect one in five people worldwide. “It’s a huge problem and there is little known about their causes,” Silva said.

To begin to chip away at those underlying causes for conditions that often have complex causes, Silva’s team began a hunt several years ago to unravel the mechanisms responsible for a couple of single gene disorders that lead to learning disability.

In the new study, they examined mice with learning disabilities resulting from a condition called neurofibromatosis type 1. The condition stems from a defect in the Nf1 gene encoding a protein called neurofibromin. Earlier studies showed that neurofibromin controls a “Ras/Erk” signal that is involved in long-term potentiation (LTP) and learning in mice. LTP is a process that strengthens the connections between neurons in the brain–the cellular basis for learning and memory.

Now, the researchers have found that the deficits in spatial learning experienced by mice with an abnormal version of the Nf1 gene stem from an increased release by inhibitory neurons of a chemical nerve messenger (or neurotransmitter) called GABA. GABA is the chief inhibitory neurotransmitter in the central nervous systems of mammals.

That rise in GABA leads to deficits in the plasticity of neurons required for learning and memory. Importantly, they also show that the learning deficits in the mice can be reversed with treatments that reign GABA levels back in. They also show that GABA levels normally swell when mice learn, suggesting that a balance of GABA is the key.

Silva’s team notes another recent study implicating changes in GABA inhibition in the learning deficits exhibited by an animal model of Down’s syndrome. Although learning disability – characterized by profound changes in one part of brain function – differs widely from mental retardation, that finding together with the new study suggest there may nevertheless be a common thread, Silva said.

Ultimately, these insights could lead to new ways to treat learning disabilities, although reaching that goal won’t be a simple proposition.

” It won’t be a single step from the mechanism to finding a drug,” Silva said. As with other complex disorders like cancer, he said, it will likely take years of exploration to turn scientific advances into medical applications. Nevertheless, “the more insight we have into the mechanisms responsible, the more likely it is that our treatment efforts will be effective. ”

The new study is also representative of the exciting advances in the study of neuroscience more broadly.

” We are at the beginning of a wonderful journey into how the human mind works,” Silva said. “We are developing a highly detailed view of what goes on in the brain when we learn and remember. There is nothing more inspiring; it’s what makes us who we are.”

The researchers include Yijun Cui, University of California, Los Angeles, Los Angeles, CA; Rui M. Costa, University of California, Los Angeles, Los Angeles, CA, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD; Geoffrey G. Murphy, University of California, Los Angeles, Los Angeles, CA, University of Michigan, Ann Arbor, MI; Ype Elgersma, University of California, Los Angeles, Los Angeles, CA; Erasmus MC, Rotterdam, The Netherlands; Yuan Zhu, University of Michigan Medical School, Ann Arbor, MI; David H. Gutmann, Washington University School of Medicine, St. Louis, MO; Luis F. Parada, University of Texas Southwestern Medical Center, Dallas, TX; Istvan Mody, University of California, Los Angeles, Los Angeles, CA; and Alcino J. Silva, University of California, Los Angeles, Los Angeles, CA.

Source: Cathleen Genova

Cell Press Continue reading →

A protein called RecQ takes on a totally opposite function in the bacteria Escherichia coli to the one it fulfills in yeast and in humans, indicating that people seeking to understand the role of different forms in human cells and disease need to consider both possibilities, said researchers from Baylor College of Medicine in a report in Molecular Cell.

Humans have five forms of this particular protein, and three are associated with syndromes that predispose people to cancer, said Dr. Susan Rosenberg, professor of molecular and human genetics at Baylor College of Medicine. Two of the forms are not associated with cancer syndromes.

Other organisms have forms of this protein in varying numbers, said Rosenberg. For example, E. coli has only one. All forms appear to be very similar, no matter what the organism. When proteins are found in a variety of organisms, they are called conserved.

“It was thought that because these were so well conserved, they should do more or less the same thing,” said Rosenberg. However, research in her laboratory showed this was not the case.

In yeast and one of the human forms of a protein called RecQ actually works to help unzip DNA strands when chromosomes repair DNA damage using a process called genetic recombination. In this kind of repair, one chromosome aggregates with a partner chromosome – usually its twin chromosome following DNA replication – and then disaggregates following repair. If the repair aggregates are not unzipped, the chromosomes can’t separate for reproduction. The yeast and human Werner syndrome enzymes helps prevent the buildup of unwanted intermediates of aggregated chromosomes that can actually kill the cells if not unzipped.

When that protein is lacking, the intermediates buildup and the cells die. However, while many people think all such proteins work similarly in repair, recent work by Rosenberg and others in her laboratory demonstrates that the protein works in exactly the opposite manner in E. coli.

In yeast, she said, the protein’s job is to get the two chromosomes apart. One form of the protein does this also in humans, and when this protein is mutated or missing, a premature aging and cancer-predisposition disease called Werner syndrome results. Cancer results from destabilizing the chromosomes.

“When people knock out Werner (protein), they see these intermediates piling up and the cells die from failure to resolve this,” she said.

Daniel B. Magner and Matthew D. Blankschien, both graduate students in Rosenberg’s laboratory, found that Eli/RecQ promotes the accumulation of these intermediates, actually promoting the cell’s death by this method.

When scientists begin considering the possible of effects of other relatives of RecQ in humans and other organisms, they should be aware of this finding and consider both possibilities when seeking to link mutations in the protein to disease, said Rosenberg.

Others who took part in the research include: Drs. Jennifer a. Lee, Jeanine M. Pennington and James R. Lupski, all of BCM.

Support for this work came from the U.S. Department of Defense Breast Cancer Research Program, the Baylor College of Medicine Mental Retardation Research Center and National Institutes of Health.

Click here for a summary of the article

Contact: Graciela Gutierrez

Baylor College of Medicine Continue reading →

A team of scientists at Cold Spring Harbor Laboratory (CSHL) has determined a hierarchical set of criteria that explain how the molecular precursors of gene-regulating small RNAs are sorted by the cellular machinery.

Led by Benjamin Czech, a group working in the laboratory of CSHL Professor Gregory Hannon posed the question: can distinct patterns be observed in the process that unfolds when double-stranded RNAs enter the RNAi pathway? Shorthand for RNA interference, RNAi is a biological response to double-stranded RNA that can culminate in the regulation of gene expression. It has been observed in a vast range of organisms ranging from plants to worms to flies to man.

An enzyme called Dicer cuts double-stranded RNAs into smaller double-stranded pieces called duplexes. Czech, Hannon and colleagues propose rules governing the next step in the RNAi pathway, in which duplexes are sorted to proteins called Argonautes which are at the core of a molecular complex called RISC (the RNA-Induced Silencing Complex).

“Only one strand of each duplex is chosen,” explains Czech, “and which one makes all the difference. In the fruit flies that we used as models for this series of experiments, the selection of one or another strand effectively determines whether the short RNA will seek out and regulate a gene, or whether it will perform another function such as protecting a cell against a viral invader.”

The rules determining how a duplex is processed and sorted are discussed in a paper the team published recently in Molecular Cell. These include the overall arrangement of the nucleotides in the duplex; how many bases are paired; where they’re paired and unpaired; and how tightly the ends of the duplex are stuck together.

“These rules for sorting are important for two reasons,” according to Hannon, who is also an Investigator of the Howard Hughes Medical Institute. “One is that since small RNAs play critical biological roles in nearly every process, understanding which strands of the small RNAs entering RISC act as regulators of gene expression is critical for our fundamental understanding.

“The rules are also important because scientists are hoping to use small RNAs one day as therapeutics. By understanding the rules by which small RNAs are processed and sorted, we move closer to the goal of being able to manipulate the RNAi pathway, bend it to the purpose of addressing disease.”

“Hierarchical Rules for Argonaute Loading in Drosophila” appeared in Molecular Cell, Vol. 36, No. 3. The authors are: Benjamin Czech, Rui Zhou, Yaniv Erlich, Julius Brennecke, Richard Binari, Christians Villalta, Assaf gordon, Norbert Perrimon and Gregory J. Hannon.

Source: Peter Tarr

Cold Spring Harbor Laboratory Continue reading →

Calculating individual genetic cancer risk and taking age into account could mean fewer women would need to be screened for breast cancer, according to research published in the British Journal of Cancer1, today (Wednesday).

Based on work funded by Cancer Research UK and the European Community (COGS project), researchers say this new screening concept would still detect the same number of cancers but could also potentially reduce some of the risks associated with screening – such as false positives and subsequent anxiety – as well as saving the NHS money.

The researchers used a statistical model to compare a hypothetical age based screening programme and the number of cancers potentially detected with how many cancers would be detected if people were invited to screening based on their genetic risk of cancer as well as their age.

In England almost 31,000 cases of breast cancer are diagnosed in women aged 35 to 79. Screening all women between 47 and 79 – in a hypothetical age based screening programme – means 65 per cent of women aged 35 to 79 would be screened. And, if all women went for screening and the test was 100 per cent perfect, 85 per cent of cancers diagnosed in the 35 to 79 age group would potentially be detected.

But by using a genetic test to identify women at a higher risk of breast cancer the researchers found that the number of women screened could be reduced without reducing the number of cancers detected by screening2.

In theory, it could mean that fewer women would be screened and has the potential to reduce some of the risks linked with screening such as over diagnosis and overtreatment3.

Lead author Dr Nora Pashayan of the PHG Foundation and Cancer Research UK training Fellow, said: “This is an alternative approach to the existing screening programme and might even have the potential to reduce over-diagnosis, and in turn, lower costs.

“For our model to be used women would need to have a genetic test before the age of 35. This would be a simple blood test to identify genetic risk and, depending on the results, the age at which they should be invited for screening could be calculated. For some women this would be when they’re 35, for others not until they’re in their 50s or 60s or even later.

“This approach means that screening women at high risk of the disease when they are younger will pick up some cancers earlier. These cancers tend to be more aggressive so the earlier they are picked up the better.

“And as more genetic information becomes available, the efficiency of screening approach that takes account of genetic risk will further improve”.

The researchers also calculated a statistical model of how a similar approach might be relevant to prostate cancer screening if a programme were to be introduced in the UK.

Professor Paul Pharaoh, a Cancer Research UK expert in genetics and study author, said: “Even though our analysis is based on a theoretical model which assumes that there’s a 100 per cent attendance for breast cancer screening it still shows that personalised screening has the potential to reduce the disadvantages of a screening programme without losing any of its benefits. We now need more research to find out what effect genetic testing would have on over-diagnosis and whether deaths from breast cancer would fall. And we also need to consider the wider ethical and legal issues with more personalised screening”.

Reference

1. Polygenic susceptibility to prostate and breast cancer: implications for personalised screening N Pashayan, S W Duffy, S Chowdhury, T Dent, H Burton, D E Neal, D F Easton, R Eeles, P Pharoah
British Journal of Cancer doi:10.1038/bjc.2011.118

Notes

2. This model can be adapted to explore different outcomes depending on the risk threshold. As you increase the risk threshold, fewer women would be screened but a higher proportion of cancers would be detected within this group as women with higher risk are being screened;

- Screening depending on risk threshold of 2 per cent: 2 per cent fewer women would be screened and the same number of cancer cases would be detected.

- Screening depending on risk threshold of 2.02 per cent: the same number of women would be screened as the age based screening programme but the number of screen detected cases would be 1 per cent greater.

- Screening depending on a risk threshold of 2.5 per cent: leads to screening 50 per cent of women aged 35- 79 years old with 73 per cent of cases detected. This means a larger proportion of women from a smaller age range will be detected by screening.

With more knowledge about different gene types less women would need to be screened.

3. This method was based on a hypothetical screening scenario screening women from 35 to 79 and should not be compared to the current NHS national screening programme because the researchers have assumed that 100 per cent of women will attend screening and all possible cancers will be identified to simplify the calculations.

In England almost 31,000 cases of breast cancer are diagnosed in women aged 35 to 79.
In the UK in 2008 almost 47,700 women were diagnosed with breast cancer
In 2008 in the UK around 12,000 women and around 70 men died from breast cancer.

Source:

Cancer Research UK Continue reading →

Illumina, Inc. (NASDAQ:ILMN) announced that it has delivered Hermann Hauser’s genome sequence. Dr. Hauser, Partner, Amadeus Capital Partners Ltd, is the first consumer to purchase Illumina’s individual genome sequencing service working with his physician, Michael Nova, MD, of Pathway Genomics. The genome was completed in Illumina’s CLIA-certified and College of American Pathologists (CAP) accredited laboratory using the Genome Analyzer technology. Over 110 billion base calls were generated, delivering over 30X coverage of the genome. Data analysis showed 300K novel SNPs in the genome that have not been documented elsewhere. This discovery demonstrates the power of whole genome sequencing as an exploratory tool, as these SNPs were novel but not necessarily unique.

“We are very excited to be delivering our first individual genome sequence to Hermann Hauser,” said Jay Flatley, President and CEO of Illumina. This is a landmark since just two months ago we launched the availability of this service from Illumina. The experience we created for Hermann was not only one of personal genetic exploration, but one that points to a future where genome sequencing will become a routine practice and the information generated will enable physicians to make better healthcare decisions for the individual. This information has long term value for Hermann as he can continue to access it and gain personal genomic insights as new discoveries are made.

Dr. Hauser’s genome was delivered by a team consisting of his physician, Dr. Michael Nova, a bioinformatics specialist and geneticist at Illumina’s San Diego headquarters on Thursday, August 20, 2009. The visit included a consultation, facility tour and ceremony during which Dr. Hauser’s genome was delivered on an iMac® computer using GenomeStudio® software as a genome browsing interface.

Hermann Hauser is one of the first of a small, select group of individuals who have had their genome sequenced. “Going through Illumina’s process was very exciting for me personally. I am looking forward to the information on gene variants that will give my doctors guidance on effective treatments and drug dosage based on pharmacogenetic information, for any future medical condition I may develop. This is the beginning of personalized medicine and I am delighted to be there at the start of it. As an early investor in the gene sequencing technology used in this work, I am proud that Illumina has introduced this service to consumers. It fulfills an early dream to substantially reduce the cost of whole genome sequencing,” said Hauser.

Dr. Hauser is a pioneer member of a growing community that is driving education and exchange of information for those who have had their genomes sequenced. As more information becomes available, participants will be in a position to mine their personal genome sequence data to understand their identity in ways which have never been possible before. For more information about Illumina’s individual genome sequencing service, please visit everygenome.

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