Nanoparticles connected to antibodies are luminescent in two spectral ranges. This makes it possible

 to check the homogeneous occupation of the sensor electrode. (Credit: Fraunhofer ISC/Ingo Peters)



Fraunhofer-Gesellschaft, February 9, 2010  —  The earlier the doctor finds the tumor, the better the patient’s chances of recovery. A new testing method aims to detect the disease in its initial stages. The technology is based on a microfluidic chip with tiny channels in which a blood sample from the patient circulates. The chip traces marker proteins which are indicative of cancer. The measured concentration of the tumor marker in the blood will help doctors to diagnose the disease at an early stage.

Similar testing systems already exist but their measurements are not very precise and they can only detect molecules that are present in the blood in large quantities. What’s more, the tests have to be carried out in a laboratory, which is time-consuming and costly.

A project funded by the German Ministry of Education and Research and coordinated by the Fraunhofer FIT aims to improve matters. Biofunctionalized nanoparticles developed by research scientists at the Fraunhofer Institute for Silicate Research ISC in Würzburg are the key element in the new sensor. “We have improved the detection limit compared with the present state of the art by a factor of one hundred,” explains Dr. Jörn Probst, Head of the Business Unit Life Science at the ISC. “Whereas previously a hundred molecules were needed in a certain quantity of blood to detect tumor markers, we now need only one. This means that diseases can be diagnosed much earlier than with present methods.”

But how does the biosensor integrated in the chip register the few biomolecules swimming around in the blood that are indicative of a certain disease? “We have placed antibody-occupied nanoparticles on the sensor electrode which fish out the relevant proteins. For this purpose, we repeatedly pump the blood across the electrode surface. As with a river, the flow is fastest in mid-channel and the water runs more slowly near the bank. We have therefore made a sort of fishing rod using nanoparticles which registers the antibodies in the middle of the blood flow where most proteins swim by per unit of time.« If an antibody catches the matching protein, a tumor marker, the electrical charge distribution shifts and this is picked up by the electrode.”

The researcher groups are now developing a first demonstrator combining four independent single-molecule-sensitive biosensors. The experts are also working on the simultaneous detection of several tumor markers, which will increase the clarity of tests. The system will be ready to enter the market in a few years’ time.

Source: Fraunhofer-Gesellschaft  —

Scientists announced they have identified for the first time definitive variants associated with biological ageing in humans. (Credit: iStockphoto/Anne De Haas), February 9, 2010  —  Scientists announced they have identified for the first time definitive variants associated with biological ageing in humans. The team analyzed more than 500,000 genetic variations across the entire human genome to identify the variants which are located near a gene called TERC.

The study in Nature Genetics published by researchers from the University of Leicester and King’s College London, working with University of Groningen in the Netherlands, was funded by The Wellcome Trust and the British Heart Foundation.

British Heart Foundation Professor of Cardiology at the University of Leicester Professor Nilesh Samani, of the Department of Cardiovascular Sciences, who co-led the project explained that there are two forms of ageing — chronological ageing i.e. how old you are in years and biological ageing whereby the cells of some individuals are older (or younger) than suggested by their actual age.

He said: “There is accumulating evidence that the risk of age-associated diseases including heart disease and some types of cancers are more closely related to biological rather than chronological age.

“What we studied are structures called telomeres which are parts of one’s chromosomes. Individuals are born with telomeres of certain length and in many cells telomeres shorten as the cells divide and age. Telomere length is therefore considered a marker of biological ageing.

“In this study what we found was that those individuals carrying a particular genetic variant had shorter telomeres i.e. looked biologically older. Given the association of shorter telomeres with age-associated diseases, the finding raises the question whether individuals carrying the variant are at greater risk of developing such diseases”

Professor Tim Spector from King’s College London and director of the TwinsUK study, who co-led this project, added:

“The variants identified lies near a gene called TERC which is already known to play an important role in maintaining telomere length. What our study suggests is that some people are genetically programmed to age at a faster rate. The effect was quite considerable in those with the variant, equivalent to between 3-4 years of ‘biological aging” as measured by telomere length loss. Alternatively genetically susceptible people may age even faster when exposed to proven ‘bad’ environments for telomeres like smoking, obesity or lack of exercise — and end up several years biologically older or succumbing to more age-related diseases. ”

The paper, was published online in Nature Genetics on 07 February 2010.

Read more about genes and aging……………, January/February 2010  —  A team of researchers, at Washington University School of Medicine, St Louis, has identified a group of 12 genetic variants in the HSPB7 gene that is associated with heart failure in humans.

The research is reported in the Journal of Clinical Investigation.

The team, led by Gerald Dorn, used an approach they have recently developed that allows ultra-high-throughput targeted DNA sequencing to identify genetic variation in four genes with biological relevance to heart failure. They identified in a large group of Caucasian individuals with heart failure, 129 separate genetic variants in the four genes, including 23 that seemed to be novel.

Further analysis of 1117 Caucasian individuals with heart failure and 625 nonaffected Caucasians indicated that a block of 12 genetic variants in the HSPB7 gene was associated with heart failure. Confirmation of this association was provided by analysis of an independent group of individuals.

The authors hope to use the same approach to identify further genetic variants associated with heart failure, a disease that is influenced by multiple genetic factors.

Source: Adapted from materials provided by Journal of Clinical Investigation,

Read more about genes, ageing and disease…………………..  (Academy of Finland)  —  Finnish Academy Professors Lauri Aaltonen and Jussi Taipale have identified and described a mechanism whereby a single-base change in the human genome increases the risk of colorectal cancer.

The focus in this study was on a common single-base variant occurring in chromosome 8, which in itself causes only a slightly increased risk of cancer. However, the risk allele is carried by 75% of people of European origin and by almost 100% of African populations.

The high frequency of the gene variant makes it a very common cause of cancer at the population level. At the individual level, however, the variant does not cause significant disease predisposition because that can often be considerably reduced by lifestyle changes. Colorectal cancer is the third most common cancer worldwide and a major cause of cancer mortality.

Mutation mechanisms activate pathways regulating cancer

The variant that increases the risk of colorectal cancer was found to be located in a regulatory region, where it changes the function of a key regulatory element important for the development of colorectal cancer. The scientists showed that the risk allele strengthens the binding of a regulatory factor in cancer cells, which activates pathways that are central to the development of cancer. The impacts of this altered genetic regulation on cell division are probably mediated via the MYC cancer gene, which is one of the best known accelerator genes in cancer.

Single-base changes are the most common type of variation found in the human genome. Genome-wide studies of interindividual differences in common variants can be studied using DNA chip technology, which has greatly facilitated efforts to understand the genetic basis of multifactorial diseases. To date, scientists have identified more than 400 variants in the human genome that are associated with an increased risk of common diseases, such as cancer, diabetes and cardiovascular diseases.

Multidisciplinary research

The findings of this research lend support to the theory that human disease susceptibility is explained in part by differences in regulatory regions of the genome, and in gene expression. A closer understanding of the biological mechanisms involved will help to clarify the aetiology of colorectal cancer and pave the way to more effective cancer prevention. Apart from hereditary tumor predisposition, another area of major strength for Finnish research is gene regulation. It was hardly surprising therefore that Aaltonen’s and Taipale’s research teams found each other so easily. The research project supervised by Aaltonen and Taipale involved molecular biologists, medical doctors and data processing researchers from Finland and the UK. For instance, the project made use of the EEL software developed by Professor Esko Ukkonen and his team at the CoE for Algorithmic Data Analysis.

The research was funded by the Academy of Finland, the European Union, the Sigrid Juselius Foundation and the Cancer Foundation.

The results of the study was published in the journal Nature Genetics. DOI 10.1038/ng.406

Using a new method, scientists reprogram adult cells to develop into myriad cell types,, February 9, 2010, by Robert Preidt  —  Scientists say they’ve developed a new and easier way to create what’s known as pluripotent stem cells — cells that can develop into one of many cell types for use in regenerative medicine.

Unlike many other methods, this new technique doesn’t use viruses to introduce genes into cells or permanently alter a cell’s genome. Instead, tiny circles of DNA are used to transform stem cells taken from human fat into induced pluripotent stem cells, which are the starting point for research into many human diseases.

This is the first time that adult (non-embryonic) stem cells have been reprogrammed this way and it could be an important advance toward the use of such cells in humans, according to the Stanford University School of Medicine researchers.

“This technique is not only safer, it’s relatively simple,” study co-author Dr. Michael Longaker, a professor of surgery and deputy director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, said in a Stanford news release. “It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine.”

The researchers plan to create pluripotent stem cells to learn more about, and perhaps some day treat, human heart disease.

“Imagine doing a fat or skin biopsy from a member of a family with heart problems, reprogramming the cells to pluripotency and then making cardiac cells to study in a laboratory dish. This would be much easier and less invasive than taking cell samples from a patient’s heart,” study senior author Dr. Joseph Wu, an assistant professor of cardiology and radiology and a member of Stanford’s Cardiovascular Institute, said in the news release.

The study was published online Feb. 7 in the journal Nature Methods.

More information

The U.S. National Institutes of Health has more about stem cells.

Stanford University School of Medicine, February 9, 2010  —  Tiny circles of DNA are the key to a new and easier way to transform stem cells from human fat into induced pluripotent stem cells for use in regenerative medicine, say scientists at the Stanford University School of Medicine. Unlike other commonly used techniques, the method, which is based on standard molecular biology practices, does not use viruses to introduce genes into the cells or permanently alter a cell’s genome.

It is the first example of reprogramming adult cells to pluripotency in this manner, and is hailed by the researchers as a major step toward the use of such cells in humans. They hope that the ease of the technique and its relative safety will smooth its way through the necessary FDA approval process.

“This technique is not only safer, it’s relatively simple,” said Stanford surgery professor Michael Longaker, MD, and co-author of the paper. “It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine.”

The Stanford researchers used the so-called minicircles — rings of DNA about one-half the size of those usually used to reprogram cell — to induce pluripotency in stem cells from human fat. Pluripotent cells can then be induced to become many different specialized cell types. Although the researchers plan to first use these cells to better understand — and perhaps one day treat-human heart disease, induced pluripotent stem cells, or iPS cells, are a starting point for research on many human diseases.

“Imagine doing a fat or skin biopsy from a member of a family with heart problems, reprogramming the cells to pluripotency and then making cardiac cells to study in a laboratory dish,” said cardiologist Joseph Wu, MD, PhD. “This would be much easier and less invasive than taking cell samples from a patient’s heart.” Wu is the senior author of the research, which will be published online Feb. 7 in Nature Methods. Research assistant Fangjun Jia, PhD is the lead author of the work.

Longaker is the deputy director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and director of children’s surgical research at Lucile Packard Children’s Hospital. Wu is an assistant professor of cardiology and of radiology, and a member of Stanford’s Cardiovascular Institute. A third author, Mark Kay, MD, PhD, is the Dennis Farrey Family Professor in Pediatrics and professor of genetics.

The finding brings together disparate areas of Stanford research. Kay’s laboratory invented the minicircles several years ago in a quest to develop suitable gene therapy techniques. At the same time, Longaker was discovering the unusual prevalence and developmental flexibility of stem cells from human fat. Meanwhile, Wu was searching for ways to create patient-specific cell lines to study some of the common, yet devastating, heart problems he was seeing in the clinic.

“About three years ago Mark gave a talk and I asked him if we could use minicircles for cardiac gene therapy,” said Wu. “And then it clicked for me, that we should also be able to use them for non-viral reprogramming of adult cells.”

The minicircle reprogramming vector works so well because it is made of only the four genes needed to reprogram the cells (plus a gene for a green fluorescent protein to track minicircle-containing cells). Unlike the larger, more commonly used DNA circles called plasmids, the minicircles contain no bacterial DNA, meaning that the cells containing the minicircles are less likely than plasmids to be perceived as foreign by the body. The expression of minicircle genes is also more robust, and the smaller size of the minicircles allows them to enter the cells more easily than the larger plasmids. Finally, because they don’t replicate they are naturally lost as the cells divide, rather than hanging around to potentially muck up any subsequent therapeutic applications.

The researchers chose to test the reprogramming efficiency of the minicircles in stem cells from human fat because previous work in Wu and Longaker’s lab has shown that the cells are numerous, easy to isolate and amenable to the iPS transformation, probably because of the naturally higher levels of expression of some reprogramming genes. They found that about 10.8 percent of the stem cells took up the minicircles and expressed the green fluorescent protein, or GFP, versus about 2.7 percent of cells treated with a more traditional DNA plasmid.

When the researchers isolated the GFP-expressing cells and grew them in a laboratory dish, they found that the minicircles were gradually lost over a period of four weeks. To be sure the cells got a good dose of the genes, they reapplied the minicircles at days four and six. After 14 to 16 days, they began to observe clusters of cells resembling embryonic stem cell colonies — some of which no longer expressed GFP.

They isolated these GFP-free clusters and found that they exhibited all of the hallmarks of induced pluripotent cells: they expressed embryonic stem cell genes, they had similar patterns of DNA methylation, they could become multiple types of cells and they could form tumors called teratomas when injected under the skin of laboratory mice. They also confirmed that the minicircles had truly been lost and had not integrated into the stem cells’ DNA.

Altogether, the researchers were able to make 22 new iPS cell lines from adult human adipose stem cells and adult human fibroblasts. Although the overall reprogramming efficiency of the minicircle method is lower than that of methods using viral vectors to introduce the genes (about 0.005 percent vs. about 0.01-0.05 percent, respectively), it still surpasses that of using conventional bacterial-based plasmids. Furthermore, stem cells from fat, and, for that matter, fat itself, are so prevalent that a slight reduction in efficiency should be easily overcome.

“This is a great example of collaboration,” said Longaker. “This discovery represents research from four different departments: pediatrics, surgery, cardiology and radiology. We were all doing our own things, and it wasn’t until we focused on cross-applications of our research that we realized the potential.”

“We knew minicircles worked better than plasmids for gene therapy,” agreed Kay, “but it wasn’t until I started talking to stem cell people like Joe and Mike that we started thinking of using minicircles for this purpose. Now it’s kind of like ‘why didn’t we think of this sooner?'”

In addition to Longaker, Wu, Kay and Jia, other Stanford researchers involved in the work include Kitchener Wilson, MD; Ning Sun, PhD; Deepak Gupta, MD; Mei Huang, PhD; Zongjin Li, MD, PhD; Nicholas Panetta, MD; Zhi Ying Chen, PhD; and Robert Robbins, MD.

The research was supported by the Mallinckrodt Foundation, the National Institutes of Health, the Burroughs Wellcome Foundation, the American Heart Association, the California Institute for Regenerative Medicine, the Oak Foundation and the Hagey Laboratory for Pediatric Regenerative Medicine., January/February 2010  —  Medicines commonly used to treat high blood pressure and heart disease may cut the risk of developing Alzheimer’s disease and dementia, U.S. scientists said on Wednesday.

Researchers from Boston found that older people taking a certain type of blood pressure medication known as angiotensin receptor blockers (ARBs) were significantly less likely to develop the brain-wasting illnesses.

Dementia affects some 35 million people around the world and the number of cases — and their impact on health policy and the economic and social costs of healthcare — is set to grow dramatically as populations age.

Despite decades of research, doctors still have few effective weapons against dementia and experts commenting on the latest study said it could have major implications.

Alzheimer’s Disease International predicts the number of dementia sufferers globally will almost double every 20 years — to 66 million in 2030 and more than 115 million in 2050 — with much of the rise coming in poorer nations.

The study, led by Benjamin Wolozin from Boston University School of Medicine, looked at the incidence of dementia in 800,000 mostly male patients in the United States from 2002 to 2006. They all had heart disease and were 65 or older.

One group was using ARBs, another was taking a different type of the blood pressure lowering drug, an ACE inhibitor called lisinopril, and a third was on other heart medications.

The results, published in the British Medical Journal, show that those taking ARBs were significantly less likely to develop Alzheimer’s disease or dementia, Wolozin said.

High blood pressure is a known risk factor for vascular dementia, where brain function is damaged by a series of small strokes.

Diovan, or valsartan, made by Swiss drug firm Novartis, and Atacand, or candesartan, made by the Anglo-Swedish firm AstraZeneca, are two of the biggest selling ARB medicines.

The team also found that ARBs have an added effect when combined with angiotensin-converting enzyme (ACE) inhibitors in patients who had already developed Alzheimer’s or dementia. Those taking both drugs were less likely to die early or be admitted to nursing homes.

“The public health implications of finding an effective way of preventing dementia are immense,” said Colleen Maxwell and David Hogan, experts in geriatric medicine at the University of Calgary, Canada, who wrote a commentary on the study.

But they said further work was needed to verify whether blood pressure drugs, and ARBs in particular, could help.

Previous studies have suggested that taking steps to stave off heart disease and diabetes may also improve the chances of avoiding dementia and Alzheimer’s.

Research found that people who take cholesterol-lowering drugs known as statins have a lower risk of developing all forms of dementia. And diabetics who take pills that help their bodies use insulin better have a lower risk of Alzheimer’s

Two patients with rare lesions to the brain have provided direct of evidence of how we make decisions — and what makes us dislike the thought of losing money. (Credit: iStockphoto)



California Institute of Technology, February 9, 2010  —  Two patients with rare lesions to the brain have provided direct of evidence of how we make decisions — and what makes us dislike the thought of losing money.

Researchers at the California Institute of Technology studied a phenomenon known as ‘loss aversion’ in two patients with lesions to the amygdala, a region deep within the brain involved in emotions and decision-making. The results of the study, part-funded by the Wellcome Trust, are published February 8 in the journal Proceedings of the National Academy of Sciences.

Loss aversion describes the avoidance of choices which can lead to losses, even when accompanied by equal or much larger gains. Examples in the everyday life include how we make a decision on whether to proceed with an operation: the more serious the potential complications from the operation — even if the risk is low compared to the chances of success — the less likely we would be to proceed. It even has implications on organ donation rates — if people are required to ‘opt-in’ to a system, they are less likely to move away from the default option.

Dr Benedetto De Martino, a Sir Henry Wellcome Trust Postdoctoral Fellow and first author of the report, explains: “Imagine you’re on Who Wants to Be a Millionaire. You’ve just answered the £500,000 question correctly and have moved on to the final question. You’re down to your 50:50 lifeline but don’t know the answer. If you get it right, you’ll win £1 million; if you get it wrong, you’ll drop back to £32,000. The vast majority of people would take the ‘loss averse option’ and walk away with £500,000.”

This new study has explored whether loss aversion is mediated by the amygdala, as is currently hypothesised. The researchers studied two patients affected by a rare genetic condition which has led to the formation of lesions to the amygdala. These lesions prevent the patients from perceiving, recognising or feeling fear. For example, the patients can recognise all other emotions in a person’s face, but if shown a fearful face they cannot say what emotion that person is experiencing.

Each patient — together with twelve ‘healthy’ controls — took part in a task designed to test whether the chance of losing money affected people’s likelihood to gamble

At the beginning of the experiment, each participant was given $50 with which to gamble on the outcome of flipping a coin, which carries a 50:50 chance of winning (or losing). However, each time, the amount that the volunteers could win or lose varied. For example, one time they might stand to win $50 or lose $20 depending on the outcome. The second time, they might stand to win $30 or lose $40.

The researchers found that, as expected, the healthy individuals were less likely to gamble when the difference between the potential winnings and potential losses was smaller — for example, whilst they might gamble if they stood to win $50 but lose only $10, they would be less likely to gamble if they stood to win only $20 but lose $15. When the potential losses outweighed the potential gains, the controls would not gamble.

However, the two patients with impaired amygdala activity were much less affected by the disparity between potential gains and losses; occasionally, even when the potential losses outweighed the potential gains they would choose to gamble, showing a lack of loss aversion.

“A fully-functioning amygdala appears to make us more cautious,” explains Ralph Adolphs, the Bren Professor of Psychology and Neuroscience. “We already know that the amygdala is involved in processing fear, and it also appears to make us ‘afraid’ to risk losing money.”

“It may be that the amygdala controls a very general biological mechanism for inhibiting risky behaviour when outcomes are potentially negative, such as the monetary loss aversion which shapes our everyday financial decisions,” comments Dr De Martino, a visiting researcher from UCL (University College London).

“Loss aversion has been observed in many economic studies, from monkeys trading tokens for food to people on high-stakes game shows,” adds Colin Camerer, the Robert Kirby Professor of Behavioral Economics, “but this is the first clear evidence of a special brain structure which is responsible for fear of those losses.”

Dr De Martino and colleagues also investigated whether, as well as being ‘loss averse’, the patients were also ‘risk averse’. Risk aversion and loss aversion are two similar, but not identical, processes and as such can be easily confused. People who are ‘risk averse’ are less likely to take chances even when they do not stand to lose anything.

The volunteers were again asked to make a decision based on the outcome of a coin toss. However, in this situation, the options were either to take a set amount without gambling (for example, $5), or gamble with a chance of winning $10 or receiving nothing but not losses were involved. In this experiment, both patients and controls showed little difference in their decisions, suggesting that the amygdala goes not control this aspect of risk taking.

The research was supported by the Gordon and Betty Moore Foundation, the Human Frontier Science Program, the Wellcome Trust, the National Institutes of Health, the Simons Foundation, and a global Center of Excellence grant from the Japanese government.


Read more about regions of the brain and how/what they influence……………….

A piece of the brain’s hypothalamus (shown in middle of the above model) is key to animals’ fear of territorial rivals and predators, according to a new study. Without it, animals lose all sense of caution. (Credit: iStockphoto/Karen Roach)

University of Southern California  —  Mice lose their fear of territorial rivals when a tiny piece of their brain is neutralized, a study reports.

The study adds to evidence that primal fear responses do not depend on the amygdala – long a favored region of fear researchers – but on an obscure corner of the primeval brain.

A group of neuroscientists led by Larry Swanson of the University of Southern California studied the brain activity of rats and mice exposed to cats, or to rival rodents defending their territory.

Both experiences activated neurons in the dorsal premammillary nucleus, part of an ancient brain region called the hypothalamus.

Swanson’s group then made tiny lesions in the same area. Those rodents behaved far differently.

“These animals are not afraid of a predator,” Swanson said. “It’s almost like they go up and shake hands with a predator.”

Lost fear of cats in rodents with such lesions has been observed before. More important for studies of social interaction, the study replicated the finding for male rats that wandered into another male’s territory.

Instead of adopting the usual passive pose, the intruder frequently stood upright and boxed with the resident male, avoided exposing his neck and back, and came back for more even when losing.

“It’s amazing that these lesions appear to abolish innate fear responses,” said Swanson, who added: “The same basic circuitry is found in primates and people that we find in rats and mice.”

The study was published in Proceedings of the National Academy of Sciences.

Swanson predicted that his group’s findings would shift some research away from the amygdala, a major target of fear studies for the past 30 years.

“This is a new perspective on what part of the brain controls fear,” he said.

He explained that most amygdala studies have focused on a different type of fear, which might more accurately be called caution or risk aversion.

In those studies, animals receive an electric shock to their feet. When placed in the same environment a few days later, they display caution and increased activity of the amygdala.

But the emotion experienced in that case may differ from the response to a physical attack.

“We’re not just dealing with one system that controls all fear,” Swanson said.

Swanson and collaborators have been studying the role of the hypothalamus in the fear response since 1992.

Because of its role in basic survival functions such as feeding, reproduction and the sleep-wake cycle, the hypothalamus seems a plausible candidate for fear studies.

Yet, said Swanson, “nobody’s paid any attention to it.”

The PNAS study is the most recent of several by Swanson on fear and the hypothalamus. The few other researchers in the area include Newton Canteras of the University of Sao Paulo in Brazil, who collaborated with Swanson on the PNAS study, as well as Robert and Caroline Blanchard of the University of Hawaii.

The other authors on the PNAS study were Simone Motta, Marina Goto, Flavia Gouveia and Marcus Baldo, all from the University of Sao Paulo.

The Brazilian government funded the study.  Story Source:  Adapted from materials provided by University of Southern California,