Genome project


The United States National Cancer Institute (NCI) and the US National Human Genome Research Institute (NHGRI), have announced another two of the components of The Cancer Genome Atlas (TCGA) Pilot Project, a three-year, US$100 million collaboration to test the feasibility of using largescale genome analysis technologies to identify important genetic changes involved in cancer.

Lung, brain (glioblastoma), and ovarian cancers have been chosen as the tumours for study by TCGA Pilot Project. Five Cancer Genome Characterization Centers (CGCCs) in the US will work as a network, with each centre using advanced genome analysis technologies to identify major changes in the genomes of the cancers chosen for the TCGA pilot programme.

TCGA was launched in December 2005. When fully operational, it will consist of four integrated components: the CGCCs and the Data Coordinating Center, as well as the Biospecimen Core Resource, and the Genome Sequencing Centers, which will be selected in the near future.

“We are, today, gaining new insights into the genetic changes that accumulate over a lifetime and are associated with malignancy,” said John E Niederhuber, MD, NCI director. “TCGA holds the potential to help turn what we know into what we can harness – to be able to study changes in a patient’s genetic sequence over time and then use that information to design highly targeted, individually based interventions.” “The Cancer Genome Atlas Pilot Project will generate large quantities of data that will require an immense amount of expertise and coordination,” said Francis S Collins, MD, PhD, NHGRI director.

“The Data Coordinating Center is an essential component of The Cancer Genome Atlas Pilot Project and will help researchers take advantage of the molecular information describing the genomic changes in the cancers studied. The integration of these data will enable individual researchers throughout the world to discover new cancer targets and inform the design of a new generation of cancer drugs.”



New 3D imaging

Researchers from Umeå University in Sweden have discovered a new method for 3D imaging and quantification of biological preparations 10 times larger than the limit for the traditional confocal microscope. The research is published in the journal Nature Methods.

The study describes an elaboration of the technology for optical projection tomography (OPT) that the two former researchers helped describe in the journal Science four years ago. The scientists have combined improvements in sample processing and tomographic data processing to develop a new method that make it possible to create 3D images of specifically dyed preparation that are one centimetre in size, of organs from adult mice and rats, for example.

The authors describe how the new method can be used to automatically measure the number and volume of specifically dyed structures in large biological preparations. The technique requires no specially developed biological marker substances; instead, it makes use of antibodies that are in routine use in many research laboratories. The researchers project that it will be possible to use their method to address a great number of medical and biological issues.

This may include such diverse fields as the formation of blood vessels in tumor models, the analysis of biopsies taken from patients (in cirrhosis of the liver, for instance), and autoimmune infiltration processes.



Boost for diagnostics

World leaders in the field of diagnostics assembled at Dublin City University in mid December to participate in the launch of the Biomedical Diagnostics Institute.

The Biomedical Diagnostics Institute (BDI) is a unique industrial-clinical-academic research collaboration focused on the development of next generation biomedical diagnostic devices for use in the home or at the Point-of-Care.

These advanced devices will enable the detection of life-threatening events long before the critical stage is reached – thus improving people’s lives and enhancing the efficiency of our healthcare system. Research is being carried out to exploit “markers” in blood, breath and saliva that will give these early warnings in illnesses like cancer, heart disease and diabetes, with “exquisite accuracy” according to Professor Brian MacCraith, director of the BDI. The integration of fundamental and applied research, from the wide-ranging scientific and engineering disciplines required, into working device demonstrators is a unique feature of the BDI.

The BDI brings together key academic researchers, led and hosted by Dublin City University, including the Royal College Surgeons Ireland, National University Ireland Galway and University College Cork; six industrial partners, Amic, Analog Devices, Becton Dickinson, Enfer Scientific, Hospira, and Inverness Medical Innovations/Unipath, as well as the clinical environment, to form an integrated, cohesive, multi-disciplinary team of more than 70 people.



Human genome revelation

More than 10% of the human genome might be different among humans. This difference can hold the key for differences in the predisposition to common disease and different response to treatment Five years after the publication of the initial sequence of the human genome, it has been uncovered that this sequence is not identical among different individuals and that the existing variability is ten times greater than it was supposed in the initial studies.

Up to now it was thought that each person differed from another in a million of the more than 3 billion nucleotides (the letters in which information is encrypted in the genome sequence: A, C, G and T) that compose the human genome. A study carried out by a Consortium of American, Spanish, Canadian, British and Japanese investigators has revealed that any two people differ in more than 20 million nucleotides, that are grouped in at least 1,400 discrete regions of the genome.

The difference between one person and another is not in the sequence itself but in a varying number of copies. Those regions, that are termed “Copy Number Variants” or CNVs, suppose more than 360 million differences with respect to the original sequence published in early 2003 by the International Human Genome Project Consortium. The study of the structural variation of the human genome was due to be published in the 23 November, 2006 issue of Nature.

This research, carried out in samples coming from individuals of Asian, African and European ancestry, represents the most exhaustive study of large-scale variability thus far published, after the definition of the reference sequence of the human genome and the study of nucleotide diversity HapMap), published in Nature at the end of 2005. The work clearly shows that it does not exist as a unique sequence of the human genome, but a plethora of different sequences.

The 1,400 variable regions reported do indeed contain genes, besides of other functional structures, and many of them correspond to regions involved in human diseases, such as muscular dystrophies, renal and many other developmental disorders. Besides, the regions that have been detected do contain variants that could confer sensitivity or resistance for many common diseases that affect the population, like AIDS or the systemic lupus erythematosus (SLE), among others.

The results of this investigation uncover a new dimension of the complexity of the human genome, unexpected and unexplored until now. The discovery opens the doors to numerous studies to define the causes of many human diseases, to develop more efficient pharmacological processes and to develop prenatal screening methods, which will completely change the current methodologies for the prenatal diagnostic.



Brain damage

The most common cells in the brain change their behaviour when the tissue is damaged, but their appearance does not change nearly to the extent that researchers thought. The domains of individual astrocytes are well contained in both healthy and damaged tissue. This is shown in a new study from the Sahlgrenska Academy in Gothenburg, Sweden. The study was performed in collaboration with a US research team.

The findings were presented in November 2006 at the prestigious Proceedings of the National Academy of Sciences. Astrocytes are a type of non-neuronal cells that exist in all parts of the central nervous system. They form a complex network in the brain, where their offshoots are in constant contact with other astrocytes.

“The discovery is a major step toward a better understanding of the course of events in brain damage, stroke, or dementia. Astrocytes control many neurological functions, including the brain’s capacity to repair itself,” Professor Milos Pekny of the Sahlgrenska Academy said. Until now scientists have assumed that astrocyte shoots grow longer and thicker in various pathological conditions and that this would mean that the cell shoots cross each other in the brain.

This theory has now been disproven by the study, which provides another picture of how astrocytes are affected by a disease. “It’s true that the shoots from reactive astrocytes become thicker, but the overall range of the cells does not increase. Altogether cells attain the same volume of brain tissue as previously and they do not penetrate into the territory of neighbouring astrocytes,” researcher Ulrika Wilhelmsson said.

When there is damage to the brain or if a stroke occurs, astrocytes help limit the damage, but later they also cause negative scarring, which makes it more difficult for the brain to repair itself. Previous studies have shown that in connection with brain damage astrocytes alter their production and release of molecules. “Astrocytes communicate with each other by exchanging ions and various molecules through contact with the shoots of neighboring astrocytes.

If the network is intact, as in stroke, it can be assumed that the astrocyte communication network is rather stable,” says Ulrika Wilhelmsson. Even though astrocytes are the most common cell type in the human brain, they have previously been difficult to study. The findings are based on studies of brain tissue from hippocampus and the cerebral cortex in mice.



Chlamydia

A new study led by a scientist at Children’s Hospital Oakland Research Institute (CHORI) in the US, has found that Chlamydia trachomatis is evolving at a rate faster than scientists previously thought. Chlamydia trachomatis is a bacterium that is the leading cause of sexually transmitted diseases and the second leading cause of blindness worldwide.

Scientists believe the bacterium is evolving through a process called recombination where genes from one or more strains combine to create new strains and – theoretically new diseases. The study is featured in the November 2006 issue of Genome Research and was led by Dr Deborah Dean MD, MPH, senior scientist at CHORI.

Her research suggests that since Chlamydia trachomatis evolves through recombination where one or more strains combine, the traditional method of studying single gene to track the transmission of the bacterium is wrong. “What we found is an organism that not only evolves rapidly, but in ways that we thought were rare. We also discovered that this organism can customise its attack,” said Dr Dean. “Consequently, the constant flux of the bacterium could serve as gateway for new emerging diseases, but more research needs to be conducted to understand if and how this is happening.”

Six hundred million people are infected globally with Chlamydia trachomatis and eight million are already blind or severely visually impaired. In some parts of third-world countries, more than 90% of the population is infected. Chlamydia trachomatis has a variety of strains; different strains are responsible for different diseases. Some strains cause sexually transmitted diseases while others cause eye infections.

“Large-scale comparative genomics will be necessary to understand the precise mechanisms underlying Chlamydia trachomatis recombination and how other species of chamydiae may evolve and transfer from animals to humans,” Dr Dean said.



ESC nurses

Formerly a Working Group of the European Society of Cardiology (ESC), the Council on Cardiovascular Nursing and Allied Professions has been created to co-ordinate the nursing activities of all the ESC Constituent Bodies.

This new Council aims to promote and organise research and education for cardiac nurses; gather and exchange information regarding research and activities by international networking and many other important objectives.



Flu warning

An international, interdisciplinary team of researchers led by professor Xiangming Xiao of the University of New Hampshire is taking a novel scientific approach in an attempt to understand the ecology of the avian influenza, develop better methods of predicting its spread, and provide an accurate early warning system.

Xiao and colleagues were recently awarded $1.55million for a four-year project funded by the US National Institutes for Health (NIH) as part of the Ecology of Infectious Diseases (EID) Program jointly sponsored with the US National Science Foundation.

The EID program supports research projects that develop quantitative analysis and modeling capacity for better understanding the relationship between man-made environmental change and transmission of infectious agents. The UNH project will use environmental remote sensing data from Earth observing satellites in combination with research in epidemiology, ornithology, and agriculture to provide a better picture of how the Highly Pathogenic Avian Influenza survives and gets transmitted among poultry and wild birds.

The work focuses on China, where outbreaks of the virus have been prominent. Xiao, of the UNH Institute for the Study of Earth, Oceans, and Space (EOS) Complex Systems Research Center (CSRC), is the principal investigator for a team that includes scientists from the United Nations Food and Agriculture Organization and research institutes in Belgium and China. CSRC scientist Rob Braswell is also a co-investigator.

The ecology of the avian influenza involves a complex web of factors, including environmental settings, agricultural practices of rice production and harvesting, poultry production involving huge populations of free-grazing ducks, and the migratory behavior of wild bird populations. Depending on how all of these risk factors intermingle over time, the virus can be spread through the environment by infected wild birds or domestic poultry.

Says Xiao, “The strength of our group, and of this proposal, is that over the last few years we’ve been able to pull a lot of information out of satellite observations that can help unravel the complex risk factors involved in avian flu ecology.”

For example, using imagery of varying resolution from different types of satellites, the team can map and track the spatialtemporal dynamics of crop cultivations (when planted, harvested, etc.) and wetlands. Used in conjunction with other geospatial data of environment, bird migration, and poultry production, dynamic maps of “hot spots” and “hot times” for viral transmission can be developed in nearreal- time mode and will aid the public, researchers, business, and decision-makers in preparing for a potential pandemic crisis. Xiao notes that the fouryear project represents a shift for EOS and CSRC in terms of their traditional areas of focus.

“The Institute as a whole and the center in particular have focused more on remote sensing in the areas of the carbon cycle, the water cycle, biogeochemical cycles and climate change, and this is really the first time we’ve gotten into human and animal health.” Of this new direction EOS director Berrien Moore says, “We are very proud of Xiangming Xiao and his colleagues. Exploiting new multidisciplinary approaches to complex problems is at the heart of research at EOS. His work will not only contribute to successful strategies for mitigating a serious health threat, it will also introduce our students to new ways of attacking important and difficult challenges.”



Mint for cancer

It’s been used as an antitoxin in traditional Chinese medicine since the days of the Yellow Emperor in the Han dynasty, over two thousand years ago, but now Scutellaria barbata, a Chinese relative of common garden mint, is being refined into drugs that are effective against over 90% of cancerous tumours.

By extracting and refining active ingredients of the herb, researchers at the University of Salford’s Kidscan Laboratories, Manchester, United Kingdom, have developed a range of drugs that combat cancer in a completely new way.

While drugs currently used in chemotherapy target cancerous tumours themselves, and generally have to be used in strengths that have damaging side effects, the drugs being developed and tested at Salford, work by targeting the blood vessels that surround tumours, cutting off the flow of oxygen and nutrients to the tumour and literally starving it to death. Because a tumour calls on surrounding cells to grow rapidly to feed it, cells and blood vessels surrounding the tumour do not have the inherent strength and coherence of other cells, and these drugs cause them to change shape, making them incapable of carrying blood, clogging blood vessels and cutting off supplies to the tumour.

While cancers can develop resistance to existing drugs, requiring higher doses and becoming less effective over time, it is thought that this new range, because it only impacts on weaker cells surrounding the tumour, will not encounter resistance in the same way. Because they work on a micro-vascular level the drugs also have applications in other illnesses like endometriosis and diabetes where blood vessels grow rapidly. Now new funding by the “Kidscan” charity will allow Dr Sylvie Ducki and her research team to develop these drugs for clinical trials in about a year’s time, ensuring they have no toxic side effects, of which there is so far no sign.

This Chinese relative of mint offers the potential for a range of gentler, more “natural” drugs, and the prospect of less toxic cancer treatments, particularly suitable for the treatment of young children. Once again it would seem that by looking to history and to nature, we can find more natural ways to treat illnesses, one reason why the interest in traditional Chinese medicine has prompted a growth of over 20% each year in the last three years in the Chinese pharmaceutical industry.



Magnetic stents

Mayo Clinic heart researchers have devised a new strategy to improve the effectiveness and safety of heart stents, which are used to open narrowed blood vessels and have been the recent subject of clotting concerns. Their novel approach is based on magnetising healing cells from the patient’s blood so the cells are quickly drawn to magnetically coated stents. The research report appears in the 7 November 2006 issue of the Journal of the American College of Cardiology.

The Mayo team describes encouraging results from preclinical testing. In the study, the cells were extracted from blood, and tiny iron-based paramagnetic particles were placed within the cells. Each stent was implanted through a catheter. Researchers then introduced the iron-tagged cells back into the blood vessel to test how well the magnetised stents captured the cells.

Because the healing cells – also known as endothelial progenitor cells derived from circulating blood – naturally fight blood clot formation, their swift magnetically guided arrival to the stent may reduce the chances of blood clot formation by lining the site fully and quickly, Mayo researchers say. Results show a six-fold to 30-fold improvement in the magnetised stents’ performance in capturing the healing endothelial cells, compared to the standard stents’ ability to do so.

“The ability to rapidly coat implanted devices with living cells could accelerate local tissue healing and thereby reduce the risk of blood clot formation,” said cardiologist Gurpreet Sandhu, MD, PhD, lead investigator. “Our approach of magnetic cell targeting is the next generation of strategies for improving the safety of stents – and it appears that magnetic forces may provide an elegant solution for cell capture. Additionally, this new magnetic targeting technology can be adapted to develop new cell-, geneand drug-based treatments for cancer and other human diseases.”

Dr Sandhu adds that, while encouraging, the method is still experimental and not ready to be used on human patients. Researchers are refining their approach, including developing new biomaterials.



Non-systolic heart failure

Researchers at Johns Hopkins in the US have reported evidence to support a dramatic change in the way hundreds of thousands of people with non-systolic heart failure should be treated. In a follow up to previous work, Hopkins cardiologists say patients with nonsystolic heart failure may benefit more from pacemakers to speed up the heartbeat rather than from continual, long-term use of beta blockers, drugs that slow down the heartbeat.

“Cardiologists are constantly being forced to rethink heart failure because one size does not fit all,” says senior study investigator David Kass, MD, a professor at The Johns Hopkins University School of Medicine and its Heart Institute. “We really have to be careful about how we diagnose and approach its treatment.

“We also need to understand all facets and manifestations of the disease because we are seeing everincreasing numbers of older adults who have heart failure, mostly women over age 50, whose heart pumping appears to be normal. And their cases are clearly different from traditional, systolic heart failure, where pumping function is depressed. However, almost all of the research over the last three decades has applied only to those with systolic heart failure,” Dr Kass says.

Non-systolic heart failure is characterised by fairly normal function of the heart’s pumping action, or so-called ejection fraction, when a person is at rest. This action falters, however, once daily physical activity begins, and the heart becomes increasingly unable to squeeze out sufficient blood flow to energystarved muscles. Even small tasks, such as getting dressed in the morning, can leave people exhausted and short of breath. Until now, Dr Kass notes, researchers had long thought the problem was that these hearts could simply not relax properly, a so-called failure of their diastolic function.

The Hopkins team plans to launch within the next year a US-wide study of the use of pacemakers in patients with this form of the disorder, which is sometimes referred to as heart failure with preserved ejection fraction or heart failure with normal ejection fraction. The latest report from the Hopkins team is published in the journal Circulation online 6 November 2006. If the new study validates their preliminary work, Dr Kass predicts that his research could change the practice guidelines about how beta blockers and pacemakers are used in this form of heart failure.



Robotic sense of touch

By substituting mechanical instruments for human fingers, robotic tools give surgeons a new way to perform medical procedures with great precision in small spaces. But as the surgeon directs these tools from a computer console, an important component is lost: the sense of touch.

Johns Hopkins researchers are trying to change that by adding such sensations, known as haptic feedback, to medical robotic systems. “Haptic” refers to the sense of touch. “The surgeons have asked for this kind of feedback,” says Allison Okamura, an associate professor of mechanical engineering at Johns Hopkins. “So we’re using our understanding of haptic technology to try to give surgeons back the sense of touch that they lose when they use robotic medical tools.”

Okamura is a leading researcher in humanmachine interaction, particularly involving mechanical devices that convey touchlike sensations to a human operator. In recent years, she has focused on medical applications as a participant in the National Science Foundation Engineering Research Center for Computer-Integrated Surgical Systems and Technology, based at Johns Hopkins.

With funding from the US National Institutes of Health and the NSF, she has established a collaboration with Intuitive Surgical, maker of the da Vinci robotic system used in many hospitals for heart and prostate operations. In the da Vinci system, a surgeon sits at a computer console, looks through a three-dimensional video display of the surgery site and moves finger controls that direct the motion of robotic tools inside the patient.

Currently, this system does not send haptic feedback to the surgeon to convey what the mechanical tool “feels” inside the body. Okamura’s team seeks to add these sensations to the da Vinci and similar machines. Through the arrangement with Intuitive Surgical, Okamura’s lab has acquired da Vinci hardware and software that allow her to conduct experiments toward achieving that goal.

For example, the da Vinci’s tools can be directed to tie sutures, but if the operator causes the tools to pull too hard, the thread can break. The Johns Hopkins researchers want the human operator to be able to feel resistance when too much force is applied. To address this, Okamura’s team is experimenting with several techniques that could give some of those sensations back to the surgeons. One option is to attach to the robotic tools force sensors capable of conveying to the human operator how much force the machine is applying during surgery.

Another idea is to create mathematical computer models that represent the moves made by the robotic tools, and then use this data to send haptic feedback to the operator. “I’m exploring both approaches to see which produces the best results,” Okamura says. “The most important thing is that the haptic feedback sent to the human operator must feel right because the fingers aren’t easily fooled.”



Torcetrapib trial stopped

Pharmaceutical company Pfizer has stopped all torcetrapib clinical trials in the interests of patient safety.

Torcetrapib was a promising experimental drug, intended to treat heart disease. The company’s decision to terminate the drug, following the deaths of 82 people in the clinical trial, has cost the company nearly US$1 billion which it had invested in it development. The company said it had “terminated the ILLUMINATE morbidity and mortality study for torcetrapib”.

Their decision was based on the recommendations of the Independent Data Safety Monitoring Board for the trial. According to a report in the New York Times torcetrapib has actually caused an increase in deaths and heart problems. “Eighty-two people had died so far in a clinical trial, versus 51 people in the same trial who had not taken it.” Pfizer emphasised that Lipitor, the most studied statin in reducing cardiovascular outcomes and which was used as a comparator for safety and efficacy in the ILLUMINATE trial, remained completely safe.

“The only reason the study was stopped early was due to the torcetrapib data. The ILLUMINATE Steering Committee wants to reassure physicians and patients that nothing in the trial has any impact on the safety or efficacy of Lipitor, whatsoever.”

Torcetrapib had been in development since the 1990s and held great promise as a drug that would raise levels of ‘good’ cholesterol and reduce cardiovascular plaque build-up. Pfizer, which has 106,000 employees and about $50billion in annual sales, is highly profitable and company directors said the $1billion loss would not affect the company’s financial plans for 2007 and 2008.



Road traffic victims

The World Day of Remembrance for Road Traffic Victims was marked on the third Sunday (19th) of November, in an initiative that was begun in 2005 by the United Nations General Assembly.

The statistics are harrowing. According to the World Health Organisation (WHO) road crashes are the second leading cause of death globally among young people aged five to 29 and the third leading cause of death among people aged 30 to 44 years. Road crashes kill 1.2 million people every year and injure or disable as many as 50 million more.

The economic impact is also significant. In low- and middle-income countries, the cost of road traffic injuries is estimated at US$65 billion, exceeding the total amount these countries receive in development assistance. Road traffic injuries cost countries between 1% and 2% of gross national product, amounting to US$518 billion every year. Yet most road traffic crashes are preventable.

There are many available and affordable interventions which can save lives and prevent injuries and disabilities. These include legislation, enforcement and sharing of information about the use of seat-belts, helmets, and child restraints and about the dangers of speed and drink-driving as well as improvements in road design and infrastructure and emergency trauma services.

Statistics for countries in the Middle East were not shown on the a recent table reflecting ‘Mortality caused by road traffic accidents’ for countries around the world. Iran is reputed to have one of the highest road traffic fatality rates in the world. According to a report in the Tehran Times in March 2006, around 27,000 people, in a population of 70 million, are killed on the country’s roads each year.

That equates to a staggering road traffic mortality rate 73 people a day. About 250,000 people are injured on Iran’s roads each year.


 

                                  
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