Death of a tumor: This PET scan, taken just days after radiation therapy, shows a hot spot of cell-death activity in a brain tumor–a good indication that the therapy is working. Credit: Aaron Allen, Davidoff Comprehensive Cancer Center, Rabin Medical Center
An earlier measure of treatment could improve patients’ prognosis
MIT Technology Review, February 1, 2010, by Lauren Gravitz — When it comes to aggressive cancers, in the brain or lung for example, oncologists know that the sooner they can determine whether a treatment is unsuccessful, the sooner they can reevaluate and, if necessary, prescribe a new course of action. But typically, it takes two months or more to do the before-and-after comparisons that help determine whether a tumor is shrinking. Now an Israeli company called Aposense says it may have found a way to drastically speed up the process: an imaging marker that, when used with PET scans, indicates the presence of dying cells.
Apoptosis, the process by which cells commit suicide, is a vital mechanism in the body that weeds out damaged, infected, or otherwise unhealthy cells. No matter what the disease or the tissue, cells undergoing apoptosis have very distinct characteristics–the electrical profile of their membrane changes, the cells become more acidic, and lipids in the membrane lose their rigid order and become jumbled. Aposense believes it has found a way to target a trace marker to this combination of traits, which would let doctors image cell death and thereby determine whether radiation and chemotherapy are working within just a few days after treatment begins.
“We have designed small molecules with very high specificity for the apoptotic cell,” says chief scientist Ilan Ziv. “When this small molecule recognizes the set of alterations in the apoptotic membrane, it binds to the cell, goes through the membrane, and accumulates.”
The tracer is delivered to patients in an inactive state, and the acidic environment surrounding apoptotic cells causes the molecule to activate. The new conformation then recognizes the dying cells by their altered membrane potential, binds to the membrane, and works its way into the cell by taking advantage of the scrambled lipids. The tracer can be linked to the imaging isotope fluoride-18 to make it easy for PET scans to pick up the signal.
In an early study on seven patients with brain tumors, Aposense investigators imaged patients before, immediately following, and six to eight weeks after their radiation therapy. Their results showed a strong correlation between identifying the apoptosis marker and subsequent tumor shrinkage. “Since you can see if a patient gets no benefit from radiation, you could start right away thinking about alternate treatments,” says Aposense CEO Yoram Asher.
The group is now in phase II clinical trials in collaboration with a few major cancer centers across the U.S., looking at solid brain, lung, head, and neck tumors. “We’re always looking for ways to measure a response to effectiveness of our therapy,” says Aaron Allen, a radiation oncologist at Dana-Farber/Harvard Cancer Center and the trial’s lead investigator. And the more personalized the treatment, the better off a patient will be, he says. “We want to develop a way for each tumor to be treated in the way that it requires. And any tool we can use to accurately measure the effect of our therapy as early as possibly creates an opportunity to personalize the treatment.”
The product also has potential as a research aid. Michael Zalefsky, a radiational oncologist at Memorial Sloan-Kettering Cancer Center in New York and another investigator in the clinical trial, does research on radiational-seed implants for prostate cancer. “As we learn more about [the Aposense tracer], it may help us predict how sensitive the tumor cells are to the particular treatment that we are utilizing,” he says. “It has a lot of great potential benefit, but all this needs to be explored in prospective studies.”
Because the characteristics of apoptotic cells are universal, Aposense says that its tracer might also be used to investigate other ailments. In neurology, the company’s researchers believe, the tracer could be used to image damage from a stroke; in cardiology, it might identify areas of blood vessels with unstable atherosclerotic plaque; in organ transplantation, it might identify rejection at its earliest stages.
But the technology still has a long way to go to prove itself, and some worry that Aposense may be getting ahead of itself. Francis Blankenberg, an associate professor of radiology and pediatrics at Stanford University who specializes in apoptosis-imaging research, has been following the company’s progress for a long time. He’s unconvinced that the tracer molecule works as described– he says Aposense has never published more than speculation about its mode of action in a peer-reviewed journal. He also worries that the molecule’s uptake is so poor that the dose required for imaging is excessive. “It’s not a tracer anymore when they use anything in those quantities,” he says.
Whether Aposense’s marker is effective in cancer treatments should be established soon enough. The company hopes to complete its phase II trials with somewhere between 90 and 100 patients this year, and aims to have a larger, phase III trial concluded by 2012. Asher hopes the results will herald a new era in personalized cancer treatments. “When you’re trying to predict the response of a patient before treatment, you need to account for many variables,” he says. “What we’re providing is a way to see the effects of therapy in vivo. We can do this repeatedly in patient during treatment, and that offers an opportunity to individualize treatment.”
The procedure turns out to be fairly simple
In a finding that seems to suggest differentiated, adult cells are actually a lot more flexible than originally thought, researchers have recently been able to demonstrate a simple conversion method that turns skin cells called fibroblasts into fully functioning nerve cells. The process involved in this type of transformation turned out to be a lot simpler than anyone imagined, biologists at the Stanford University Institute for Stem Cell Biology and Regenerative Medicine write in the latest issue of the esteemed scientific journal Nature.
But the greatest news about this is that it turns out that adult cells don’t necessarily have to be reverted to their embryonic state, in order for the conversion to become possible. This is an incredible finding, because some of the most complex processes associated with changing the function of a set of cells were related to reverting the differentiated cells to a pluripotent state. The new accomplishment was made using just minor genetic tweaks to the original fibroblasts, and the team is currently looking at ways of replicating the findings on cells harvested from humans as well.
If the results of this investigation can be transferred to human patients as well, then a host of neurodegenerative diseases, including Parkinson’s, could get new courses of treatment in the near future, experts believe. One major advantage that this approach could have would be the fact that the nerve cells, obtained from each individual’s own skin graft, would be genetically identical to the ones already inside their brains, which would remove the risk of incompatibility, and reduce the incidence of cases in which the immune system attacks the transplant, endangering that person’s life.
“It’s almost scary to see how flexible these cell fates are. You just need a few factors, and within four to five days you see signs of neuronal properties in these cells,” ISCBRM biologist Marius Wernig, who has also been the leader of the research team behind the findings, explains. The work was conducted on a batch of only 20 genetic transcription factors, which are basically genes that dictate the expression or suppression of other genes, upon binding to DNA. Three of these factors proved to have the ability to convert fibroblasts into neurons, the team concludes, quoted by Technology Review.
The New York Times, February 2, 2010, by Roni Caryn Rabin — Some abnormal heart rhythms that do not respond to drugs should instead be treated with a procedure that cauterizes the muscle around a vein that carries blood from the lungs to the heart, a new study suggests.
The study, published Wednesday in The Journal of the American Medical Association, was one of the most comprehensive clinical trials of the procedure as it is currently practiced, said the lead author, Dr. David J. Wilber, director of the Cardiovascular Institute at Loyola University Medical Center. It was financed by Biosense Webster, maker of the catheters used in the procedures.
The trial, in 19 hospitals, included 167 patients whose intermittent atrial fibrillation had not responded to medication; 106 were randomly assigned to receive the procedure, called catheter ablation; 61 were given another drug.
After nine months, 66 percent of the patients who underwent catheter ablation were free of fibrillation episodes, compared with only 16 percent of those treated with anti-arrhythmic drugs.
Dr. Wilber compared the procedure to cutting down a swath of trees to prevent a forest fire from spreading. The ablation works by “creating a ring of dead muscle around the pulmonary veins, so you can get rid of the electrical activity there,” he said, adding, “There is a lot of reserve muscle in the heart.”
A website highlights common genetic variations that made a splash in 2009
MIT Technology Review, February 2, 2010, by Emily Singer — SNPedia, a wiki-based database of single nucleotide polymorphisms (SNPs), has created my favorite top 10 list yet–the best SNPs of 2009, ranked according to “an elusive and ultimately subjective combination of medical importance, statistical believability, and overall general interest.”
SNPs are common genetic variations that have been highly scrutinized in recent years for their link to disease. SPNedia has compiled information on each of these SNPs, allowing people to analyze their own genetic profile by running their SNP data through it. (Tech Review contributors David Ewing Duncan and Misha Angrist have both tried it out.)
Topping the list is rs4244285, a variation in the drug metabolizing gene, CYP2C19, which determines how well you can metabolize the antiplatelet drug Plavix and other drugs. I wrote about this SNP last month and new devices being developed to easily identify it in hospitals and doctor’s offices.
The list includes a number of other variations that affect metabolism of a number of drugs, such as warfarin, or the susceptibility to side effects from certain drugs, such as muscle pain or weakness associated with statins and liver toxicity linked to the antibiotic floxacillin.
Read more at……………
SNPedia now contains nearly 10,000 SNPs and to welcome 2010 we’d like to highlight at least 10. These SNPs have been selected based on an elusive and ultimately subjective combination of medical importance, statistical believability, and overall general interest. This isn’t objective science though, so feel free to comment about why your favorite SNPs should have made the list.
1. rs4244285: The antiplatelet drug clopidogrel (Plavix) is the #2 selling drug in the world. This SNP in the CYP2C19 gene can tell you if it’s unlikely to be doing you much good; carriers of 1 or especially 2 A alleles don’t benefit much in terms of lowered heart attack incidence based on several studies published over the last year. And actually, this fairly common SNP affects how you metabolize plenty of other drugs as well, including anti-depressants and anti-ulcer drugs.
2. rs4149056: Speaking of bestselling (>100 million prescriptions/year) drugs, one of the adverse effects associated with statin use is the possibility of myopathy (muscle problems including weakness, cramping or pain). Carriers of 1 or 2 C alleles for this SNP in the SLCO1B1 gene taking statins are at ~5 or 17 fold higher risk, respectively, for statin-triggered myopathy. Ouch.
3. rs1799853, rs1057910 & rs8050894: How about one more – actually three more – affecting a widely prescribed drug? When assessed together, these SNPs in the CYP2C9 & VKORC1 genes help predict something that’s otherwise both tricky and overly empirical to determine: the optimal dose of the anticoagulant drug warfarin (Coumadin ), used primarily to help prevent thrombosis and embolism in patients with high blood pressure. The FDA now recommends – but doesn’t require – testing warfarin patients for these SNPs. Here’s a long-standing wish, good for 2010 and most likely beyond: Medicare announces it will reimburse for testing these SNPs, given that over 1 million Medicare beneficiaries take warfarin each year.
4. rs10757278: The region of chromosome 9p21 with this SNP (and it’s neighbor, rs1333049) has been shown in 2009 by several large studies to indicate at least somewhat increased (~1.3 or 1.7x) risk for coronary artery disease and it’s consequences (like heart attacks). But has it added anything to what a cardiologist would already have known based on traditional risk factors like hypertension and family history? Actually, yes – you can classify a patient’s risk better when you add the status of this SNP to all the other factors you’ve already assessed.
5. rs1537415: Sure, lots of SNPs are of interest to MDs, but here’s one for DDS’s. Over half of us carry at least one allele of this SNP and are therefore at increased risk for periodontitis – so keep flossing!
6. rs3892097: This SNP encodes the CYP2D6*4 allele, the most common nonfunctional variant for this gene. While it can therefore affect the metabolism of about 25% of all known drugs, it’s on our list this year due to increasing evidence for poorer outcome among breast cancer patients treated with tamoxifen, the gold standard drug for roughly the last 30 years. Women are typically treated with tamoxifen for 5 or more years, but evidence is mounting that less functional CYP2D6 alleles lead to less endoxifen, which is the active form formed via CYP2D6 metabolism of tamoxifen. Less of the active form means a poorer outcome, so now the question is becoming, can higher doses of tamoxifen overcome this, or should alternative drugs replace it as the gold standard?
7. rs1447295: And now here’s one for the guys: this SNP has turned up in studies totaling tens of thousands of patients across multiple ethnic groups as connected to an increased risk for prostate cancer, the second deadliest cancer among men. Although on it’s own the increased risk isn’t that high (perhaps a doubling of risk even for those carrying two copies), there are now over 20 more SNPs that can be used together to help classify risk. We can hope that more aggressive screening of those deemed to be at higher genetic risk will help decrease prostate cancer deaths.
8. gs138, gs139, gs140: These three genosets (hence the ‘gs’ prefix) represent the rapid, intermediate, and slow metabolizers amongst you for the detoxifying enzyme NAT2. Debuting in 2009, the algorithms described in SNPedia using seven NAT2 SNPs allow the Promethease software to classify your NAT2 status and thus estimate just how fast you’ll clear various toxins (or that hangover?) out of your system. Looking into the 2010 crystal ball: we foresee the use of lots more genosets to predict phenotypes (and ancestry) based on combinations of SNPs.
9. rs17646946 & rs11803731: Two SNPs, both on chromosome 1, yet 27 million bases apart; one is part of the trichohyalin gene, the other abuts a trichohyalin-like gene. One found by a genome-wide association scan by academic researchers, the other by a company harnessing the power of the internet , DNA chips, and customer interest in correlating their DNA with common traits – in this case, hair curliness. We applaud the use of people-power to help prove (and disprove) DNA associations, and in 2009 we began having SNPedia/Promethease users self-report their own associations for a variety of SNPS, regardless of which company they got their genome data from.
10. rs2395029: This SNP just keeps getting more associations every year! As the SNP predicting the presence of an HLA-B*5701 allele, it’s been previously associated with a variety of conditions (like psoriasis, or as the FDA agreed last year, abacavir hypersensitivity). This year, it demands attention for the remarkable increase in risk (45 to 80 fold) for liver damage among patients taking the antibiotic flucloxacillin (aka floxacillin). While this SNP is quite rare, it’s a good example of a more “deterministic” type of SNP that we can carry.
On that last note, the intersection of less expensive full genomic sequence with greater coverage of rare variations bodes well for all. Think well of all the researchers who make this possible – we thank you for your hard work, we encourage you to choose open access publications, and we look forward to all of your contributions in the coming year!
GoogleNews.com, February 2, 2010, by Carla K. Johnson — Fish oil pills may be able to save some young people with signs of mental illness from descending into schizophrenia, according to a preliminary but first-of-its-kind study.
The Austrian study of just 81 patients comes from leaders in the field of youth mental health and adds to evidence suggesting severe mental illness might be prevented with the right intervention.
Though it sounds incredibly simple, fish oil fits one hypothesis for what causes schizophrenia, a possible difference in how the body handles fatty acids.
“If it works, it will be an absolutely tremendous development,” said Dr. Jeffrey Lieberman, chairman of psychiatry at Columbia University Medical Center in New York, who wasn’t involved in the new study.
More research is needed to see if the results are accurate, he said.
The researchers are beginning a larger international study in eight cities with hopes of replicating their findings, which appear in February’s Archives of General Psychiatry, released Monday.
Schizophrenia is a severe mental illness that strikes adolescents and young adults. About 2.4 million Americans have the disorder, which is treated with antipsychotic medication.
Since the 1990s, researchers have wondered if the disease could be stopped in its earliest stages, before it fully overpowers a person’s grip on reality. Studies have tried antipsychotics in select young people, but troubling side effects pose ethical questions and results have been mixed.
For the new study, researchers identified 81 people, ages 13 to 25, with warning signs of psychosis.
The signs include sleeping dramatically more or less than usual, growing suspicious of others, believing someone is putting thoughts in their head or thinking they have magical powers. The young people in the study sought professional help and most were referred by psychiatrists at the Medical University of Vienna, Austria.
Researchers randomly assigned 41 of the patients to take four fish oil pills a day for three months. The daily dose of 1,200 milligrams was about what many people take to get the protective benefits of fish oil for the heart and costs less than 40 cents a day.
The rest of the patients received dummy pills. After one year of monitoring, 2 of 41 patients in the fish oil group, or about 5 percent, had become psychotic, or completely out of touch with reality. In the placebo group, 11 of 40 became psychotic, about 28 percent.
Four people would need to take fish oil to prevent one transition to a psychotic disorder during a year, according to the researchers.
No one knows what causes schizophrenia but one hypothesis says people with the disease don’t process fatty acids correctly, leading to damaged brain cells.
Omega-3 fatty acids in fish oil could help brain cells to repair and stabilize, the researchers speculate. Some prior studies on omega-3 supplements in people with full-blown schizophrenia have shown benefits.
“Schizophrenia is among the most mysterious and costliest diseases in terms of human suffering, so anything that gives some hope to avoid this is great,” said lead author Dr. G. Paul Amminger, formerly in Vienna and now at the Orygen Youth Health Research Center at the University of Melbourne in Australia.
Side effects of antipsychotics, including sexual dysfunction and weight gain, are troubling to young people, Amminger said. Fish oil, recommended for heart health, is more acceptable to patients with warning symptoms.
Scientists in the field greeted the findings with cautious excitement.
“The results are very impressive and very striking and really represent a step forward potentially for patients and their families,” said Dr. Neil Richtand, a schizophrenia researcher at the University of Cincinnati College of Medicine.
Dr. Janet Wozniak of Harvard Medical School said the findings, while preliminary, might reasonably cause psychiatrists to recommend fish oil to some patients because there are known benefits and little risk.
Wozniak advised consumers to look for high quality nutritional supplements. Most fish oil capsules are free from contaminants and test highly for quality, said William Obermeyer of ConsumerLab.com, which tests supplements for manufacturers and publishes ratings for subscribers.
The research was funded by the Stanley Medical Research Institute, a nonprofit in Chevy Chase, Md., that supports research on schizophrenia and bipolar disorder.
On the Net:
Archives of General Psychiatry:http://www.archgenpsychiatry.com
Flex your power: A Princeton researcher holds a square of silicone embedded with a ribbon of a crystalline material that generates an electrical current when flexed.
Credit: Frank Wojciechowski
Material could charge portable electronics with every step
MIT Technology Review, February 1, 2010, by Katherine Bourzac — Researchers at Princeton University have created a flexible material that harvests record amounts of energy when stressed. The researchers say the material could be incorporated into the soles of shoes to power portable electronics, or even placed on a heart patient’s lungs to recharge a pacemaker as he breathes.
The energy-harvesting rubber sandwiches ribbons of a piezoelectric material called PZT between pieces of silicone. When mechanically stressed, a piezoelectric material generates a voltage that can be used to produce electrical current; a current can also be converted back into mechanical movement.
The rubber material can harness 80 percent of the energy applied when it is flexed–four times more than existing flexible piezoelectric materials.
Flexibility could prove vital if energy-harvesting technology is to take off. For example, the military tested stiff-soled piezoelectric shoes as a power source, but soldiers complained of foot pain. And previous flexible energy harvesters–based on piezoelectric polymers, nanowires, or other types of crystal–put out little electrical current.
PZT is the most efficient piezoelectric material known, but its crystalline structure means that it must be grown at high temperatures, which normally melt a flexible substrate. The Princeton researchers, led by mechanical engineering professor Michael McAlpine, got around this by making PZT at high temperatures and then transferring thin ribbons of the material onto silicone.
First, the researchers treat the PZT with a chemical etching bath that removes a thin ribbon from the surface of the crystal. They then use a polymer stamp to pick up the ribbon and place it on a silicone film before covering it with a second piece of silicone and sealing it. “All the processes we use to make flexible PZT ribbons are extremely simple and straightforward,” says McAlpine. Crucially, the researchers found that the process doesn’t compromise PZT’s energy-conversion efficiency.
Proof-of-concept tests described this week in the journal Nano Letters show that the rubber-encased PZT ribbons maintain their high power-conversion efficiency. McAlpine says the simple printing process should readily scale up to make larger sheets; he has filed a patent on the process.
McAlpine is particularly focused on biomedical applications for the material and says it could cut down on the number of surgeries that patients with implants must undergo. For example, doctors could place a power-generating sheet against the lungs during the initial surgery; the constant movement of the organs could help recharge a battery, McAlpine says.
Jim Grotberg, professor of surgery and biomedical engineering at the University of Michigan, says wireless monitoring and drug delivery for patients with chronic medical problems are other potential applications. “If you have a sensor that monitors heart-rate, brain activity, or blood pressure, or an implantable insulin-injection system, you need a battery,” he says.
PZT itself is not biocompatible–the “p” comes from the chemical symbol for lead, one of its components along with zirconium and titanium. But the crystal ribbons are completely encapsulated in silicone, a material that is approved by the U.S. Food and Drug Administration for medical implants.
Even animal testing is still a ways off. But the Princeton researchers are now making prototype devices from the sheets to test how much electricity they can generate when they are built into shoes.