Test May Reduce the Need for Surgery to Diagnose Thyroid Cancer.


A new test may spare some patients with suspicious thyroid nodules from diagnostic surgery. Researchers analyzed thyroid nodule samples collected via fine-needle aspiration (FNA) for the expression of a panel of 167 genes and found that the test accurately identified whether nodules were cancerous. Their results were published June 25 in the New England Journal of Medicine.

About 15 to 30 percent of patients undergoing FNA for suspicious thyroid nodules have indeterminate findings on standard cytology tests—that is, the tests show cellular changes that indicate a possible cancer but the findings are inconclusive. Although the majority of those with inconclusive cytology results have a benign condition, most have thyroid surgery to determine whether cancer is present.

Several researchers said the test has the potential to change clinical practice by eliminating or delaying the need for such surgery in some patients.

The researchers collected more than 4,800 aspirate samples from nearly 3,800 patients treated at 49 academic centers and community hospitals over a 19-month period. Of these, they analyzed indeterminate FNA samples from 265 nodules for which surgical samples were also available. The FNA samples were analyzed using the 167-gene panel that the researchers had developed based on earlier research.

Overall, when the results from the gene expression test were compared with diagnostic results from thyroid samples removed during surgery, the test correctly identified 92 percent of the malignant samples and 93 percent of the benign samples. But about half of the samples that the gene expression test identified as suspicious—not clearly malignant or clearly benign—were actually benign on surgical analysis.

For patients with indeterminate cytology results, the gene expression test “can be useful in making important [patient] management decisions, such as recommending watchful waiting in lieu of diagnostic surgery,” wrote lead author Dr. Erik Alexander of Brigham and Women’s Hospital and his colleagues.

Dr. Ann Gramza of NCI’s Center for Cancer Research agreed. But she cautioned that “a negative result should not dismiss a patient from further follow-up surveillance of the nodule.”

“The risk…is that 5 to 10 percent of nodules classified as benign…are likely to be malignant [false negatives], particularly those that are cytologically indeterminate but suggestive of cancer,” wrote Dr. J. Larry Jameson of the University of Pennsylvania in an accompanying editorial. In such patients, he explained, “it might be reasonable” to do another FNA biopsy or perform a diagnostic surgical procedure.

One recent study, Dr. Jameson noted, suggested that the reduction in surgeries that could result from its use—about 25,000 fewer operations per year—”could result in substantial cost savings,” even with the added cost of the test.

Skin Cancers Traced to Previously Unknown Effect of UV Radiation

The harmful effects of the sun on the outer layer of skin (the epidermis) are well documented. But ultraviolet (UV) radiation from the sun also may alter cells in the underlying layer of skin (the dermis), setting the stage for the development of cancer in the epidermis, according to findings published June 8 in Cell.

In the study, researchers observed epidermal changes in mice that were similar to those seen in UV-induced human premalignant skin lesions called actinic keratosis, which can progress to squamous cell carcinoma, the most common skin cancer in humans. In the mice, the Notch signaling pathway was lost in stromal cells, which contribute to the dermal compartment of the skin.

The loss of Notch signaling appeared to be sufficient for tumors to emerge in the overlying epidermis, the researchers observed. The increased inflammation that accompanied the loss of Notch signaling also may have played a role in tumor development, they added.

“This study says that changes in the stroma are as important as changes in the epidermis, and we probably need to pay attention to them,” said lead investigator Dr. G. Paolo Dotto of Massachusetts General Hospital and the University of Lausanne, Switzerland.

To investigate the clinical relevance of the mouse findings, the researchers analyzed tissue from human patients with actinic keratosis. They found that Notch signaling was reduced in human stromal cells near precancerous lesions. Moreover, similar molecular changes were induced by UVA radiation, which is an environmental cause of skin cancer, the study authors noted.

The findings may provide insights into the phenomenon of field cancerization, in which a patch or field of cells, rather than a single initiating cell, changes when exposed to a carcinogen and has the potential to become premalignant, Dr. Dotto pointed out.

In an accompanying editorial, Drs. Sakari Vanharanta and Joan Massagué of Memorial Sloan-Kettering Cancer Center praised the study for raising the possibility that, in addition to causing mutations, UV radiation may lead to tumor-promoting changes in dermal cells.

The findings add to the extensive list of harmful effects of excessive sun exposure. “This should give [people] one more reason to cover up,” wrote Drs. Vanharanta and Massagué.

Experimental Drug Based on Plant Toxin Targets and Kills Tumor Cells

Researchers have engineered a drug that can deliver a potent cell-killing toxin to tumors while largely sparing normal tissues. The drug, known as G202, shrank xenograft tumors of several human cancers in mice, including prostate, breast, kidney, and bladder cancer, and had relatively few toxic effects. On the basis of these findings, reported June 27 in Science Translational Medicine, researchers have initiated an early-phase clinical trial of G202 in patients with advanced cancer.

G202 delivers its toxic payload—a potent analog of the plant substance thapsigargin—to tumors by binding specifically to a protein known as prostate-specific membrane antigen (PSMA). PSMA is found in high levels in most prostate cancers. It is also found in tumor endothelial cells, which line blood vessels in a variety of solid tumors but not in normal endothelial cells. PSMA is an enzyme that spans the cell membrane and can cut proteins in specific places.

Researchers designed G202 so that it not only binds to PSMA but is also a target for PSMA’s protein-cutting activity. G202 is an inactive “prodrug,” and PSMA causes the release of the active, cell-killing thapsigargin analog from the prodrug form. This release takes place outside the cell, in the tumor microenvironment. Once released, the thapsigargin analog is taken up by nearby tumor cells, where it inhibits a protein known as the SERCA pump. Shutting down the SERCA pump floods the cell with calcium and triggers programmed cell death.

Unlike commonly used chemotherapy drugs, which typically work by killing rapidly dividing cells, “[thapsigargin] and its analogs can kill both rapidly proliferating and nonproliferating cells with equal potency,” wrote Drs. Samuel Denmeade and John Isaacs of Johns Hopkins University and their colleagues. This ability, they noted, makes a thapsigargin-based drug particularly suitable for treating prostate cancer because most cancer cells in metastatic prostate cancer are not dividing.

Safety studies of G202 that are required before the drug can be tested in humans showed that it caused transient reversible kidney toxicity in rats and monkeys. G202 did not cause bone marrow toxicity—a common side effect of traditional cell-killing chemotherapy—in mice, rats, or monkeys.

Source: NCI.

 

To Eat or Not to Eat: With Cancer Therapies, That Is the Question.


When we are healthy, we tend to eat what we want, when we want, and without much thought about how our bodies process food and anything else we ingest. But what we eat and when we eat it can affect the way our bodies absorb and react to medications, sometimes to the extent of altering treatment outcomes.

Food intake, therefore, is an important variable when determining the optimal treatment for many diseases. And cancer researchers are now exploring whether manipulating food intake could help reduce the side effects of some treatments or make them more effective, as well as more cost-effective.

A Double Challenge to Cancer Cells

What we eat and when we eat it can affect the way the body absorbs and reacts to cancer treatments.

In 2008, the laboratory of Dr. Valter Longo, a professor of gerontology and biological science at the University of Southern California (USC), showed that fasting for 2 to 3 days protected normal cells and mice from chemotherapy drugs without protecting cancer cells—an effect they called differential stress resistance.

Dr. Longo and oncologists from USC later published a study of 10 elderly cancer patients who voluntarily underwent short-term fasting before and/or after cytotoxic chemotherapy infusion. Patients reported fewer side effects, including fatigue, weakness, and gastrointestinal problems, when they fasted. However, some doctors still worried that fasting could also protect cancer cells, explained Dr. Longo, which would negate its use in cancer patients.

A recent study by the USC research team, published March 7 in Science Translational Medicine, addressed this concern by showing that, contrary to such fears, fasting renders cancer cells more sensitive to chemotherapy.

The researchers found that fasting conditions in cell culture and in mice caused normal and cancer cells to radically change their gene expression patterns—but in very different ways. Normal cells reduced the expression of genes associated with cell growth and division and diverted their energy to cellular maintenance pathways that protect normal cells from stressful conditions and repair stress-induced damage. In contrast, cancer cells reduced the expression of many protective genes, which made them more likely to die, explained Dr. Longo.

Fasting results in “more investment in a variety of systems that protect the [normal] cell,” Dr. Longo said. This shift to maintenance (instead of growth) has an added benefit for normal cells: Nondividing cells that enter a maintenance mode are less likely to be damaged by chemotherapy drugs that target the process of cell division.

In contrast, cancer cells contain mutations that may hinder their ability to respond to starvation conditions by shifting their resources away from growth, as normal cells do. Fasting also deprives cancer cells of the glucose and other molecules they need to fuel their endless cell division. Therefore, fasting adds a second stressor on top of chemotherapy, forcing cancer cells to deal “with two extreme environments at once,” explained Dr. Longo.

Fasting adds a second stressor on top of chemotherapy, forcing cancer cells to deal with two extreme environments at once.

—Dr. Valter Longo

This combination of stressors led to promising results in animal studies. In mice with implanted breast cancer cells, short-term fasting alone delayed tumor growth to the same extent as treatment with the drug cyclophosphamide. Fasting before administering the drug had a stronger effect: the tumors of fasting mice given cyclophosphamide grew to less than half the size of those in nonfasting mice. The researchers saw similar results in mice implanted with melanoma or glioma cells.

In mouse models of metastatic melanoma, breast cancer, and neuroblastoma, fasting combined with high-dose chemotherapy extended survival compared with high-dose chemotherapy without fasting. The combination also reduced the overall number of metastatic tumors. Moreover, 20 to 40 percent of fasting mice with neuroblastoma had a long-term remission, which was not observed in mice that received chemotherapy without fasting.

The USC team is now studying how fasting can reduce side effects in people receiving chemotherapy. Dr. Longo has helped design three ongoing early-phase clinical trials examining this question (at USC, the Mayo Clinic, and Leiden University in the Netherlands).

And a consortium of 12 hospitals in the United States and Europe is planning two trials, each with more than 800 patients, Dr. Longo noted. One trial will look at whether fasting can reduce chemotherapy side effects, and the other will look at whether fasting can influence both side effects and drug efficacy (as observed in mice).

According to a survey by the USC team, more than 70 percent of eligible patients would refuse a water-only fast, so the international trials will use a substitution diet called Chemolieve that the research team developed and commercially marketed under an NCI Small Business Innovation Research (SBIR) contract. The researchers designed the diet to provide a minimum amount of nutrients to cancer cells while providing nourishment to the patients, sparing them the discomfort of fasting.

Danger, But Also Opportunity

On the flip side of the coin, researchers at the University of Chicago are exploring whether the bioavailability of some oral cancer drugs—the amount of drug absorbed and used by the body—can be increased by taking the drugs with food.

For many oral drugs, whether a patient takes them with food is irrelevant. But some oral drugs have a clinically significant food effect, which means that taking them at the prescribed dose with food causes a substantial change in their bioavailability. If a food effect leads to a marked decrease in bioavailability, too little drug will reach the bloodstream. If a food effect leads to a large increase in bioavailability, patients taking the drug with food risk overdosing.

This second scenario is a concern for several oral cancer drugs, including nilotinib (Tasigna) for chronic myelogenous leukemia and lapatinib for advanced breast cancer. The risk of sudden cardiac death from taking nilotinib at its prescribed dose with food is so high that the manufacturer has included a boxed warning about the dangers and developed a corresponding risk evaluation and mitigation strategy.

Dr. Mark Ratain, professor of medicine at the University of Chicago, sees opportunity instead of danger in the food effect, as well as a major flaw in what has become the default strategy for oral cancer drug development.

Oral Cancer Drugs That Are More Potent When Taken with Food

Cancer Drug

Approximate Increase in AUC*
When Taken with Food

Estimated Monthly Cost at the
Prescribed Dose (2011)

Lapatinib

150%

$3,400

Nilotinib

100%

$8,800

Erlotinib

 50%

$4,800

Pazopanib

100%

$6,000

Abiraterone

300%

$5,000

*AUC = area under the curve; a measurement used to estimate the bioavailability of drugs. (Data courtesy of Dr. Mark Ratain, University of Chicago)

For many noncancer drugs that have a greater bioavailability with food, that food effect has been exploited, explained Dr. Ratain. For example, drugs such as darunavir for HIV or telaprevir for hepatitis C are prescribed at lower doses to be taken with a meal.

In oncology, the opposite has happened. Discovery of a food effect has led to the development of a high prescribed dose to be given without food. “That’s not convenient for patients” who may take these drugs for years and are otherwise healthy, said Dr. Ratain, such as patients with chronic myelogenous leukemia who achieve complete remission on nilotinib but who must continue taking the drug every day.

Testing oral oncology drugs that have a food effect at lower doses with food might substantially reduce side effects and costs, suggests Dr. Ratain. His research group is testing this concept in a phase II clinical trial of abiraterone acetate (Zytiga), approved for metastatic prostate cancer. Dr. Ratain and his colleagues are testing whether men can safely reduce their dose of the drug by 75 percent by taking it with food. And, in turn, reducing the dose might cut drug costs, he added.

Some oral drugs have what scientists call a clinically significant food effect—taking them at the prescribed dose with food causes either a major increase or decrease in bioavailability.

The researchers are randomly assigning participants to one of two treatment groups: the approved dose of 1,000 mg without food or 250 mg taken with a low-fat breakfast. The reduction in prostate-specific antigen (PSA), variability in pharmacokinetics, and effects on the hormonal targets of the drug will be compared between the two groups.

“When one is starting with a drug and wants to study the pharmacokinetics in healthy volunteers, the cleanest thing to do is to study [the drug during] fasting. But just because fasting potentially provides less variability in dose between patients, that doesn’t mean it’s the best way to administer any given drug,” said Dr. Ratain. “We’re asking questions that I think the FDA should require companies [to answer]—what is the variability [in dose] over time, with food and with fasting?”

This is beginning to happen. The FDA’s Center for Drug Evaluation and Research (CDER) now recommends to all pharmaceutical sponsors that “the impact of food intake on oral oncology drugs should be assessed early in drug development—during the pre-Investigational New Drug (IND) and phase I development periods,” said Dr. Atiqur Rahman of CDER’s Office of Clinical Pharmacology.

“Information obtained from these evaluations should be incorporated in the phase II and phase III development trials to guide dosing recommendations with regard to food intake,” he continued. CDER also informs the sponsors that studying food effect in the late phase of drug development may be necessary if the formulation or dosage is significantly altered from the one tested during early clinical development.

But “whether a particular oral oncology drug can be allowed to be developed with food will depend on many factors, such as the magnitude and variability of the food effect, the therapeutic window of the drug, as well as the characteristics of the disease and the patient population,” Dr. Rahman concluded.

Source: NCI.

 

 

MRI-Guided Focal Laser Therapy for Low-Risk Prostate Cancer.


Name of the Trial
MRI-Guided Focal Therapy in Prostate Cancer (NCI-11-C-0158). See the protocol summary.

Principal Investigator
Dr. Peter Pinto, NCI Center for Cancer Research

Why This Trial Is Important
Roughly 240,000 men will be diagnosed with prostate cancer in the United States this year. Most of them will receive their diagnosis after a prostate biopsy that was triggered by screening with the PSA test rather than by symptoms. Consequently, many of these men will have cancer that is confined to a small portion of the prostate gland (low-volume disease) and is likely to grow so slowly that it may never jeopardize their health (low-grade disease).

Management options for men with such low-risk prostate cancer include treatment and active surveillance, in which the cancer is monitored and treatment is delayed until there are signs of disease progression. Current treatment options include surgery to remove the prostate (radical prostatectomy) and radiation or ablation therapy to destroy the entire prostate gland. Although active surveillance may be recommended, most men seek immediate treatment.

Unfortunately, the available treatments target the entire prostate and often affect nearby nerves and muscles that help control urinary continence and erectile function. Because of the high likelihood of serious side effects and the typical slow course of prostate cancer growth, the U.S. Preventive Services Task Force recently recommended against routine PSA screening for men of any age. However, this recommendation has been questioned by many doctors and patient groups.

Given that PSA screening is unlikely to be abandoned in the short term and that many men diagnosed with low-risk disease will still seek treatment, researchers are eager to develop new approaches to treating low-volume, low-grade prostate cancer that carry less risk for serious side effects.

In this pilot study, which is being conducted at the NIH Clinical Center, men diagnosed with low-risk prostate cancer and men with suspected prostate cancer will undergo advanced magnetic-resonance imaging (MRI) techniques developed at NCI to visualize the prostate and tumor tissue in high detail and guide a biopsy to that area. The men will then be treated at a later date using MRI-guided focal laser ablation therapy to only the area of the prostate that has cancer. The study will assess the feasibility and safety of this therapy.

“Some of the recommendations against PSA screening are based on data from large clinical trials conducted in both Europe and the United States which found that, to save one life from prostate cancer, you have to treat many men who then may suffer the harms of treatment,” said Dr. Pinto. “We are trying to find a better way to treat prostate cancer without the side effects of traditional whole-prostate therapy.

“Our approach is to use focal therapy to treat only the area of the prostate where the tumor is. This involves inserting a laser fiber into the tumor nodule with MRI guidance, heating the tumor with a laser, and using MRI to watch in real-time as the heat from the laser destroys the tumor while leaving the remaining prostate gland intact and the surrounding nerves and muscles unharmed,” he explained.

Source: NCI.

 

 

US agency hopes to curb prescription painkiller abuse with education.



The US Food and Drug Administration (FDA) announced that doctors and patients will have access to training and educational materials on the risks of abuse and addiction associated with opioids, a class of medications prescribed for severe pain.

In the United States, opioids such as Oxycontin are abused both by patients for whom they’re prescribed and recreational users. They accounted for 14,800 deaths by overdose in 2008 and 15,597 deaths in 2009, according to the Centers for Disease Control and Prevention. Last year, more people died from prescription-opioid overdoses than from heroine and cocaine overdoses combined.

“Prescription-drug abuse is our nation’s fastest-growing drug problem,” said FDA commissioner Margaret Hamburg at a press briefing on the measure. “Today, the FDA is taking the next critical step in risk management.”

The FDA is requiring companies that manufacture long-lasting or extended release opioids to pay for educational materials that teach doctors how to communicate the risk of opioid dependence to patients and how to handle those who’ve become addicted. Between now and March 2013, some 20 companies will develop educational strategies, which must adhere to a blueprint issued by the FDA. A third party will audit the materials to ensure that they are comprehensive and free from bias.

This risk-management plan has been two years in the making. It was included as a proposal in the Administration’s 2011 Prescription Drug Abuse Prevention Plan.

One clear shortcoming of the approach is that opioid prescribers can skip training sessions, and patients might not read pamphlets that health-care providers give them. In other words, it’s mandatory for companies to provide education, but not for people to listen. Hamburg says that the agency expects 60% of the current 320,000 prescribers to attend the training sessions by 2016. “We’d like to see a higher number,” she adds, “and we are working with Congress to explore a way of mandating training.”

Before that happens, the FDA must demonstrate that the training would not add additional burdens to busy healthcare providers, or restrict opioid access to deserving patients. Surveys conducted once the plan is in place should shed light on both of these concerns, Hamburg says.

Source: Nature.

 

 

Dark matter’s tendrils revealed.


Direct measurement of a dark-matter ‘filament’ confirms its existence in a galaxy supercluster.

A ‘finger’ of the Universe’s dark-matter skeleton, which ultimately dictates where galaxies form, has been observed for the first time. Researchers have directly detected a slim bridge of dark matter joining two clusters of galaxies, using a technique that could eventually help astrophysicists to understand the structure of the Universe and identify what makes up the mysterious invisible substance known as dark matter.

According to the standard model of cosmology, visible stars and galaxies trace a pattern across the sky known as the cosmic web, which was originally etched out by dark matter — the substance thought to account for almost 80% of the Universe’s matter. Soon after the Big Bang, regions that were slightly denser than others pulled in dark matter, which clumped together and eventually collapsed into flat ‘pancakes’. “Where these pancakes intersect, you get long strands of dark matter, or filaments,” explains Jörg Dietrich, a cosmologist at the University Observatory Munich in Germany. Clusters of galaxies then formed at the nodes of the cosmic web, where these filaments crossed.

The presence of dark matter is usually inferred by the way its strong gravity bends light travelling from distant galaxies that lie behind it — distorting their apparent shapes as seen by telescopes on Earth. But it is difficult to observe this ‘gravitational lensing’ by dark matter in filaments because they contain relatively little mass.

Dietrich and his colleagues got around this problem by studying a particularly massive filament, 18 megaparsecs long, that bridges the galaxy clusters Abell 222 and Abell 223. Luckily, this dark bridge is oriented so that most of its mass lies along the line of sight to Earth, enhancing the lensing effect, explains Dietrich. The team examined the distortion of more than 40,000 background galaxies, and calculated that the mass in the filament is between 6.5 × 1013 and 9.8 × 1013 times the mass of the Sun. Their results are reported in Nature today1.

Mass equation

By examining X-rays from plasma in the filament, observed by the XMM-Newton spacecraft2, the team calculated that no more than 9% of the filament’s mass could be made up of hot gas. The team’s computer simulations suggest that roughly another 10% of the mass could be due to visible stars and galaxies. The bulk, therefore, must be dark matter, says Dietrich.

Mark Bautz, an astrophysicist at the Massachusetts Institute of Technology in Cambridge, notes that astrophysicists do not know precisely how visible matter follows the paths laid out by dark matter. “What’s exciting is that in this unusual system we can map both dark matter and visible matter together and try to figure out how they connect and evolve along the filament,” he says. Japan’s Astro-H X-ray space telescope, due to launch in 2014, will be able to characterize the ionization state and temperature of the plasma in the filament, which will help to discriminate between different models of how the structure formed.

Refining the technique could also help to pin down the identity of dark matter — whether it is a cold (slow-moving) particle or a warm (fast-moving) one, like a neutrino — because different particles will clump differently along the filament. The Euclid space mission, due to launch in 2019, will provide more lensing data. “This will complement direct dark-matter searches, for example at the Large Hadron Collider,” says Alexandre Refregier, a cosmologist at ETH Zurich, the Swiss Federal Institute of Technology in Zurich.

Source: Nature

 

Science in three dimensions: The print revolution.


Three-dimensional printers are opening up new worlds to research.

Christoph Zollikofer witnessed the first birth of a Neanderthal in the modern age. In his anthropology lab at the University of Zurich, Switzerland, in 2007, the skull of a baby Homo neanderthalensis emerged from a photocopier-sized machine after a 20-hour noisy but painless delivery of whirring motors and spitting plastic. This modern miracle had endured a lengthy gestation: it took years for Zollikofer’s collaborators to find suitable bones from a Neanderthal neonate, analyse them with a computed-tomography (CT) scanner and digitally stitch them together on the computer screen. The labour, however, was simple: Zollikofer just pressed ‘print’ on his lab’s US$50,000 three-dimensional (3D) printer.

A pioneer in the use of 3D printing for research, Zollikofer started 20 years ago with a prototype that was even more expensive and required toxic materials and solvents — limitations that put off most scientists. But now newer, cheaper technology is catching on. Just as an inkjet printer sprays ink onto a page line by line, many modern 3D devices spray material — usually plastic — layer by layer onto a surface, building up a shape. Others fuse solid layers out of a vat of liquid or powdered plastic, often using ultraviolet or infrared light. Any complex shape can be printed, sometimes with the help of temporary scaffolding that is later dissolved or chipped away. These days, personal kits go for as little as $500, says Terry Wohlers, a consultant and market analyst based in Fort Collins, Colorado — although industrial systems cost an average of $73,000. Last year, he says, nearly 30,000 printers were sold worldwide, with academic institutions buying one-third of those in the $15,000–30,000 price range.

Early adopters are using the technology to investigate complex molecules, fashion custom lab tools, share rare artefacts and even print cardiac tissue that beats like a heart. At palaeontology and anthropology conferences, more and more people are carrying printouts of their favourite fossils or bones. “Anyone who thinks of themselves as an anthropologist needs the right computer graphics and a 3D printer. Otherwise it’s like being a geneticist without a sequencer,” says Zollikofer.

The printouts are yielding insights that are not possible with more conventional methods. Neanderthal neonate fossils, for example, are extremely rare, so Zollikofer did not want to risk copying his fragile specimen with the usual plaster-casting methods. With the printout, however, Zollikofer could explore the logistics of Neanderthal births. Along with the neonate skull, he printed out an adult, female Neanderthal pelvis and literally re-enacted a delivery. Some researchers had speculated that Neanderthals’ wide hips made labour easier than it is for modern humans, but Zollikofer’s experiment showed that the bigger skulls of Neanderthal neonates counteracted that advantage (M. S. Ponce de León et al. Proc. Natl Acad. Sci. USA 105, 13764–13768; 2008). Like humans today, Neanderthals had the biggest heads — and brains — possible at birth, giving them a jump-start on development.

In his work, Zollikofer swaps back and forth between printed models and virtual ones. The computer models are good for calculating volumes or piecing together bone fragments — researchers can position them in space without gravity causing them to fall. But with the virtual models, he says, “you lose the sensation of touch, and even a notion of the size of the fossils”. The physical models are far better for seeing how pieces should fit together in the first place, he adds.

Molecular playground

Chemists and molecular biologists have long used models to get a feel for molecular structures and make sense of X-ray and crystallography data. Just look at James Watson and Francis Crick, who in 1953 made their seminal discovery of DNA’s structure with the help of a rickety construction of balls and sticks.

 

These days, 3D printing is being used to mock up far more complex systems, says Arthur Olson, who founded the molecular graphics lab at the Scripps Research Institute in La Jolla, California, 30 years ago. These include molecular environments made up of thousands of interacting proteins, which would be onerous-to-impossible to make any other way. With 3D printers, Olson says, “anybody can make a custom model”. But not everybody does: many researchers lack easy access to a printer, aren’t aware of the option or can’t afford the printouts (which can cost $100 or more).

Yet Olson says that these models can bring important insights. When he printed out one protein for a colleague, they found a curvy ‘tunnel’ of empty space running right through it. The conduit couldn’t be seen clearly on the computer screen, but a puff of air blown into one side of the model emerged from the other. Determining the length of such tunnels can help researchers to work out whether, and how, those channels transport molecules. Doing that on the computer would have required some new code; with a model, a bit of string did the trick.

Software that lets researchers twist and turn such structures on a computer screen is extremely useful, says Olson, but inadequate. Even the most advanced software will let two atoms occupy the same space. And tinkering with molecules inside a computer is a grind — it takes time for the computer to re-render an object after every turn, and interpreting the pictures requires mental effort. Fiddling with a physical model, on the other hand, is more like play. “I don’t have to think about it; I just do it,” says Olson.

Olson is now trying to meld the tactile advantages of 3D printing with computer power: he has tagged printed models with small paper labels that can be recognized by a webcam, to create an ‘augmented reality’ view. In this way, a user can play with a physical model, while at the same time using the computer to explore aspects such as the potential energy of a given molecular arrangement. Olson is also looking forward to using printers that can more easily swap between rigid and bendable materials, so as to better replicate molecular behaviour such as protein folding.

The cellular matrix

Printer ‘inks’ aren’t limited to plastic. Biologists have been experimenting with printing human cells — either individually or in multi-cell blobs — that fuse together naturally. These techniques have successfully produced blood vessels and beating heart tissue. The ultimate dream of printing out working organs is still a long way off — if it proves possible at all. But in the short term, researchers see potential for printing out 3D cell structures far more life-like than the typical flat ones that grow in a Petri dish.

For example, Organovo, a company based in San Diego, California, has developed a printer to build 3D tissue structures that could be used to test pharmaceuticals. The most advanced model it has created so far is for fibrosis: an excess of hard fibrous tissue and scarring that arises from interactions between an organ’s internal cells and its outer layer. The company’s next step will be to test drugs on this system. “It might be the case that 3D printing isn’t the only way to do this, but it’s a good way,” says Keith Murphy, a chemical engineer and chief executive of Organovo.

Other groups are using 3D printing of plastic or collagen to construct scaffolds on which cells can grow. Carl Simon, a biologist with the biomaterials group at the US National Institute of Standards and Technology in Gaithersburg, Maryland, says that the intricacies of scaffold shape can help to determine how cells grow, or how stem cells differentiate into different cell types. With 3D printing, researchers have a very controlled way to play with different scaffold configurations to see which work best. One problem, however, is that most 3D printers can produce details on the scale of only tens to hundreds of micrometres, whereas cells sense differences at the single-micrometre level. Top-quality printers can currently achieve 100-nanometre resolutions by using very short laser bursts to cure plastics, says Neil Hopkinson, an engineer who works with 3D printing at the University of Sheffield, UK, but this is “still very much in the lab”.

Custom tools

In the meantime, basic plastic 3D printers are starting to allow researchers to knock out customized tools. Leroy Cronin, a chemist at the University of Glasgow, UK, grabbed headlines this year with his invention of ‘reactionware’ — printed plastic vessels for small-scale chemistry (M. D. Symes et al. Nature Chem. 4, 349–354; 2012). Cronin replaced the ‘inks’ in a $2,000 commercially available printer with silicone-based shower sealant, a catalyst and reactants, so that entire reaction set-ups could be printed out. The point, he says, is to make customizable chemistry widely accessible. His paper showed how reactionware might be harnessed to produce new chemicals or to make tiny amounts of specific pharmaceuticals on demand. For now, other chemists see the idea as a clever gimmick, and are waiting to see what applications will follow.

Researchers in other fields have found a more immediate use for the technology. Philippe Baveye, an environmental engineer at Rensselaer Polytechnic Institute in Troy, New York, uses 3D printing to make custom parts for a permeameter — a device used to measure the flow of water through soils. Although commercially available devices are fine for routine work, he has often had to design his own for more precise research — a task that previously required many hours on a lathe. Printing, he says, is much easier.

Perhaps more importantly, Baveye can share his product just by publishing the design file. “The idea of being able to reproduce experiments described in the literature is taking on a new meaning,” he says.

Others agree that the real power of 3D printing lies in its ability to put science into the hands of the many. Cronin wants to enable anyone — whether in the far corners of Africa or in outer space — to print their own tiny drug factory. Museums can already distribute exact copies of rare or delicate fossils as widely as they wish. And students can print out whatever molecule they’re trying to come to grips with. “Through 3D printing,’ says Olson, “the ability to make physical models has become democratized.”

Source: Nature

Arsenic-loving bacterium needs phosphorus after all.



After 18 months of controversy, the official verdict is in: an arsenic-tolerant bacterium found in California’s Mono Lake cannot live without phosphorus.

In 2010, a group led by Felisa Wolfe-Simon, a microbiologist now at the Lawrence Berkeley National Laboratory in Berkeley, California, reported online in Science1 that the Halomonadaceae bacterium GFAJ-1 could include atoms of arsenic instead of phosphorus in crucial biochemicals such as DNA.

 

GFAJ-1 bacteria can live in high concentrations of arsenic — but do not incorporate the element in to their DNA.

Science/AAAS

The bacteria were discovered thriving in the arsenic-rich sediment of the shallow saline Mono Lake, famed for its appearance on a picture-postcard insert to Pink Floyd’s 1975 album Wish You Were Here.

All known forms of life depend on at least six elements: hydrogen, carbon, nitrogen, oxygen, phosphorus and sulphur. Arsenic has some chemical similarities with phosphorus, but is usually toxic to life, so the suggestion that it could sustain life triggered a storm of questions, as well as criticism about how the find was revealed at an enthusiastic NASA press conference (see ‘Microbe gets toxic response’).

As a result of the controversy, when Wolfe-Simon’s paper appeared in print in Science last June, it was accompanied by eight technical comments2–9 from scientists responding to it.

Rosie Redfield, a microbiologist at the University of British Columbia in Vancouver, Canada, set about testing the finding. Earlier this year, she said that she could not reproduce Wolfe-Simon’s results in laboratory experiments (see ‘Study challenges existence of arsenic-based life’).

Redfield is now a co-author of one of two papers that confirm that, although the bacteria can tolerate arsenic, they do depend on phosphorus. The papers were published10, 11 by Science on 8 July.

Toxicity tolerance

Redfield and her colleagues report10 that when GFAJ-1 bacteria were grown in a medium containing arsenic and a very small amount of phosphorus, their DNA contained no detectable arsenic compounds, such as arsenate (the arsenic analogue of phosphate). In the second paper, Julia Vorholt, a microbiologist at the Federal Institute of Technology in Zurich, Switzerland, and her colleagues report11 that the bacterium cannot grow in a phosphorus-free medium in the presence of arsenate. It can, however, grow in low-phosphate conditions in the presence of arsenate. GFAJ-1 “is an arsenate-resistant, but still a phosphate-dependent bacterium”, the team writes.

“I think we have now very solid evidence that the metabolism of GFAJ-1 is as dependent on phosphorus, as are all other known forms of organic life,” says Vorholt. “These very robust and very well-adapted microbes appear to be able to efficiently extract nutrients from their extremely phosphorus-poor environments.”

The samples that Wolfe-Simon’s team had used for their original experiments apparently contained larger concentrations of phosphorus than was first thought, Vorholt adds.

In a statement, Science said: “The new research shows that GFAJ-1 does not break the long-held rules of life, contrary to how Wolfe-Simon had interpreted her group’s data.”

“The original GFAJ-1 paper emphasized tolerance to arsenic, but suggested the cells required phosphorus, as seen in these two new papers,” says Wolfe-Simon. “However, our data implied that a very small amount of arsenate may be incorporated into cells and biomolecules, helping cells to survive in environments of high arsenate and very low phosphate. Such low amounts of arsenic incorporation may be challenging to find and unstable once cells are opened.”

The story of GFAJ-1 is far from over, she adds. “The key questions are: how do these cells thrive in lethal concentrations of arsenic? And where does the arsenic go?”

Source: Nature

Law spurs regulators to heed patients’ priorities.


US  to consider risks and benefits more explicitly in drug approvals.

When the prescription weight-loss drug Belviq (lorcaserin) was approved on 27 June, onlookers wondered what had changed. Two years ago, the US Food and Drug Administration (FDA) rejected the drug because of the possibility that it can damage heart valves, like similar anti-obesity drugs. Had the agency revised its thinking after hearing pleas from obese people who wanted the drug, deciding that the benefits outweighed the risks? “Right now, it’s impossible for us to understand how the benefit–risk calculation was conducted,” says Marc Boutin, executive vice-president of the National Health Council, a patient-advocacy group in Washington DC.

That situation is due to change. The agency is working to establish a framework that formally takes into account the trade-offs between risks and benefits — including the way they are prioritized by patients. Patient and industry groups hope that the approach will result in greater transparency for FDA reviews, and perhaps more drug approvals for a wider array of patient populations. On 9 July, the agency’s efforts received a further push, when President Barack Obama signed into law the FDA Safety and Innovation Act, which, among many other provisions, orders the agency to forge ahead with the framework.

If the FDA’s procedures are in place by October 2013 as planned, the agency should be better equipped to explain why it approved a drug such as Belviq for a specific group of people in the population. “Let’s make the risks and benefits as clear as a food label, so the decision can be articulated in a way that people understand,” says Boutin.

One challenge is how to incorporate patients’ views. Although patients and their advocates sometimes speak briefly at FDA advisory meetings, they may not represent all patients, and it is unclear how reviewers take their views into account. Boutin notes that the priorities of sick people can be very different from what healthy people assume them to be. For example, he says, FDA reviewers might assume that patients with psoriasis want treatments that are most effective at shrinking the size of their skin lesions, regardless of where they occur. But in fact, he says, people with psoriasis care most about eliminating lesions on their faces.

To gain a better sense of patients’ views, the FDA will hold 20 disorder-specific meetings with patient groups over the next five years. One way of structuring the meetings, suggested by the National Health Council, would be to divide people into groups who may have common views about the risk–benefit trade-offs, such as those with progressively worsening conditions, and those in their final years of life. “We’ll experiment until we get it right,” says Janet Woodcock, head of the FDA’s drug-approval centre.

Boutin says that he expects drug approvals under the new system to better reflect the risk–benefit trade-offs in the minds of people needing the drugs, not those reviewing them. Because patients with crippling conditions may tolerate higher risks than those with milder problems, this could mean that medicines for certain severe illnesses — especially diseases with few treatment options — have a greater chance of being approved, he says. However, Woodcock says that the FDA isn’t aiming to alter approval rates, but rather to create a more consistent and transparent approval process.

Industry will benefit, says Peter Greenleaf, president of MedImmune — the biologics arm of pharmaceutical company AstraZeneca — based in Gaithersburg, Mary­land. Greenleaf says that the mandate to create a risk–benefit framework is one of the most important parts of the new FDA law. “Hopefully, this will allow for a higher degree of alignment between how industry assesses the risks and benefits of a drug and how the FDA does, so that we’re not just shooting in the dark,” he says. That would allow companies to streamline their studies, Greenleaf adds.

However, the FDA’s pilot framework won’t weigh up risks and benefits with numbers, as some stakeholders had hoped, but will instead assess them in words. The Centre for Innovation in Regulatory Science (CIRS) in London has spent years constructing quantitative risk–benefit assessment models, and drug companies already use them in pre-approval market research. In theory, such models provide more consistent results between drug-approval cases because they are less subjective. But Woodcock says that models with too many numbers would hamper the FDA’s efforts to communicate its decisions to the public. “You start losing people,” she says.

A few years ago, Europe’s drug-regulatory body, the London-based European Medicines Agency, piloted the use of quantitative models, but earlier this year gave them up in favour of a qualitative approach. But Stuart Walker of the CIRS predicts that regulatory agencies around the world will eventually shift to numerical models. Still, he adds, “I think building an explicit framework is a super first step”.

Source: Nature.

Genome study highlights risk factor for multiple sclerosis.


Discovery of genetic variant could help to improve clinical trials of potential therapies.

Like diabetes, most forms of cancer and other common diseases, there is no single gene that causes the autoimmune condition multiple sclerosis (MS). Dozens of genetic variations act in concert with environmental factors to cause the debilitating neurological disease.

Yet a single genetic variant may explain why drugs that treat other autoimmune diseases tend to make MS symptoms worse, and could identify other MS patients who might benefit from the therapies. Researchers say that the findings, which are published online in Nature1, also highlight how genome-wide association studies (GWAS) can yield useful medical insights.

GWAS compare thousands of people who have a particular disease, detailing hundreds of thousands of genetic variations between them. The goal is to identify variations that are more common in people with the condition than in healthy people. Most such studies uncover scores of genetic variants associated with the disease in question, each increasing a person’s chances of developing the condition by a small percentage.

Such is the case for a DNA letter in the gene that encodes the protein called tumour necrosis factor receptor 1 (TNFR1). The protein senses a potent immune molecule called tumour necrosis factor (TNF) that destroys cancerous cells but that is also implicated in autoimmune disease. People of European ancestry who have two ‘A’s at that particular spot on the genome are 12% more likely to develop MS than those with two ‘G’s at that spot.

Lars Fugger, a neurologist at the University of Oxford, UK, and his team discovered that the variant A shortens the TNF receptor 1 protein. Normally, the protein sits within a cell’s membrane, where it can sense TNF molecules circulating outside the cell and convey their instructions to that cell. The protein starts a cascade that can lead to inflammation and cell death. But the shortened form of the protein never makes it into the membrane, Fugger’s team found. Instead it is probably shunted outside the cell, where it can bind TNF molecules, stopping them from signalling to cells.

Biologic drugs that block TNF from signalling to cells have revolutionized treatment for autoimmune conditions such as rheumatoid arthritis over the past decade, says Fugger. Yet despite achieving some encouraging results in animal models of MS, drugs that block the activity of TNF tend not work in patients with MS. In fact, they usually make symptoms worse, and they may even have caused the disease in people predisposed to it, says Fugger. He thinks the variation his team studied could explain why.

Fugger says it is unclear how TNF influences MS, but in patients with the gene variant, the TNF-blocking drugs could be providing a double-whammy by suppressing TNF signalling further. The normal receptor prevents mice from developing symptoms of a model of MS2.

It is not clear whether TNF-blocking drugs might help MS patients who don’t have the TNF variant, says Fugger, but taking a closer look at the genetics of the patients who received the treatment as part of clinical trials in the 1990s could provide the answer.

Alastair Compston, a neurologist at the University of Cambridge, UK, who led a consortium that last year identified dozens of genetic risk factors for MS in nearly 10,000 MS patients3, says there is overwhelming genetic evidence that TNF is somehow involved in the condition. “Therefore the potential for manipulating it therapeutically is real,” he says.

Fugger hopes that his team’s study will also help to dispel the notion that genome-wide association studies will never offer much that can be used in patient care (see ‘Human genetics: Hit or miss‘). If doctors had known that TNF-blocking drugs mimic the effects of a major risk factor for the disease, they might have designed their clinical trials differently, he says. “The idea is you can use GWAS studies to decide which drugs should be used and which should not be used,” Fugger says.

Source: Nature

 

 

Surprising Cancer-Fighting Benefits of Pineapple Enzyme.


One of the reasons why conventional cancer treatment is such a dismal failure in the United States is because it relies on chemotherapy.

Chemotherapy drugs are, by their very nature, extremely toxic and typically work against your body’s natural ability to fight cancer, e.g. destroying host immunity instead of supporting it.

One of the biggest drawbacks to chemotherapy is the fact that it destroys healthy cells throughout your body right along with cancer cells, a “side effect” that often leads to accelerated death, not healing.

Another devastating side effect of chemotherapy is the way it actually supports the more chemo resistant and malignant cell subpopulations within tumors (e.g. cancer stem cells), both killing the more benign cells and/or senescent cells within the tumor that keep it slow-growing, or even harmless.

As a result, this unleashes a more aggressive, treatment-resistant type of cancer to wreak havoc on the body.

A handful of natural compounds have been discovered, however, which exhibit an effect called “selective cytotoxicity.”  This means they are able to kill cancer cells while leaving healthy cells and tissue unharmed.

This type of cancer treatment is intelligent, targeted and will not result in the death of the patient from “collateral damage” in what is increasingly a failed war not against the cancer being treated, but the patient’s own irreversibly devastated body.

Bromelain in Pineapples Kills Cancer Cells Without Harming You

One such compound is bromelain, an enzyme that can be extracted from pineapple stems. Research published in the journal Planta Medica found that bromelain was superior to the chemotherapy drug 5-fluorauracil in treating cancer in an animal study.i Researchers stated:

“This antitumoral effect [of bromelain] was superior to that of 5-FU [5-fluorouracil], whose survival index was approximately 263 %, relative to the untreated control.”

What makes this impact particularly impressive is that the bromelain worked without causing additional harm to the animals. The chemo drug 5-fluorauracil, on the other hand, has a relatively unsuccessful and dangerous track record despite being used for nearly 40 years.

As written by GreenMedInfo:

“As a highly toxic, fluoride-bound form of the nucleic acid uracil, a normal component of RNA, the drug is supposed to work by tricking more rapidly dividing cells — which include both cancer and healthy intestinal, hair follicle, and immune cells — into taking it up, thereby inhibiting (read: poisoning) RNA replication enzymes and RNA synthesis.…

When a person dies following conventional cancer treatment it is all too easy to “blame the victim” and simply write that patient’s cancer off as “chemo-resistant,” or “exceptionally aggressive,” when in fact the non-selective nature of the chemotoxic agent is what ultimately lead to their death.”

Selective cytotoxicity is indeed a property that is only found among natural compounds; no chemotherapy drug yet developed is capable of this effect. Aside from bromelain, other examples of natural compounds that have been found to kill cancer cells without harming healthy cells include:

  • Vitamin C — Dr. Ronald Hunninghake carried out a 15-year research project called RECNAC (cancer spelled backwards). His groundbreaking research in cell cultures showed that vitamin C was selectively cytotoxic against cancer cells.
  • Eggplant extract: Solasodine rhamnosyl glycosides (BEC), which is a fancy name for extracts from plants of the Solanaceae family, such as eggplant, tomato, potato, Bell peppers, and tobacco, also impact only cancerous cells leaving normal cells alone. Eggplant extract cream appears to be particularly useful in treating skin cancer. Dr. Bill E. Cham, a leading researcher in this area, explains:

“The mode of action of SRGs [glycoalkaloids solasodine rhamnosy glycosides (BEC)] is unlike any current antineoplastic [anti-tumor] agent. Specific receptors for the SRGs present only on cancer cells but not normal cells are the first step of events that lead to apoptosis in cancer cells only, and this may explain why during treatment the cancer cells were being eliminated and normal cells were replacing the killed cancer cells with no scar tissue being formed.”

  • Turmeric (Curcumin Extract): Of all the natural cancer fighters out there, this spice has been the most intensely researched for exhibiting selective cytotoxicity.ii Remarkably, in a 2011 study published in the Journal of Nutritional Biochemistry, rats administered curcumin, the primary polyphenol in turmeric, saw a decrease in experimentally-induced brain tumors in 9 out of 11 treated, while noting that the curcumin did not affect the viability of brain cells “suggesting that curcumin selectively targets the transformed [cancerous] cells.”

How Enzymes Might Help Treat Cancer

Bromelainis a proteolyticenzyme (an enzyme that digests proteins). In the Planta Medica study, it was injected directly into the abdominal cavity. Getting enzymes from your digestive tract into your bloodstream isn’t as easy as it would seem, as enzymes are very susceptible to denaturing and must be helped to survive the highly acidic environment in your stomach. They are often given an “enteric coating” to help them survive the journey through your digestive tract.

And then, there is the matter of absorption. For nearly 100 years, medical dogma insisted that enzymes taken orally were too large to pass through the digestive tract wall.

However, there is now a good deal of research that they can indeed pass through your intestine intactiii and into your bloodstream and lymphatic system, where they can deliver their services to the rest of your body… one of the mysteries of medical science.

Now that we know this is possible, systemic oral enzymes have been used to treat problems ranging from sports injuries to arthritis to heart disease and cancer, particularly in European countries. But most of the research has been published in non-English language journals.

Is Cancer the Result of Diminished Pancreatic Enzymes?

This systemic use of enzymes is just now taking off in the United States, but the use of enzymes to treat cancer has its roots all the way back to 1911 with John Beard’s The Enzyme Treatment of Cancer and Its Scientific Basis. Beard believed cancer was a result of diminished pancreatic enzymes, impairing your immune response. A study in 1999iv suggests he may have been right on target.

Ten patients with inoperable pancreatic cancer were treated with large doses of oral pancreatic enzymes (along with detoxification and an organic diet), and their survival rates were 3 to 4 times higher than patients receiving conventional treatment. Proteolytic enzymes can be helpful in treating cancer because they help restore balance to your immune system. Dr. Nick Gonzalez in New York City, NY has also done a lot of work on enzymes in cancer treatment and has written a book on the subject.v

Some of the ways proteolytic enzymes can be helpful in the fight against cancer are:vi

  • Boosting cytokines, particularly interferon and tumor necrosis factor, which are very important warriors in destroying cancer cells.
  • Decreasing inflammation.
  • Dissolving fibrin: Cancer cells hide under a cloak of fibrin to escape detection. Once the cancer cells are “uncloaked,” they can be spotted and attacked by your immune system. It is also thought that fibrin makes cancer cells “stick together,” which increases the chance for metastases.
  • German studies have shown that systemic enzymes increase the potency of macrophages and killer cells 12-fold.

Fortunately, you get (or should be getting) many enzymes from the foods you consume—particularly, raw foods. These directly help with your digestive process. The more raw foods you eat, the lower the burden on your body to produce the enzymes it needs, not only for digestion, but for practically everything. Whatever enzymes are not used up in digestion are then available to help with other important physiological processes.

This is one of the reasons why it is so important to eat a diet rich in fresh, organic, raw foods. You may even want to try juicing some of your vegetables, and the core of your pineapple, as a way of getting more nutrients—and enzymes—into your body. In the event you use enzymes in supplement form, it is crucial that, in order for enzymes to be used systemically, they must be consumed on an empty stomach. Otherwise, your body will use them for digesting your food, instead of being absorbed into the blood and doing their work there.

Looking for an Alternative to Chemo for Cancer Treatment?

Dr. Gonzalez is on the front lines and actively engaged in helping people by coaching them with natural alternatives instead of toxic drugs and radiation for cancer. I would personally not hesitate to recommend him to a family member or a friend diagnosed with cancer. His website, www.dr-gonzalez.com, also contains information on how to become a patient, and everything a potential patient needs to know.

Another source for more information about alternative cancer treatments in general is Suzanne Somers’ book, Knockout. She reviews Dr. Gonzalez’ work in one chapter, and Dr. Gonzalez personally recommends the book as a well-researched resource for anyone interested in getting more information.

Additionally, Dr. Gonzalez has written a series of books, two of which have already been published and received five-star reviews: The Trophoblast and the Origins of Cancer and One Man Alone: An Investigation of Nutrition, Cancer, and William Donald Kelley. Three others are in the works, one of which will contain 100 of Dr. Gonzalez’ case reports of patients with advanced cancer who successfully recovered on his program.

Source: Dr. Mercola