Melanoma antibody approved

The March 25 US Food and Drug Administration (FDA) approval of Bristol-Myers Squibb’s Yervoy (ipilimumab) for metastatic melanoma was expected, but the breadth of the approval was not. Yervoy, a human monoclonal antibody targeting cytotoxic T-lymphocyte activator-4 (CTLA4) developed by the New York–based company, is the first agent to prolong survival in a phase 3 trial in metastatic melanoma . The FDA has given the green light for Yervoy to be used in a first-line setting even though the pivotal trial included only individuals who had progressed on other treatments. It was “exactly the right decision,” says oncologist Mario Sznol of Yale University in New Haven, Connecticut, as no current first-line treatment improves survival in metastatic melanoma. FDA approval also allows patients who respond initially to Yervoy, but who later relapse, to receive another course of the drug. Sznol expects rapid adoption of the drug by oncologists, despite a $120,000 wholesale price tag for a single four-infusion course of treatment. “The first thing that has to be on your mind when somebody comes in with metastatic melanoma would be ipilimumab, based on the data,” Sznol says. Chris Schott, a pharma analyst at JP Morgan in New York, raised his earlier Yervoy estimates based on the higher-than-expected pricing, and now forecasts sales of $170 million in 2011, growing to $1.25 billion by 2015. Defending the price, Bristol-Myers Squibb spokesperson Sarah Koenig stresses the company’s aggressive patient-assistance program. In the US, this “will enable coverage of virtually all, approximately 98%, of uninsured patients,” she writes in an e-mail. Another metastatic melanoma drug likely to win approval in the near term is PLX4032 (vemurafenib). PLX4032, a small-molecule inhibitor of mutant BRAF, was developed by the Berkeley, California–based Plexxikon, which was acquired by the Tokyo-based Daiichi Sankyo on April 4. PLX4032 produces higher response rates than Yervoy and an undisclosed survival benefit, although virtually all individuals taking the treatment relapse. So the drug probably won’t hurt Yervoy sales even in the roughly half of metastatic melanoma patients who qualify for PLX4032, says Sznol, as most will end up taking Yervoy eventually. Plexxikon plans to apply for FDA registration this year.

source: nature biotechnology

New Strategies in Muscle-Invasive Bladder Cancer: On the Road to Personalized Medicine

Bladder cancer remains one of the most deadly and expensive diseases affecting modern society. The options currently available to patients with muscle-invasive bladder cancer have remained essentially unchanged for the last generation. As the roles for surgery and chemotherapy in the management of this lethal disease have become better defined, so too have the limitations of these two treatment modalities. Despite the lack of groundbreaking clinical advances over the past two decades, recent years have witnessed a notable increase in the amount of promising preclinical and early translational research that will greatly improve our understanding of the molecular underpinnings of bladder cancer. If this momentum in bladder cancer research continues to build, it is likely that in the next 5 to 10 years we will be able to achieve our goal of bringing bladder cancer treatment into the age of personalized medicine.

source: clinical cancer research

Antiuniverse here we come

A controversial cosmic-ray detector destined for the International Space Station will soon get to prove its worth.

The Alpha Magnetic Spectrometer will ride to orbit in the space shuttle Endeavour’s cargo bay.M. Famiglietti/AMS Collaboration

The next space-shuttle launch will inaugurate a quest for a realm of the Universe that few believe exists.

Nothing in the laws of physics rules out the possibility that vast regions of the cosmos consist mainly of antimatter, with antigalaxies, antistars, even antiplanets populated with antilife. “If there’s matter, there must be antimatter. The question is, where’s the Universe made of antimatter?” says Samuel Ting, a Nobel-prizewinning physicist at the Massachusetts Institute of Technology in Cambridge, Massachusetts. But most physicists reason that if such antimatter regions existed, we would have seen the light emitted when the particles annihilated each other along the boundaries between the antimatter and the matter realms.

No wonder, then, that Ting’s brainchild, a US$2-billion space mission sold partly on the promise of looking for particles emanating from antigalaxies, is fraught with controversy. But the project has other, more mainstream scientific goals. So most critics held their tongues last week as the space shuttle Endeavour prepared to deliver the Alpha Magnetic Spectrometer (AMS) to the International Space Station, in a flight delayed by shuttle problems until later this month.

Pushing the boundaries

Seventeen years in the making, the AMS is the product of former NASA administrator Dan Goldin’s quest to find remarkable science projects for the space station and of Ting’s fascination with antimatter. Funded by NASA, the US Department of Energy and a consortium of partners from 16 countries, it has prevailed despite delays and technical problems, and the doubts of many high-energy and particle physicists.

“Physics is not about doubt,” says Roberto Battiston, deputy spokesman for the AMS and a physicist at the University of Perugia, Italy. “It is about precision measurement.” As their experiment headed to the launch pad, he and other scientists were keen to emphasize the AMS’s unprecedented sensitivity to the gamut of cosmic rays that rain down on Earth. That should allow it not just to detect errant chunks of antimatter from the far Universe, but also to measure the properties of cosmic rays, the high-energy, charged particles flung from sources ranging from the Sun to distant supernovae and γ-ray bursts.

On Earth, cosmic rays can only be detected indirectly, from the showers of secondary particles they produce when they slam into molecules of air high above the ground. From space, the AMS will get an undistorted view. “We’ll be able to measure cosmic-ray fluxes very precisely,” says collaboration member physicist Fernando Barão of the Laboratory of Instrumentation and Experimental Particle Physics in Lisbon. “The best place to be is space because you don’t have Earth’s atmosphere that is going to destroy those cosmic rays.” No matter what happens with the more speculative search for antimatter, the AMS should produce a definitive map of the cosmic-ray sky, helping to build a kind of astronomy that doesn’t depend on light.

The AMS consists of a powerful permanent magnet surrounded by a suite of particle detectors. Over the ten or so years that the experiment will run, the magnet will bend the paths of cosmic rays by an amount that reveals their energy and charge, and therefore their identity. Some will turn out to be heavy atomic nuclei, and any made from antimatter will reveal themselves by bending in the opposite direction from their matter counterparts.

Click for larger image

By counting positrons — antimatter electrons — the AMS could also chase a tentative signal of dark matter, the so-far-undetected stuff that is thought to account for much of the mass of the Universe. In 2009, researchers with the Russian–Italian Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics, flying on a Russian satellite, published evidence of an excess of positrons in the space environment surrounding Earth . One potential source is the annihilation of dark-matter particles in the halo that envelops the Galaxy.

Another speculative quest is to follow up on hints of ‘strange’ matter, a hypothetical substance, perhaps found in some collapsed stars, that contains strange quarks along with the up and down quarks in ordinary nuclei. NASA’s AMS programme manager, Mark Sistilli, says that hints of strange matter were seen in a pilot flight of the AMS aboard the shuttle in 1998, but that the results were too tentative to publish.

Thanks to its status as an exploration mission, the AMS did not need to go through the peer review that NASA would normally require of a science mission. But Sistilli emphasizes that it earned flying colours from committees convened by the energy department, which is supplying $50 million of the funding. Now their confidence will be put to the test.

source: nature news

Sirtuins, Longevity, and Adaptations to Nutrient Availability

Over the last century, scientists have provided several hypotheses to explain how and why organisms age. Though at times seemingly unconnected, these hypotheses are beginning to be stitched together by newly uncovered biochemistry, much of which involves a class of enzymes known as sirtuins. Almost 80 years ago researchers Clive McCay and Mary Crowell at Cornell University found that caloric restriction extended the life span of rats. In the mid 1950s, Denham Harman of the University of California, Berkeley advanced the idea that aging was caused by oxygen free radical species within the body. Sirtuins entered the biochemical discussion of aging in 1995 with a publication by Leonard Guarente’s group in Cell in which they indicated that SIRT4 extended the lifespan of yeast.

As of this meeting on February 22, 2011, nearly 1200 papers have been published about these enzymes compared with just a handful published by 2000. Organized by Anthony Sauve of Weill Cornell Medical College and Jennifer Henry of the New York Academy of Sciences, this session of the Biochemical Pharmacology Discussion Group brought together several of the leading researchers studying the biology and biochemistry of sirtuins and their role in aging and aging-related diseases such as diabetes, cancer, and neurogenerative disorders. Johan Auwerx of the Ecole Polytechnique Fédérale Lausanne described his laboratory’s efforts to understand nicotinamide adenine dinucleotide (NAD+), a cofactor that facilitates protein deacetylation by sirtuins, in metabolism. Leonard Guarente of MIT discussed the involvement of sirtuins in reproduction, cancer, and neurodegenerative diseases. Eric Verdin of the Gladstone Institute at UCSF explored SIRT3’s role in fat metabolism. David Sinclair of Harvard Medical School described work with resveratrol and other small molecules to modulate sirtuin activity. Anthony Sauve of Weill Cornell Medical College discussed work to uncover the details of the biochemistry of sirtuins to understand and visualize their function within cells.

source: the Newyork academy of science

Mice with PTSD help neuroscientists understand memories

Scientists are homing in on the structures that help the brain avoid faulty recall. These help keep memories precise by preventing unrelated events from evoking them.

Understanding the (mal)functioning of memory retrieval may help deal with memory disorders and learning disabilities.

A group led by Pico Caroni at the Friedrich Miescher Institute looked at synaptic structures – the structures involved in signal transmission from neuron to neuron – in the hippocampus region of mouse brains.

These mice went through a fear-conditioning procedure where their paws received electric shocks in a particular room.

  1. If, after a couple days, they entered that room, they would freeze in fear. In a different but similar room, they sniffed about as normal.
  2. However, after about 2 weeks, the mice froze in both rooms. The memory had been generalized, producing a response to a wide range of cues instead of the specific one that had been learned.

“The memory is still there, it might be there forever,” says Caroni. “But it changes.”

As the team followed changes in the hippocampus during the conditioning process, they found a large increase in the numbers of synaptic structures at the ends of neurons called granule cells. These have axons called large mossy fibres after the memories were formed. By the time the memory had been generalized, these synaptic structures had disappeared.

  1. Then the researchers put mice that lacked a protein necessary to form the synaptic connections through the same shock treatments. In these mice, the memory became generalized after only one day.
  2. But when the team introduced that protein into the mossy-fibre neurons in the hippocampus, the mice recovered the ability to maintain precise memories for weeks.

New synapses form when new skills are learned, and Caroni’s experiments suggest that one of their roles is to inhibit the retrieval of the memory in response to unrelated cues.

With post-traumatic stress disorder (PTSD), traumatic memories are evoked by environments very different from those in which they originated. Signals in safe places can mistakenly evoke emotions that rightly belong to a battlefield tragedy.

The generalization of the mouse memories was a form of PTSD, but when the mice were reintroduced to the environment in which they were fear-conditioned, the synaptic structures reappeared within a couple hours and the precise memories were reinforced, saving them from anxiety in other environments.

In the same vein, one treatment for PTSD is exposure therapy, when patients are reintroduced to the place where the traumatic events happened in order to help them control their fears.

Loss of suppression of spurious associations may also be involved in other neuropsychiatric disorders, including autism spectrum disorders and schizophrenia.

source:  Nature News.

How a nanotechnology advance could make drug development faster.

Researchers at Stanford University are using nanosensors to transform a centimeter-sized microchip into a stand-in for the human body in the drug development process. A tiny, protein-packed chip could let drug developers measure a medication’s affinity for every human protein with just one test.

I spoke last week with Richard Gaster, a PhD candidate in bioengineering and medicine and first author of the paper in Nature Nanotechnology. Below are excerpts from our interview.

How could a centimeter-sized microchip with nanosensors impact the drug development process?

The advantage to using a nanosensor is we can pack many, many sensors into one small array. It’s just as costly for us to have one sensor in a centimeter square as it is to have a thousand. By using nanotechnology to make these high-density sensor arrays, we are able to screen for many different interactions simultaneously. You have a unique protein on each sensor. Sensor 1 will have liver protein. Sensor 2 will have kidney protein. Sensor 3 will have brain protein and so on. We can add the drug to the sensor array to see how strong the drug binds to these different proteins. Instead of looking for interactions to each of these in separate experiments, we can look at everything [in one experiment].

Take me through the process of using this microchip during drug development.

The goal is to test once a drug is developed. If you’re developing a breast cancer drug, you want to see how strongly it binds to the breast cancer target. You keep modifying it to make it stronger. But before you put it in a human, you want to know how strongly it binds to other targets as well. We’re not developing the drugs. Our goal is to test them before you put them in a human.

The sensors we’re using are actually used in your computer hard drive. We’re using the same sensor technology to detect proteins that are labeled with a magnetic bead. As a protein comes closer to our sensor, the magnetic bead that is bound to it comes closer and can detect the presence of the protein. We’ll label the drug with the magnetic bead. By employing this magnetic label, we can get much more sensitive detection and much quicker results. Part of the innovation is that people haven’t used these labels for kinetic information. We have to write a new mathematical model to understand what we’re seeing. We then compared the existing standard technology to ours. We got equally quantifiable data, but we can do it on a more massive scale and much quicker.

Can you explain in greater detail how this advances the current standard?

Adding a tag — this magnetic label — to the protein changes the binding interaction. We have to be able to understand how it changes the binding interaction to calculate the affinity without the label. By writing a new model to account for this effect, we can remove the effect in the end.

What’s the next step for this work?

The next step is to put this into real practice. Doing experiments in the laboratory setting is the first step to the proof of principle. The ultimate goal is to scale it up [and] be able to test every protein in the human body. [We want] to start putting different drugs on it to see how these drugs interact with all the proteins. When these drugs are put in human patients, we want to see whether our technology is capable of predicting adverse effects.

source: IBM smart planet

Intel debuts 3-D transistors; cars, phones, spacecraft get smarter.

The electronics in your world — from your car to your smartphone to your appliances and even wind turbines — just took another leap forward.

Intel on Wednesday announced the debut of its Tri-Gate transistors, the world’s first in three dimensions and the next step in sustaining Moore’s Law.

The new transistors — which will first appear in 22-nanometer microprocessors codenamed “Ivy Bridge” — will allow higher performing gadgets with less power consumption.

Transistors, of course, are the building block of electronics. They’re in the processor in your laptop, they’re in the control systems in your space shuttle, they’re in medical devices and household appliances and virtually anything that has some degree of intelligence to it.

The problem with sustaining the pace of Moore’s Law — in which transistor density doubles every two years — is that device dimensions have become so small that Moore’s Law was running up against the laws of physics itself. Intel claims the transistor’s new three-dimensional structure removes this hurdle.

It also allows for higher performance and increased energy efficiency compared to conventional transistors. That means more electronics in more places taking up less space — important if we plan to digitize the real world, taking computing out of the computer and putting it into highways, bus stops and other everyday objects that could use a dose of smarts.

The new transistor, as described by Intel:

The 3-D Tri-Gate transistors are a reinvention of the transistor. The traditional “flat” two-dimensional planar gate is replaced with an incredibly thin three-dimensional silicon fin that rises up vertically from the silicon substrate. Control of current is accomplished by implementing a gate on each of the three sides of the fin – two on each side and one across the top — rather than just one on top, as is the case with the 2-D planar transistor. The additional control enables as much transistor current flowing as possible when the transistor is in the “on” state (for performance), and as close to zero as possible when it is in the “off” state (to minimize power), and enables the transistor to switch very quickly between the two states (again, for performance).

Intel says its structure allows engineers to manage density, not unlike a skyscraper in a crowded city, which allows more use of less space by looking up.

“Amazing, world-shaping devices will be created from this capability as we advance Moore’s Law into new realms,” Intel CEO Paul Otellini said in a statement.

source: IBM/ smart planet

Emergence of Promising Therapies in Diabetes Mellitus

Diabetes mellitus (DM) results from defects in insulin secretion (type 1) or insulin resistance (type 2). Insulin is used to manage type 1 DM, and oral hypoglycemic agents are used to manage type 2 DM. These therapies are inconsistent in maintaining glycemic control and cause some severe adverse effects such as undue weight gain and hypoglycemia. New and appropriate therapies are needed to overcome these problems. Drugs that are in the pipeline include oral insulins for type 1 DM and incretin mimetics, incretin enhancers, gastric inhibitory peptides, amylin analogues, peroxisome proliferator-activated receptor-α/γ ligands, sodium-dependent glucose transporter inhibitors, and fructose 1,6-bisphosphatase inhibitors for type 2 DM. This article describes the mechanisms of action and relative advantages and disadvantages of the promising therapies.

source: journal of clinical pharmacology

FDA Warns About Teething Medication

Main Ingredient Benzocaine Linked to Rare, Serious Disease
baby chewing on teething ring

The FDA has issued a warning to consumers about the use of benzocaine, the main ingredient in over-the-counter liquids and gels used to reduce teething pain in very young children.

Benzocaine is associated with a rare but serious condition called methemoglobinemia, which greatly reduces the amount of oxygen carried through the bloodstream. In the most severe cases, the condition can be life-threatening.

Benzocaine by Various Names

Benzocaine gels and liquids are sold under numerous brand names, including Anbesol, Hurricaine, Orajel, Baby Orajel, and Orabase, as well as store brands. It also is sold as lozenges and in spray solutions.

The products are used to treat pain caused by teething, canker sores, and irritation of the mouth and gums.

The FDA says methemoglobinemia has been reported with all strengths of benzocaine gels and liquids, including concentrations as low as 7.5%. The federal agency says most cases occur in children aged 2 or younger who were treated with a gel for teething discomfort.

The FDA says people who develop the condition may become pale or gray, become short of breath, feel fatigued, confused, and lightheaded. It also may cause a rapid heart rate.

Immediately Seek Medical Help for Symptoms

Signs and symptoms of a reaction to benzocaine usually appear within minutes to hours of using it. The FDA says adults should seek immediate medical attention if symptoms show up after using benzocaine.

The FDA says benzocaine products should not be given to children younger than age 2 unless under the supervision of a health care professional. The American Academy of Pediatrics recommends giving children with teething problems a teething ring that has been chilled in a refrigerator, or gently rubbing the child’s gums with a finger.

Adults who use benzocaine gels or liquids in the mouth should follow recommendations on the label of the product, which should be stored where it can’t be reached by children, the FDA says.

However, the FDA says labels of marketed benzocaine products do not, as of yet, contain warnings about the risks of methemoglobinemia.

The FDA offers these tips for parents:

  • If benzocaine products are used, watch carefully for signs and symptoms of methemoglobinemia, including pale, gray, or blue-colored skin, lips, and nail beds. Also, shortness of breath, fatigue, confusion, headache, lightheadedness, and rapid heart rate are symptoms of a reaction. If any symptoms occur, seek medical attention immediately.
  • Keep in mind that problems caused by benzocaine can show up after a single administration of the product.
  • Use benzocaine gels and liquids sparingly, and only when needed, and not more than four times a day.
  • Side effects should be reported immediately to the FDA Medwatch program.

source: webMD

Infant-Strength Acetaminophen to Be Discontinued, Just One Children’s Concentration Will Be Available

Infant-strength drops of acetaminophen, sold at a concentration of 80 mg/0.8 mL, will be pulled from the market by the middle of this year in an effort to have just one concentration (160 mg/5 mL) of liquid acetaminophen available to children under 12 years of age, according to a midweek announcement from the Consumer Healthcare Products Association.

The association’s president and CEO said the change should “make it easier for parents and caregivers to appropriately use single-ingredient liquid acetaminophen.”

When marketed for infants, the 160-mg/5-mL acetaminophen will come with syringes and flow restrictors; for older children, the drug will continue to come with dosing cups.

Source: Consumer Healthcare Products Association news release