Predictive Medicine-Scientists SeekTo Predict Viral Mutations Before They Happen

HuMod.com-Preparing vaccines and therapeutics that target a future mutant strain of H5N1 influenza virus sounds like science fiction, but it may be possible, according to a team of scientists at the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), and a collaborator at Emory University School of Medicine. Success hinges on anticipating and predicting the crucial mutations that would help the virus spread easily from person to person.

Led by Gary Nabel, M.D., Ph.D., director of the NIAID's Dale and Betty Bumpers Vaccine Research Center (VRC), the team is reporting in the August 10, 2007 issue of the journal "Science" that they have developed a strategy to generate vaccines and therapeutic antibodies that could target predicted H5N1 mutants before these viruses evolve naturally. This advance was made possible by creating mutations in the region of the H5N1 hemagglutinin (HA) protein that directs the virus to bird or human cells and eliciting antibodies to it.

Articles like these lead me to believe that Super AI and Non-Biological Human Intelligence will excel at their predictive abilities. As they gain knowledge, they'll form more and more accurate models of the future. If we were to extrapolate this out to its final conclusion, then the question becomes, what will be their final prediction? Will it be that a stalemate with a future universe is inevitable or will it be a checkmate with the score Universe one, intelligence zero. What then does SAI and NBHI do then, reboot perhaps?

Right now, some of us have already concluded that biological humans will be, if not extinct, then resigned to being a pet of Super AI. If we can reasonably predict this then what reasons would SAI have to not predict, likewise, it's own end. If it predicts a particular technological advancement or, even better, many technological advancements and then makes technological predictions of those advancements and so on through hundreds of thousands of iterations, what would they see? And if they can continue making highly accurate predictions then what would be the incentive to actually carry out physical experiments? Why not just continue until the accuracy drops below an always improving threshold. What if SAI gets so good at running predictive simulations that it decides that it doesn't need to do anything else. It decides instead, to just lay quietly, diligently, expertly, and feverously, computing and using its results as feedback for further simulations thereby reaching ever silently into the future...until?

Chemists using light-activated molecules to kill cancer cells

A key challenge facing doctors as they treat patients suffering from cancer or other diseases resulting from genetic mutations is that the drugs at their disposal often don’t discriminate between healthy cells and dangerous ones -- think of the brute-force approach of chemotherapy, for instance. To address this challenge, Florida State University researchers are investigating techniques for using certain molecules that, when exposed to light, will kill only the harmful cells.

Please visit PhysOrg.com for completed article.

Electric fields have potential as a cancer treatment

Healthy cells have regulating mechanisms that generally limit how rapidly they can divide. Skin cells, for example, normally divide about once every 30 days, but they can divide faster in response to a wound that needs healing. Cancer, however, is characterized by cell division that has gone out of control. In cancer cells, the mechanisms that regulate division break down, and the cells spend less time in the quiescent state and more time dividing.

Many chemotherapy drugs work by interfering with the cell-division cycle. The drugs reach healthy cells and cancer cells alike, but they do most of their damage to the cancer cells. Unfortunately, some types of healthy cells divide as rapidly as cancer cells and are badly damaged as well. Such cells are found in bone marrow, the lining of the digestive tract, and hair follicles, so chemotherapy patients often lose their hair and are susceptible to infection. The damage to healthy cells limits the drug dose that a patient can tolerate and therefore limits the treatment's effectiveness.

Yoram Palti, of the Technion–Israel Institute of Technology in Haifa, and his colleagues have demonstrated another way to disrupt cell division: alternating electric fields with intensities of just 1–2 V/cm. The fields they use, with frequencies in the hundreds of kilohertz, were previously thought to do nothing significant to living cells other than heating them. But Palti and colleagues have conducted a small clinical trial showing that the fields have an effect in slowing the growth of tumors.¹

Proposed mechanisms

Figure 1

In studies of tumor cells in vitro, Palti and colleagues observed two distinct effects, both of which depend on the direction of cell division with respect to the applied field.² First, they found that cells in the electric field take longer than usual to divide, as shown in figure 1a. Second, they found that dividing cells sometimes disintegrate just before the division process is complete, as shown in figure 1, panels b and c. They offer an explanation for each effect.

The researchers suggest that cell division is slowed because the electric field hinders the formation and function of the mitotic spindle, the structure that guides the newly replicated chromosomes as they separate into the two daughter cells. The mitotic spindle is made up of microtubules, formed by the polymerization of dimers of the protein tubulin. (Microtubules and other cellular structures are illustrated in PHYSICS TODAY, September 2006, page 80.) The tubulin dimers and polymers have large dipole moments, so they are affected by the electric field. But most other biochemical processes also involve polar molecules and structures, and small oscillating electric forces don't appear to have much of an effect on them. The difference, says Palti, is that when the tubulin dimers assemble into the mitotic spindle, they all line up in the same direction. If that direction happens to be orthogonal to the direction of the electric field, the microtubules are less likely to function normally.

Figure 2

The proposed mechanism for the destruction of dividing cells stems from the distribution of the electric field in each cell. The cell membrane, a lipid bilayer, acts as a capacitor with high impedance at the frequencies used, so the electric field doesn't readily penetrate the cell membrane. In a quiescent cell, the electric field inside the cell (shown in figure 2a) is much smaller than the field outside the cell and is largely uniform. But in the late stages of cell division, a higher-field region forms at the bottleneck point, or furrow, between the two newly forming cells, as shown in figure 2b. The nonuniform electric field generates a so-called dielectrophoretic force that draws polarizable molecules and structures in the direction of the higher-field region. The researchers calculate that the force, which can be as large as 60 pN, is enough to cause the organelles to pile up at the furrow within a few minutes.

Just how that pileup destroys the cell is still largely a matter of speculation, but Palti and his colleagues have a few ideas. "The organelles are attached to a cytoskeleton," Palti says. "They're not just floating around in the cytoplasm," so maybe the dielectrophoretic force rips them from that connective structure and kills the cell. Also, the pinching-off mechanism, by which the furrow closes and one cell becomes two, is a sensitive process that could be disrupted by the presence of molecules and organelles that are supposed to be elsewhere in the cell.

Palti's 100-kHz fields are not the only form of electrical stimulation that can hinder cell division. Luca Cucullo, Damir Janigro, and their colleagues at the Cleveland Clinic have found that low-intensity alternating current with a much lower frequency—about 50 Hz—can keep some types of cells from dividing.³ They don't yet know exactly how the process works, but their experiments suggest that the mechanism involves a particular protein that forms pores in the cell membrane to transport potassium ions into the cell. Cells whose division was halted by electric current contained more than the usual amount of the protein. And when the stimulated cells were exposed to cesium or barium, which block the potassium-transport pores, they divided at the same rate as unstimulated cells.

Clinical trial

Palti and colleagues had extensively studied the effects of the electric fields on tumor cells in vitro and in laboratory mice and rats when in 2003 they began their first clinical trial on human patients. They used their electric fields to treat glioblastoma multiforme (GBM), a type of brain tumor with a very low survival rate. When the tumor is treated by surgery, radiation, or chemotherapy, it nearly always progresses, or starts to grow again. The tumor usually kills the patient, often by the buildup of intracranial pressure that results from the tumor's sheer size.

Figure 3

The researchers recruited 10 patients for their trial. All had recurrent GBM, meaning that their tumors had been treated by other methods and had begun to grow again. The patients were fitted with electrodes, as shown in figure 3, that applied a 200-kHz electric field to their brains. At one-second intervals, the field orientation switched between front to back and side to side, so that the field would have the greatest effect on tumor cells dividing in all directions. Patients wore the electrodes 18 hours per day for up to 18 months.

Healthy cells in an adult brain don't divide, so there was little danger that the electric field would damage the normal tissue surrounding the tumor. In fact, because of the way applied fields are distributed in the body, the researchers are confident that when they apply their treatment to tumors in other parts of the body, the fields will do little damage to the bone marrow or the digestive tract. The field strength that could be used was limited not by toxicity to healthy tissues but by thermal effects in the skin: The field intensity was automatically lowered if the skin was heated enough to be in danger of thermal damage. The patients didn't lose their hair, but they had to keep their heads shaved in order for the electrodes to make good contact.

Because their small trial had no control group, the researchers compared their device's performance with historical data from other studies of GBM patients. Palti's trial found a median time to progression of 26 weeks and a median survival time of 62 weeks, whereas studies of recurrent GBM treated by other means found a time to progression of about 10 weeks and a survival time of about 30 weeks. Two years after their treatment began, 3 of the 10 patients in Palti's trial were still alive, and two were progression free.

To better evaluate their treatment's effectiveness, Palti and colleagues are currently working on a controlled study in which patients are randomly assigned to receive either the electric-field treatment or a chemotherapy regimen. They are also looking into combining the electric-field treatment with low-dose chemotherapy.

Johanna Miller

References

1. 1. E. D. Kirson et al., Proc. Natl. Acad. Sci. USA 104, 10152 (2007) [MEDLINE].
2. 2. E. D. Kirson et al., Cancer Res. 64, 3288 (2004).
3. 3. L. Cucullo et al., Glia 51, 65 (2005).

Sound Waves take Aim at Prostate Cancer

High Intensity Focused Ultrasound (HIFU) now Available at Center in Argentina

CHARLOTTE, N.C., Aug. 8 /PRNewswire/ -- USHIFU, LLC, the exclusive distributor of the Sonablate(R) 500 in North, Central and South America, announced the opening of the Argentina HIFU, the newest clinic to offer high intensity focused ultrasound for prostate cancer in Buenos Aires this month.

The urologists offering HIFU in the center are Edgardo Becher, MD; Marcelo Borghi, MD; and Luis Montes de Oca, MD. These physicians are the Directors of the Urology Center (CDU), a private center in Argentina exclusively devoted to urology and its subspecialties. These physicians completed the first HIFU treatments in Argentina last month and are excited about offering the non invasive treatment option to patients facing prostate cancer.

"These treatments also marked the first HIFU cases performed with the Sonablate(R)500 in South America," said Steve Puckett, Jr., USHIFU Chief Executive Officer. "We are thrilled to announce the initiation of a partnership with the prestigious urologists of the CDU clinic in Buenos Aires. This is a large strategic milestone for Argentina HIFU, USHIFU and its affiliates as we now have an organization that will become the center of excellence for our HIFU treatment program and physician training initiative in the region."

HIFU utilizes focused sound waves to rapidly heat and destroy the tissue within the prostate. The Sonablate(R) 500, the HIFU device, utilizes a transrectal probe to deliver ultrasound energy directly to the prostate without causing damage to areas outside the gland.

"HIFU Argentina is pleased to announce that the first HIFU treatments were held at the CDU the first week of July. We are proud to be the first center with this technology in the country and in South America, said Eric van Kregten, Manager Argentina HIFU.

"With this partnership, the CDU has enhanced their commitment to being a leader in the field of urology. We look forward to the growth of HIFU through coverage by principal medical insurance companies as well as private patients in Argentina."

Traditional treatments for prostate cancer such as surgery, radiation, or cryotherapy (freezing) can lead to undesirable side effects such as impotence and incontinence. International studies have shown that HIFU with the Sonablate(R) 500 minimizes the side effects associated with other treatment modalities and helps to preserve quality of life.

In Argentina, where HIFU is available now, the treatment is a one-time, outpatient procedure. It has also been used worldwide as a salvage therapy for patients who have had other treatments and have not been satisfied with the outcome.

For more information about Argentina HIFU or other International HIFU Centers in the Americas, visit http://www.internationalhifu.com/.

The Sonablate(R) 500 is developed and owned by Focus Surgery, Inc. and manufactured under contract by Misonix, Inc. (NASDAQ:MSON) who also holds distribution rights in Europe. Takai Hospital Supply Ltd. and THS International distribute the Sonablate(R) 500 in Southeast Asian and the Middle East.

Source: USHIFU, LLC

LAB ON A CHIP FOR ORAL CANCER SHOWS PROMISE

Finding out whether that unusual sore in your mouth is cancerous should become a lot faster and easier in the years ahead. Scientists supported by the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, have engineered the first fully automated, all-in-one test, or lab on a chip, that can be programmed to probe cells brushed from the mouth for a common sign of oral cancer.

About half the size of a toaster, the portable device yields results in just under 10 minutes, or well within the duration of a routine visit to a dentist or doctor. Currently, patients must undergo an often painful tissue biopsy and usually wait three days to a week for the lab results. “What’s exciting is the speed and efficiency that this test will bring to the diagnostic process,” said John McDevitt, Ph.D., a scientist at the University of Texas at Austin and the senior author on the paper, published in the August issue of the journal Lab on a Chip. “No longer will patients need to endure referrals, long waits for test results, and scheduling follow up consultations. Patients will get immediate results and feedback from their dentist or doctor on how best to proceed.”

McDevitt said his group’s proof of principle study showed that their test could accurately measure levels of epidermal growth factor receptor, or EGFR, on three distinct types of oral cancer cells. This protein, which is normally displayed on the surface of our cells, tends to be overproduced in oral tumor cells and serves as a measurable marker of oral cancer.

His group’s next step is to program the device to read not just EGFR levels but those of other proteins and genes that, when altered, are indicative of a developing oral tumor. This work already is well under way, and the group anticipates evaluating their test in the clinic with patients in the foreseeable future. “It could take several months to more than a year before we make the transition,” said McDevitt. “But the diagnostic platform has been built, and it’s just a matter of fine tuning the components that already are in place.”

According to McDevitt, the lab on a chip evolved from a conversation that he had a few years ago with Dr. Spencer Redding of the University of Texas Health Sciences Center in San Antonio about the difficulties of diagnosing oral cancer. Redding explained that dentists routinely face the dilemma of whether or not to refer patients to an oral surgeon for biopsies of suspicious sores, particularly possible recurrences of a previously diagnosed oral cancer. On the one hand, early detection is a key to fighting cancer and saving lives and, on the other, if the pathology report comes back negative, dentists risk upsetting their patients.

McDevitt was uniquely qualified to consider the problem. He studied in his laboratory functional molecular assemblies, or manipulating individual molecules to assemble miniaturized electronic or sensor components. This area of research has contributed greatly toward developing nano scale devices and popularizing the new discipline of nanotechnology.

The McDevitt laboratory already had an excellent track record of assembling novel, easy-to-use sensing devices that involve microfluidics, the science of precisely controlling micro or nano volumes of fluid. Among their accomplishments were a novel, miniaturized sensor to detect anthrax spores for the Nation’s biodefense efforts and thereafter a test for HIV infection and immune function in resource poor African nations. The laboratory also was working in the mouth, having received an NIDCR research grant to develop similar tests that use saliva, rather than blood, as a diagnostic fluid.

Combining these areas of research expertise, the McDevitt laboratory developed a test for oral cancer that begins with brushing cells from a suspicious lesion, suspending them in fluid, and loading roughly a drop of the mixture into their device. When activated, the device conveys the fluid down a tiny, microfluidic channel to a chamber with a porous membrane. “The cells stick to the membrane floor like starfish in a net,” said Shannon Weigum, a member of the McDevitt laboratory and lead author on the paper. “The floor has little exit holes that drain the fluid out of the chamber and allow us to pump in a cocktail of, in this case, antibodies that are tagged with a fluorescent dye and that are programmed to seek out and attach to the EGFR displayed on the cells.”

“The chamber creates a nice, miniaturized platform with a digital camera interface to display the fluorescent tags for analysis on a computer screen,” she continued. “We can then read the level of fluorescence and determine how much EGFR is present on the cell surface. It automates a process that is done now by a pathologist. Think of the test as pathology on a chip.”

In their initial experiments, the all-in-one test detected significantly higher levels of EGFR in three known oral cancer cell lines compared to normal cells, which would have been expected. This indicated that the lab on a chip had excellent specificity for its protein target. The scientists also found that their results correlated well with those using flow cytometry, the current gold-standard analytical technique to quantify protein expression.

The scientists reported that their lab-on-a-chip protocol took about nine minutes to complete, from sample collection to digital display. For flow cytometry, the protocol took two hours and five minutes. “We are doing our immune function test in eight minutes, and that includes the software manipulation and collecting the sample,” said McDevitt. “I feel comfortable saying that, with further manipulations, the oral cancer test ultimately will be completed somewhere between five and ten minutes. We have developed tests that can be performed in thirty seconds, but there is some loss in accuracy when you do things in an ultra fast manner.”

The Food and Drug Administration approved the EGFR-targeted monoclonal antibody called cetuximab in March 2006 to treat oral squamous cell carcinoma, the most common type of oral cancer. This marked the first new drug approved for this cancer in 45 years. But challenges remain to identify patients who might benefit from this therapy. With further development and clinical validation, the oral cancer lab on a chip could one day fill this diagnostic niche.

The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation’s leading funder of research on oral, dental, and craniofacial health.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Cold Laser Therapy Offers Carpal Tunnel Relief

Low-Level Laser Therapy (LLLT) System Available at Local Chiropractor's Office

FAIRVIEW, N.J., Aug. 7 /PRNewswire/ -- For many people living with painful carpal tunnel syndrome symptoms, cold laser therapy provides exceptional relief. Patients in Northern New Jersey can access this ground-breaking treatment at the Advanced Physical Medicine Center in Fairview.

Cold laser therapy, also known as low-level laser therapy (LLLT) is instrumental in treating carpel tunnel syndrome along with soft tissue injuries, cervical neck pain, repetitive stress injuries, tendonitis, hamstring injuries, arthritis, and wound healing. For carpal tunnel syndrome especially, the treatment helps to alleviate pain associated with repetitive motion in hands and wrists.

Cold laser therapy speeds up the healing process after injury to the wrists and hands. The normal reaction to acute soft tissue trauma is to splint the injury with edema, an accumulation of watery fluid in tissue spaces or cell interstices, which causes swelling. This same swelling prevents excessive movement to the tissue and causes pain, in addition to the soreness from the initial injury. The infrared laser light targets the lymphatic system, which maintains fluid balance in the body, and boosts reabsorption of the edema. This therapy reduces swelling and enhances movement capabilities, thus reducing pain as well.

The laser is a hand-held flashlight-like devise that directs a beam of narrow-spectrum light at injured tissue beneath the skin. The treatment lasts about 15 minutes and is done three times per week for six weeks. Dr. Michael Arber of the Advanced Physical Medicine Center uses it in conjunction with physical therapy to achieve maximum results.

"Our treatment is the most effective because we combine the cold laser technology along with cutting-edge physical therapy techniques to achieve relief from chronic pain," says Dr. Arber.

Cold laser therapy was accepted by the Food and Drug Administration (FDA) in 2002 and is used by athletic trainers, chiropractors and practitioners of alternative medicine.

The Advanced Physical Medicine Center specializes in chiropractic care, physical therapy, pain management and massage therapy. Located in Fairview, N.J., the facility has numerous certified professionals including chiropractors Michael Arber, BS, DC, DAAPM, and David Berk, BS, DC, MS, CCSP. To contact the office, call 201-945-1156 or visit www.advancedphysicalmedicinecenter.com.

Source: Advanced Physical Medicine Center

NEW RESEARCH DISCOVERS INDEPENDENT BRAIN NETWORKS CONTROL HUMAN WALKING

August 7, 2007 (Baltimore, MD) - In a study published in the August issue of Nature Neuroscience, researchers at the Kennedy Krieger Institute in Baltimore, Maryland found that there are separate adaptable networks controlling each leg and there are also separate networks controlling leg movements, e.g., forward or backward walking. These findings are contrary to the currently accepted theory that leg movements and adaptations are directed by a single control circuit in the brain. The ability to train the right and left legs independently opens the door to new therapeutic approaches for correcting walking abilities in patients with brain injury

Using a split-belt treadmill to separately control the legs, Kennedy Krieger researchers Dr. Amy Bastian and Julia Choi studied forty healthy adults and tracked each person’s ability to learn various walking exercises. Utilizing specialized computer software and infrared tracking devices placed on key joints, researchers found subjects could store different walking patterns for forward versus backward walking simultaneously, with no interference between the two, revealing that separate brain systems control the two directions of walking. Surprisingly, peopl

e could also walk easily with one leg moving forward and the other backward, a pattern referred to as “hybrid walking.” Adaptation of hybrid walking, in which varying speeds were applied to legs walking in opposite directions, was found to interfere with subsequent “normal” forward and backward walking. The combined results demonstrate there are distinct brain modules responsible for right/forward, right/backward, left/forward and left/backward walking. Most significantly, these modules can be individually trained, which would be critical for rehabilitation focused on correcting walking asymmetries produced by brain damage.

“The notion that we can leverage the brain’s adaptive capacity and effectively ‘dial in’ the patterns of movement that we want patients to learn is incredibly exciting,” said Dr. Amy Bastian, senior study author and Director of the Motion Analysis Laboratory at the Kennedy Krieger Institute. “These findings significantly enhance our understanding of motor skills, effective therapeutic approaches and the true adaptive nature of the brain.”

The walking adaptations studied here represent a form of short term learning from practicing on this unusual treadmill. Investigators set different speeds for each belt of the treadmill causing subjects to walk in an abnormal limping pattern. However, within 15 minutes subjects adapted and learned to walk smoothly with a normal pattern and rhythm, as verified by computer models. This indicates that the phenomenon of brain plasticity can occur in short intervals. When subjects returned to normal conditions (same speed for the two legs), this adaptation caused an after-effect that resulted in a limp that lasted for five-to-ten minutes as they “unlearned” the correction. Regardless of how hard subjects tried, they were unable to stop this after-effect, because walking patterns are controlled by automatic brain systems that recalibrate themselves according to current conditions.

“As we understand more about the way the brain learns, relearns and adapts in relation to motor skills, physical therapy professionals have a vastly expanding toolbox from which to tailor therapeutic interventions,” explains Gary Goldstein, MD, President and CEO of the Kennedy Krieger Institute. “This study and other research from Kennedy Krieger’s Motion Analysis Laboratory provide a glimpse into the rehabilitative potential made possible through the pairing of our talented researchers and cutting-edge technologies.”

Past studies by Bastian and her colleagues have found that certain types of brain damage interfere with walking ability, while others do not. For example, individuals with damage to the cerebral hemispheres can adapt while those with damage to the cerebellum are rarely able to.

This body of work sheds light on the specificity of walking adaptations and demonstrates that patients with certain types of brain damage can store a new walking pattern in the short term. Based on these findings, Bastian’s goal is to learn how to make that pattern last for an extended period. Currently, Bastian is planning a study of stroke victims in order to test the long-term benefits of split-belt treadmill therapy. She is also studying children with more extreme forms of brain damage, including those that undergo a hemispherectomy, a neurosurgical procedure to treat seizures in which an entire half of the brain is removed. The initial findings are quite promising, showing that these children can adapt in the short term and improve their walking patterns. These and other similar studies are leading researchers down the path to more targeted, rational therapies for patients with brain injuries.

Source: Kennedy Krieger Institute www.kennedykrieger.org