Ignored virus can cause liver cancer

Saturday 24 August 2013

Islamabad, Aug 25 (Newswire): Hepatitis G virus was identified in 1995. Some little research was carried out on the virus, and the U.S. Food and Drug Administration (FDA) declared it a non-harmful virus in 1997.

Researchers in Saudi Arabia, writing in the International Journal of Immunological Studies, present evidence to suggest that this may have been the wrong decision.

They claim that transmission of the virus through donated blood that was not screened for the virus as well as infection through other routes has led to an increase in cirrhosis of the liver and liver cancer.

Hepatitis G virus (HGV) was renamed as GB virus C (GBV-C) and is a virus in the Flaviviridae family but has not yet been assigned to a genus. Intriguingly, some evidence suggests that co-infection with the AIDS virus, HIV, somehow enhances the immune system in those patients.

However, it is the effects of the virus on the livers of otherwise healthy patients that is of concern to Mughis Uddin Ahmed of the King Abdulaziz Hospital (NGHA) in Al-Ahsa, Saudi Arabia. He points out that since the FDA declared the virus not to cause health problems to humans in 1997, no donated blood has been screened for this virus.

However, Mughis Uddin Ahmed has carried out a review of the scientific literature for the last 16 years that show the virus to be quite prevalent around the globe. Moreover, there is a correlation with infection with this virus and hepatitis, cirrhosis of the liver and it is possibly linked to hepatocellular carcinoma. Mughis Uddin Ahmed also found an apparent link with hematological disorders and hematological malignancies.

For this reason, he suggests that research should be carried out into this virus to determine whether it is a true human pathogen and a viral carcinogen. He also advises that screening of donated blood for this virus should be reinstated urgently rather than healthcare workers continuing to transferring the virus ignorantly to blood recipients and risking the same morbidity and mortality outcomes seen with hepatitis C virus transferred from donor to recipient until screening for that virus was adopted.

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Painting a 'bullseye' on cancer cells

Islamabad, Aug 25 (Newswire): Scientists are constantly on the hunt for treatments that can selectively target cancer cells, leaving other cells in our bodies unharmed. Now, Prof. Eytan Ruppin of Tel Aviv University's Blavatnik School of Computer Science and Sackler Faculty of Medicine and his colleagues Prof. Eyal Gottlieb of the Beatson Institute for Cancer Research in Glasgow, UK, and Dr. Tomer Shlomi of the Technion in Haifa have taken a big step forward.

They have successfully created the first computerized genome-scale model of cancer cell metabolism, which can be used to predict which drugs are lethal to the function of a cancer cell's metabolism.

By inhibiting their unique metabolic signatures, explains Prof. Ruppin, cancer cells can be killed off in a specific and selective manner. The efficacy of this method has been demonstrated in both computer and laboratory models pertaining to kidney cancer. Because the researchers' new approach is generic, it holds promise for future investigations aimed at effective drug therapies for other types of cancer as well. The results were published in the journal Nature.

The ability to specifically target cancer cells is the holy grail of cancer research. Currently, many cancer drugs are designed to target any proliferating cells in the body -- and while cancer cells certainly proliferate, so do healthy cells, such as hair and gut lining cells, the growth of which are essential to the body's overall health. This explains why many cancer treatments, including chemotherapy, have adverse side effects like nausea and hair loss.

Targeting the metabolism of the cancer cell itself may be one of the most effective ways forward. Cancer cells have a special way of metabolizing nutrients for growth and for energy. This makes cancer cell metabolism essentially different from that of a normal cell.

The researchers' computer model is a reconstruction of the thousands of metabolic reactions that characterize cancer cells. By comparing it to a pre-existing model of a normal human cell's metabolism, they could distinguish the differences between the two. They could then identify drug targets with the potential to affect the specific, special characteristics of cancer metabolism.

To test their predictions, the researchers chose to target cells from a specific type of renal cancer. "In this type of renal cancer, we predicted that using a drug that would specifically inhibit the enzyme HMOX, involved in Heme metabolism, would selectively and efficiently kill cancer cells, leaving normal cells intact," explains Prof. Ruppin. Their computer model led them to hypothesize that the Heme pathway was essential for the cancer cell's metabolism.

In an experimental study led by Prof. Gottlieb's lab, the researchers were able to verify this prediction in both mouse and human cell models, and to study these metabolic alterations in depth.

Metabolism is a large and complex network, built on thousands of reactions. It is beyond the human capability to fully understand, let alone predict how such a complicated system works, says Prof. Ruppin. Now, by allowing researchers to simulate the effects of a disorder, computer models are helping researchers to predict the efficacy of potential drugs and treatments. Though the predictions should always be verified in a lab or clinic, this method is highly cost effective and leads to exciting opportunities for accelerating future drug developments.

While the first model was built to characterize a specific type of cancer, this approach can be applied in the future for creating models for other types of cancer. "This is the next big challenge for us," says Prof. Ruppin. "We are going to continue to build models for other types of cancer, and seek selective drug therapies to defeat them."

Their multidisciplinary approach requires both the predictions of a computer model and the findings of experimental clinical trials, and may lead to the faster development of more selective and effective cancer treatments.

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Possible trigger point of epileptic seizures identified

Islamabad, Aug 25 (Newswire): Researchers at the Stanford University School of Medicine have identified a brain-circuit defect that triggers absence seizures, the most common form of childhood epilepsy.

In a study published in Nature Neuroscience, the investigators showed for the first time how defective signaling between two key brain areas -- the cerebral cortex and the thalamus -- can produce, in experimental mice, both the intermittent, brief loss of consciousness and the roughly three-times-per-second brain oscillations that characterize absence seizures in children. Young patients may spontaneously experience these seizures up to hundreds of times per day, under quite ordinary circumstances.

The new findings may lead to a better understanding of how ordinary, waking, sensory experiences can ignite seizures, said John Huguenard, PhD, the study's senior author.

Epilepsy, a pattern of recurrent seizures, will affect about one in 26 people over their lifetime. Absence, or petit-mal, seizures -- the form that epilepsy usually takes among children ages 6-15 -- feature a sudden loss of consciousness lasting 15 seconds or less. These seizures can be so subtle that they aren't noticed, or are mistaken for lack of attention. The patient remains still for several seconds, as if frozen in place.

Usually, a person who experiences an absence seizure has no memory of the episode.

"It's like pushing a pause button," said Huguenard, professor of neurology and neurological sciences and of molecular and cellular physiology.

Inside the brain, however, things more resemble an electrical storm than a freeze-frame.

The brain is, in essence, a complicated electrochemical calculating machine employing circuits that process information and share it with other, often-remote circuits, resulting in networks of sometimes staggering complexity.

A nerve cell can be thought of as a long, branching wire that can transmit electrical signals along its length and then relay these signals to up to thousands of other nerve cells by secreting specialized chemicals at points of contact with other "wires." Depending on the nature of the signaling interaction, the result can be either excitatory (increasing the likelihood that the next nerve cell in the relay will fire its own electrical impulse) or inhibitory (decreasing that likelihood).

During an absence seizure, the brain's electrical signals spontaneously coalesce into rhythmic oscillations, beginning in the neighborhood of two important brain areas, the cortex and the thalamus. Exactly where or how this pattern is initiated has been a source of controversy, said the study's lead author, Jeanne Paz, PhD, a postdoctoral researcher in Huguenard's lab.

"In order to develop better therapies, it is important to understand where and how the oscillations originate," Paz said.

The cortex and thalamus share an intimate relationship. The cortex, like a busy executive, assesses sensory information, draws conclusions, makes decisions and directs action.

To keep from being constantly bombarded by distracting sensory information from other parts of the body and from the outside world, the cortex flags its activity level by sending a steady stream of signals down to the thalamus, where nearly all sensory signals related to the outside world are processed for the last time before heading up to the cortex. In turn, the thalamus acts like an executive assistant, sifting through sensory inputs from the eyes, ears and skin, and translating their insistent patter into messages relayed up to the cortex. The thalamus carefully manages those messages in response to signals from the cortex.

These upward- and downward-bound signals are conveyed through two separate nerve tracts that each stimulate activity in the other tract. In a vacuum, this would soon lead to out-of-control mutual excitement, similar to a microphone being placed too close to a P.A. speaker. But there is a third component to the circuit: an inhibitory nerve tract that brain scientists refer to as the nRT. This tract monitors signals from both of the other two, and responds by damping activity. The overall result is a stable, self-modulating system that reliably delivers precise packets of relevant sensory information but neither veers into a chaotic state nor completely shuts itself down.

In bioengineered mice that the Stanford team studied with Wayne Frankel, PhD, of the Jackson Laboratory in Bar Harbor, Maine, this circuit is broken because the GluA4 receptor, a protein component of cells critical to the stimulation of nRT cells, is missing. Notably, these mice are prone to intermittent absence seizures. The researchers aimed to find out why, by separately studying the mouse's key corticothalamic-circuit components. Using a technique called optogenetics, they were able to selectively switch each of the two stimulatory tracts' signal transmissions on or off at will.

The researchers observed that, as expected, signals from one of the two tracts failed to excite the receptor-deficient mice's inhibitory nRT cells. Oddly, though, signals from the other tract continued to get through to the nRT tract just fine -- "a paradoxical and totally surprising result," said Huguenard.

This leaves nRT receiving signals from one tract, but not the other, which upsets the equilibrium usually maintained by the circuit. As a result, one of its components -- the thalamocortical tract -- is thrown into overdrive. Its constituent nerve cells begin firing en masse, rather than faithfully obeying the carefully orchestrated signals from the cortex. This in turn activates the nRT to an extraordinary degree, because its contact with the thalamocortical tract is not affected in these mice.

Huguenard estimates that, typically, only a very small percentage of nRT cells are firing at a given time. In the face of over-amped signaling from the thalamocortical tract, however, the fraction of excited nRT nerve cells rose much higher, perhaps as much as 50 percent -- enough to effectively silence all signaling from the thalamus to the cortex -- a key first step in a seizure.

But the shutdown was transitory. A property of thalamic cells (like other nerve cells) is that when they've been inhibited they tend to overreact and respond even more strongly than if they had been left alone. After a burst of nRT firing, this tract's overall inhibition of the thalamocortical tract all but halted activity there for about one-third of a second.

Like boisterous schoolchildren who can shut up only until the librarian leaves the room, the thalamocortical cells resumed shouting in unison as soon as the inhibition stopped, and a strong volley of signaling activity headed for the cortex. Then the nRT's inhibitory signaling recommenced, and the stream of signals from the thalamus to the cortex ceased once again.

This three-Hertz cycle of oscillations consisting of alternating quiet and exuberant periods repeated over the course of 10 or 15 seconds was the electrophysiology of a seizure.
Whether the specific nRT defect in the bioengineered mice is important in human absence seizures is not yet known, Huguenard cautioned. Most individuals who suffer from these seizures appear to have "normal" nerve cells (individually indistinguishable from those of non-epileptics) and normally formed circuits as well.

But now his group has a model experimental system with which they can try to determine why ordinary experiences can trigger these seizures in everyday life. Behavioral experiments are under way in his lab to see what kinds of common sensory exposures can trip off a similar circuit malfunction in normal mice. The resulting observations may someday help patients control their own exposures to minimize seizures, Huguenard said.

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