Cold plasma successful against brain cancer cells

For the first time, physicists from the Max Planck Institute for Extraterrestrial Physics (MPE), biologists and physicians demonstrated the synergistic effect of cold atmospheric plasma - a partly ionized gas - and chemo therapy on aggressive brain tumour cells. Laboratory tests showed that the proliferation of glioblastoma cells – the most common and aggressive brain tumour in adults – is arrested and that even resistant cell populations become sensitive to treatment with chemo therapy if pre-treated with cold atmospheric plasma. This could be the first step on the way to a new combination therapy, providing new hope for fighting this lethal cancer.

If someone is diagnosed with the type of brain tumour called glioblastoma, the prospects are dire: median survival is just a bit over one year, and less than 16% of the patients survive more than three years. It is still unknown how this cancer is triggered – only a few rare genetic factors have been identified so far – and treatment remains largely palliative, i.e. trying to alleviate the symptoms and prolonging the life of the patient. The standard therapy proceeds in three steps: Guided by an MRT scan, the tumour is removed surgically, followed by radiation and chemo therapy. But even if the treatment is successful initially, there is a high likelihood of relapse.

A recently developed new kind of treatment could offer some hope. Cold atmospheric plasma, or CAP for short, has already proven to successfully inactivate bacteria, fungi, viruses and spores, while healthy tissue remains largely unaffected. Healthcare applications such as the sterilization of surgical instruments, skin and wound disinfection paved its way into medical care. Recently also CAP sources were developed which show anti-cancer properties.

"For many patients the regular treatment is just not effective, because the brain tumours contain sub-populations for which chemo therapy does not work,” says Julia Zimmermann, who manages the Plasma Healthcare group at MPE. “So we were particularly interested to see if the CAP would be effective against these resistant tumour cells – and indeed it worked!”

For the study, the researchers used Glioblastoma cells and grew them in cell culture dishes, where they could be subjected to various combinations of treatments. For both normal and resistant tumour cell lines, the growth of the cells was more inhibited after the plasma treatment compared to the chemo therapy alone. The largest effect could be obtained for a short application time of 120 seconds; such an additional step could be easily incorporated into the clinical treatment if an appropriate plasma device can be developed.

The researchers also found that CAP stops the cell cycle and that the individual cells lose their ability to clone themselves. A combined therapy of both - CAP treatment and chemo therapy – showed the most promising results, where the amount of chemotherapeutic needed to achieve the same result as with chemo therapy alone is strongly reduced. So far, no resistance towards CAP treatment was observed. The study also showed that even those cell lines that originally were resistant against the chemo therapy drug became sensitive again after the pre-application of CAP.

“In particular, also resistant cell populations could be treated effectively with CAP, which means that there is now hope to find a therapy for the patients with a poor prognosis, i.e. those with resistant cells in the tumour,” explains Julia Köritzer, lead author of the study. Such a treatment option for resistant cells is urgently needed, because about 40% of the patients do not profit from chemo therapy. She adds: “It is a first step, now we have to further investigate the effects gained in the cell culture and integrate them for the application.”

Though, even if there is still a long way ahead before CAP can actually be used in the hospital, it offers a promising new possibility. Eventually it could be applied after surgery to treat the tissue around the extracted tumour, where some cancerous cells might have been left behind, preventing the cancer from reappearing. Devices similar to an endoscope are currently under development.

Pay attention: How we focus and concentrate

Publishing in Neuron, the team reveal the interplay of brain chemicals which help us pay attention in work funded by the Wellcome Trust and BBSRC.

By changing the way neurons respond to external stimuli we improve our perceptual abilities. While these changes can affect the strength of a neuronal response, they can also affect the fidelity of that response.

Lead author Alex Thiele, Professor of Visual Neuroscience explains: “When you communicate with others, you can make yourself better heard by speaking louder or by speaking more clearly. Neurons appear to do similar things when we’re paying attention. They send their message more intensely to their partners, which compares to speaking louder. But more importantly, they also increase the fidelity of their message, which compares to speaking more clearly.

“Our earlier work has shown that attention is able to affect the intensity of responses – in effect the loudness - by means of the brain chemical acetylcholine. Now we have shown that the fidelity of the response is altered by a different brain chemical system.”

In the paper, the team reveal that the quality of the response is altered by means of glutamate coupling to NMDA receptors (a molecular device that mediates communication between neurons). Carried out in a primate model, these studies for the first time isolate different attention mechanisms at the receptor level.

The research builds on the team’s previous studies and has potentially significant implications not only for our understanding of how our brains work but also give an insight into conditions such as schizophrenia, Alzheimer’s disease and attention deficit disorder, and may aid in the development of treatments for them.

Brain uses internal ‘average voice’ prototype to identify who is talking

The human brain is able to identify individuals’ voices by comparing them against an internal ‘average voice’ prototype, according to neuroscientists.

A study carried out by researchers at the University of Glasgow and reported in the journal Current Biology demonstrates that voice identity is coded in the brain by reference to two internal voice prototypes – one male, one female.

Voices that have the greatest difference from the prototype are perceived as more distinctive and produce greater neural activity than voices deemed very similar.

The researchers in the Institute of Neuroscience & Psychology conducted the study by generating a voice prototype through morphing 32 same-gender voices together resulting in a smooth, idealised voice with few irregularities.

They then generated different voices by altering the ‘distance-to-mean’ of the prototype voice – for example, changing the tone and pitch or morphing two or more voices together.

Using functional Magnetic Resonance Imaging (fMRI), the researchers were able to see increased neural activity the further from the prototype the voices were.

Professor Pascal Belin said: “Like faces, voices can be used to identify a person, yet the neural basis of this ability remains poorly understood. Here we provide the first evidence of a norm-based coding mechanism the brain uses to identify a speaker.

“The research indicates this is a similar process for the identification of faces, where the brain also uses an average face to compare against other faces it encounters in order to establish identity.

“So, rather than having to remember each single voice it hears every day for a lifetime, the brain facilitates the task of identification by remembering only the differences from the prototype it stores.

“It leads to a range of interesting and important questions, such as whether the prototypes are innate, stored templates or whether they are subject to environmental and cultural influences. Could the prototype consist of an average of all voices experiences during one’s life?”

(Image: Shutterstock)

Scientists Discover Cinnamon Compounds’ Potential Ability to Prevent Alzheimer’s

Cinnamon: Can the red-brown spice with the unmistakable fragrance and variety of uses offer an important benefit? The common baking spice might hold the key to delaying the onset of –– or warding off –– the effects of Alzheimer’s disease.

That is, according to Roshni George and Donald Graves, scientists at UC Santa Barbara. The results of their study, “Interaction of Cinnamaldehyde and Epicatechin with Tau: Implications of Beneficial Effects in Modulating Alzheimer’s Disease Pathogenesis,” appears in the online early edition of the Journal of Alzheimer’s Disease, and in the upcoming Volume 36, issue 1 print edition.

Alzheimer’s disease is the most common form of dementia, a neurodegenerative disease that progressively worsens over time as it kills brain cells. No cure has yet been found, nor has the major cause of Alzheimer’s been identified.

However, two compounds found in cinnamon –– cinnamaldehyde and epicatechin –– are showing some promise in the effort to fight the disease. According to George and Graves, the compounds have been shown to prevent the development of the filamentous “tangles” found in the brain cells that characterize Alzheimer’s.

Responsible for the assembly of microtubules in a cell, a protein called tau plays a large role in the structure of the neurons, as well as their function.

"The problem with tau in Alzheimer’s is that it starts aggregating," said George, a graduate student researcher. When the protein does not bind properly to the microtubules that form the cell’s structure, it has a tendency to clump together, she explained, forming insoluble fibers in the neuron. The older we get the more susceptible we are to these twists and tangles; Alzheimer’s patients develop them more often and in larger amounts.

The use of cinnamaldehyde, the compound responsible for the bright, sweet smell of cinnamon, has proven effective in preventing the tau knots. By protecting tau from oxidative stress, the compound, an oil, could inhibit the protein’s aggregation. To do this, cinnamaldehyde binds to two residues of an amino acid called cysteine on the tau protein. The cysteine residues are vulnerable to modifications, a factor that contributes to the development of Alzheimer’s.

"Take, for example, sunburn, a form of oxidative damage," said Graves, adjunct professor in UCSB’s Department of Molecular, Cellular, and Developmental Biology. "If you wore a hat, you could protect your face and head from the oxidation. In a sense this cinnamaldehyde is like a cap." While it can protect the tau protein by binding to its vulnerable cysteine residues, it can also come off, Graves added, which can ensure the proper functioning of the protein.

Oxidative stress is a major factor to consider in the health of cells in general. Through normal cellular processes, free radical-generating substances like peroxides are formed, but antioxidants in the cell work to neutralize them and prevent oxidation. Under some conditions however, the scales are tipped, with increased production of peroxides and free radicals, and decreased amounts of antioxidants, leading to oxidative stress.

Epicatechin, which is also present in other foods, such as blueberries, chocolate, and red wine, has proven to be a powerful antioxidant. Not only does it quench the burn of oxidation, it is actually activated by oxidation so the compound can interact with the cysteines on the tau protein in a way similar to the protective action of cinnamaldehyde.

"Cell membranes that are oxidized also produce reactive derivatives, such as Acrolein, that can damage the cysteines," said George. "Epicatechin also sequesters those byproducts."

Studies indicate that there is a high correlation between Type 2 diabetes and the incidence of Alzheimer’s disease. The elevated glucose levels typical of diabetes lead to the overproduction of reactive oxygen species, resulting in oxidative stress, which is a common factor in both diabetes and Alzheimer’s disease. Other research has shown cinnamon’s beneficial effects in managing blood glucose and other problems associated with diabetes.

"Since tau is vulnerable to oxidative stress, this study then asks whether Alzheimer’s disease could benefit from cinnamon, especially looking at the potential of small compounds," said George.

Although this research shows promise, Graves said, they are “still a long way from knowing whether this will work in human beings.” The researchers caution against ingesting more than the typical amounts of cinnamon already used in cooking.

If cinnamon and its compounds do live up to their promise, it could be a significant step in the ongoing battle against Alzheimer’s. A major risk factor for the disease –– age –––– is uncontrollable. In the United States, Alzheimer’s presents a particular problem as the population lives longer and the Baby Boom generation turns gray, leading to a steep rise in the prevalance of the disease. It is a phenomenon that threatens to overwhelm the U.S. health care system. According to the Alzheimer’s Association, in 2013, Alzheimer’s disease will cost the nation $203 billion.

"Wouldn’t it be interesting if a small molecule from a spice could help?" commented Graves, "perhaps prevent it, or slow down the progression."

(Image: iStockphoto)

The Secret Lives (and Deaths) of Neurons

As the human body fine-tunes its neurological wiring, nerve cells often must fix a faulty connection by amputating an axon — the “business end” of the neuron that sends electrical impulses to tissues or other neurons. It is a dance with death, however, because the molecular poison the neuron deploys to sever an axon could, if uncontained, kill the entire cell.

Researchers from the University of North Carolina School of Medicine have uncovered some surprising insights about the process of axon amputation, or “pruning,” in a study published May 21 in the journal Nature Communications. Axon pruning has mystified scientists curious to know how a neuron can unleash a self-destruct mechanism within its axon, but keep it from spreading to the rest of the cell. The researchers’ findings could offer clues about the processes underlying some neurological disorders.

“Aberrant axon pruning is thought to underlie some of the causes for neurodevelopmental disorders, such as schizophrenia and autism,” said Mohanish Deshmukh, PhD, professor of cell biology and physiology at UNC and the study’s senior author. “This study sheds light on some of the mechanisms by which neurons are able to regulate axon pruning.”

Axon pruning is part of normal development and plays a key role in learning and memory. Another important process, apoptosis — the purposeful death of an entire cell — is also crucial because it allows the body to cull broken or incorrectly placed neurons. But both processes have been linked with disease when improperly regulated.

The research team placed mouse neurons in special devices called microfluidic chambers that allowed the researchers to independently manipulate the environments surrounding the axon and cell body to induce axon pruning or apoptosis.

They found that although the nerve cell uses the same poison — a group of molecules known as Caspases — whether it intends to kill the whole cell or just the axon, it deploys the Caspases in a different way depending on the context.

“People had assumed that the mechanism was the same regardless of whether the context was axon pruning or apoptosis, but we found that it’s actually quite distinct,” said Deshmukh. “The neuron essentially uses the same components for both cases, but tweaks them in a very elegant way so the neuron knows whether it needs to undergo apoptosis or axon pruning.”

In apoptosis, the neuron deploys the deadly Caspases using an activator known as Apaf-1. In the case of axon pruning, Apaf-1 was simply not involved, despite the presence of Caspases. “This is really going to take the field by surprise,” said Deshmukh. “There’s very little precedent of Caspases being activated without Apaf-1. We just didn’t know they could be activated through a different mechanism.”

In addition, the team discovered that neurons employ other molecules as safety brakes to keep the “kill” signal contained to the axon alone. “Having this brake keeps that signal from spreading to the rest of the body,” said Deshmukh. “Remarkably, just removing one brake makes the neurons more vulnerable.”

Deshmukh said the findings offer a glimpse into how nerve cells reconfigure themselves during development and beyond. Enhancing our understanding of these basic processes could help illuminate what has gone wrong in the case of some neurological disorders.

Common Brain Processes of Anesthetic-Induced Unconsciousness Identified

A study from the June issue of Anesthesiology found feedback from the front region of the brain is a crucial building block for consciousness and that its disruption is associated with unconsciousness when the anesthetics ketamine, propofol or sevoflurane are administered.

Brain centers and mechanisms of consciousness have not been well understood, resulting in a need for better monitors of consciousness during anesthesia. In addition, how anesthetics with different structures and pharmacological properties can generate unconsciousness has been a persistent question in anesthesiology since the beginning of the field in the mid-19th century.

A team of researchers from the University of Michigan, Ann Arbor, Mich., and Asan Medical Center, Seoul, South Korea, conducted a brain wave (electroencephalographic, or EEG) study of the front and back regions of the brain in 30 surgical patients who received intravenous ketamine. They compared the results of this study to the EEG data collected from 18 surgical patients who received either intravenous propofol or inhaled sevoflurane in a previous study. These three anesthetics, known to act on different parts of the brain and produce different EEG patterns, had the same effect of disrupting communication in the brain.

“Understanding a commonality among the actions of these diverse drugs could lead to a more comprehensive theory of how general anesthetics induce unconsciousness,” said study author George Mashour, M.D., Ph.D., assistant professor and associate chair for faculty affairs, Department of Anesthesiology, University of Michigan. “Our research shows that studying general anesthesia from the perspective of consciousness may be a fruitful approach and create new avenues for further investigation of anesthetic mechanisms and monitoring.”

An accompanying editorial by Jamie W. Sleigh, M.D., professor of anaesthesiology and intensive care, Department of Anaesthesia, University of Auckland, Hamilton, New Zealand, supported the study’s ability to better understand the neurobiology of consciousness.

“If the study’s findings are confirmed by subsequent work, the paper will achieve landmark status,” said Dr. Sleigh. “The study not only sheds light on the phenomenon of general anesthesia, but also how it is necessary for certain regions of the brain to communicate accurately with one another for consciousness to emerge.”

In addition, Dr. Sleigh recognized the study’s potential to lead to the development of better depth-of-anesthesia monitors that work for all general anesthetics.

(Image: Shutterstock)

Eyes on the prey: Researchers analyse the hunting behaviour of fish larvae in virtual reality

Moving objects attract greater attention – a fact exploited by video screens in public spaces and animated advertising banners on the Internet. For most animal species, moving objects also play a major role in the processing of sensory impressions in the brain, as they often signal the presence of a welcome prey or an imminent threat. This is also true of the zebrafish larva, which has to react to the movements of its prey. Scientists at the Max Planck Institute for Medical Research in Heidelberg have investigated how the brain uses the information from the visual system for the execution of quicker movements. The animals’ visual system records the movements of the prey so that the brain can redirect the animals’ movements through targeted swim bouts in a matter of milliseconds. Two hitherto unknown types of neurons in the mid-brain are involved in the processing of movement stimuli.

In principle, the visual system of zebrafish larvae resembles that of other vertebrates. Moreover, its genome has been decoded, it is a small organism, and it has transparent skin, which is easily penetrated by light in the fluorescent microscope. Therefore, these animals are very suitable for studying visual motion perception. They also display very clear prey capture behaviour. With the help of their finely-tuned visual system, they pursue and catch small ciliates. To do this, they execute a series of swimming manoeuvres in a matter of one or two seconds, during which they repeatedly verify the direction and distance of the prey so that they can adapt their subsequent movement steps. The larva’s brain must, therefore, filter and evaluate visual information extremely rapidly so that it can select appropriate motor patterns.

Using high-speed video recordings, researchers working with Johann Bollmann at the Max Planck Institute for Medical Research began by studying the natural course of prey capture by the larvae under a variety of starting conditions. It emerged that the larvae repeatedly execute a basic motion pattern and can apply an orientation component that re-directs the hunter towards the prey with each swim bout. To do this, the larvae must process visual information in just a few hundreds of milliseconds.

Using an innovative experimental design, the scientists then modelled, in a second step, the natural swimming environment as a “virtual reality”, in which the larvae execute typical prey capture sequences without actually moving. The virtual prey consisted of computer-controlled images, which were projected onto a small screen. In this way, the role of motion parameters, for example the size and speed of the “prey”, could be studied quantitatively in relation to the processing of visual stimuli by the animals.

In the “virtual reality”, the scientists can test how the fish larvae respond to unexpected shifts in the prey after a swim bout. “When we direct our gaze at a target through movements of our eyes and head, we expect the object to appear in a central position in our field of view. In the larvae, very slight deviations from the target position or delays in the re-appearance of the virtual prey increased the reaction times. When it receives unexpected visual feedback, the larva’s brain presumably needs extra processing time to calculate the next swim bout,” explains Johann Bollmann from the Max Planck Institute in Heidelberg.

In addition, with the help of fluorescent microscopes, the researchers can examine the activity of groups of neurons in the larval brain which are likely to control the targeted prey capture movements. In a previous study, they discovered cell types that react specifically to opposing directions of movement. These previously unknown neurons in the dorsal region of the midbrain (tectum) differ in their directional sensitivity and in the structure of their finely branched projections. “It appears that different directions of motion are processed in different layers of the tectum, since the dendritic ramifications of these cell types are spatially separated from each other,” says Bollmann.