Scientists identify unique pathway for treating deadly brain cancer in kids

Researchers have discovered a new pathway that can attack and improve survival rate in an incurable type of brain cancer among children.

The study suggested that the pathway disrupts the cellular process that contributes to Diffuse Intrinsic Pontine Gliomas (DIPG).

DIPG is a highly aggressive and inoperable type of tumour that grows in the brain stem and usually strikes children less than 10 years old. Most patients do not survive more than a year after diagnosis.

Earlier studies identified a genetic mutation called PPM1D- which is critical for cell growth and cell stress response-- as a contributor to DIPG. Previous efforts to directly attack the PPM1D mutation, however, proved futile in controlling DIPG.

This study has discovered a vulnerability in the metabolic process for creating NAD,, a metabolite that is necessary for all cell life.

This is really an amazing new way to attack this cancer. We found that the mutated gene PPM1D essentially sets the stage for its own demise, said one the study authors.

Researchers found that mutated PPM1D silences a gene called NAPRT, which is key to the production of the NAD metabolite. With NAPRT unavailable, the cell switches to another protein needed to create NAD called NAMPT. By using a drug that inhibits the production of NAMPT, researchers found they could essentially starve to death those cancer cells with the PPM1D mutation.

Researchers had long thought DIPG was a childhood version of adult brain tumours, and so similar treatments for adult gliomas were tested extensively in children and failed. 

The researchers chose to look at the tumour in terms of its potential vulnerabilities, and  thus began a year-ling molecular journey to understand what role the PPM1D mutation played in altering cancer metabolism.

When epigenetic silencing results were analysed, we were gratified to discover that DIPG cells with the PPM1D mutation had created a vulnerability to a key enzyme for which small molecule inhibitors were already available, said one the study's contributing authors.

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Link found between your brain and your consciousness

Human consciousness is a topic philosophers have long struggled to define.
 
Now, a team of researchers led by neurologists at Beth Israel Deaconess Medical Center (BIDMC) has pinpointed the regions of the brain that may play a role maintaining it.

"For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness," said researcher Michael D. Fox. "A lot of pieces of evidence all came together to point to this network playing a role in human consciousness."

Classical neurology holds that arousal and awareness are two critical components of consciousness. Arousal is likely regulated by the brain stem - the portion of the brain, contiguous with the spinal cord, that is responsible for the sleep/wake cycle and cardiac and respiratory rates. Awareness, another critical component of consciousness, has long been thought to reside somewhere in the cortex, the outer layer of the brain responsible for many of its higher functions.

The researchers analyzed 36 patients with brain stem lesions, of which 12 led to coma and 24 did not. Mapping the injuries revealed that a small "coma-specific" area of the brain stem - the rostral dorsolateral pontine tegmentum - was significantly associated with coma. Ten out of the 12 coma-inducing brain stem lesions involved this area, while just one of the 24 control lesions did.

Armed with that information, Fox and colleagues, including lead author David Fischer, MD, then a medical student at Harvard Medical School, used a wiring diagram of the healthy human brain - based on a large, shared data set called the Human Connectome - to identify which other parts of the brain were connected to these coma-causing lesions. Their analysis revealed two areas in the cortex of the brain that were significantly connected to the coma-specific region of the brainstem. One sat in the left, ventral, anterior insula (AI), the other in the pregenual anterior cingulate cortex (pACC). Both regions have been implicated previously in arousal and awareness.

"We now have a great map of how the brain is wired up in the Human Connectome," said Fox. "We can look at not just the location of lesions, but also their connectivity. Over the past year, researchers in my lab have used this approach to understand visual and auditory hallucinations, impaired speech, and movement disorders. A collaborative team of neuroscientists and physicians had the insight and unique expertise needed to apply this approach to consciousness."

The team included co-lead author, Aaron Boes and co-senior author, Joel Geerling.

Finally, the team investigated whether this brainstem-cortex network was functioning in another subset of patients with disorders of consciousness, including coma. Using a special type of MRI scan, the scientists found that their newly identified "consciousness network" was disrupted in patients with impaired consciousness. 

The findings - bolstered by data from rodent studies - suggest the network between the brain stem and these two cortical regions plays a role maintaining human consciousness.

"The added value of thinking about coma as a network disorder is it presents possible targets for therapy, such as using brain stimulation to augment recovery," Boes said.

A next step, Fox notes, may be to investigate other data sets in which patients lost consciousness to find out if the same, different or overlapping neural networks are involved.

"This is most relevant if we can use these networks as a target for brain stimulation for people with disorders of consciousness," said Fox. "If we zero in on the regions and network involved, can we someday wake someone up who is in a persistent vegetative state? That's the ultimate question."

The study, which already garnered multiple awards from the American Academy of Neurology, has been published in Neurology.

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Here's how leaky calcium puts epileptics at heart risk

Sudden unexpected death in epilepsy (SUDEP) has long bedeviled doctors and now, a team of researchers may have found the cause of it.

In a paper, researchers from Baylor College of Medicine reported how a mutation in a gene involved in the regulation of calcium inside brain cells can help trigger blackouts of the brain stem, the center that controls heartbeat and breathing, and increase the risk of sudden unexpected death.

"SUDEP turns out to be the most common cause of premature death in people with epilepsy. It's not accidents or suicide, it's just this unexplained mortality," said senior author Dr Jeffrey L. Noebels.

He added, "Most people with epilepsy live long lives and do not seem to have an increased risk of SUDEP. But there is a subset of people at additional risk. We have been looking for genes that cause epilepsy to see if any of them might give us a clue as to who might be at risk. Specifically, we have been looking at genes that might explain what appears to be a collapse of the cardiac and respiratory system after a seizure."

In their years-long quest to understand the cellular and genetic mechanisms that may trigger SUDEP, Noebels and his colleagues studied the genes that are involved in the heart beat. Some of these genes are already well known to be related to sudden unexpected cardiac death.

"We wondered whether some of those same genes could also cause seizures if they were expressed in the brain, and, if so, whether those genes would also place people with epilepsy at risk, not only for having epilepsy, but an abnormal heart beat and risk of death," said Noebels. "In our first experiments we found several genes that actually filled that description: they are expressed in the brain and the heart, and mutations of those genes cause an abnormal heart beat and epilepsy in mouse models."

The researchers then found that these same genes carry an additional risk for a phenomenon called spreading depolarization, a slowly-progressing, temporary electrical blackout of a region in the brain. During a blackout, the brain cells in that area cease their activity until it is restored.

Noebels and colleagues studied another gene - RyR2 - which is also expressed in the heart and known to cause heart problems. They showed that RyR2, which is also expressed in the brain, also causes epilepsy in mice and sets up an electrical surge that makes a fatal blackout likely.

For Noebels and colleagues, the discovery of how the 'leaky' RyR2 increases the chances of SUDEP is a step forward toward a future in which neurologists could sit with a patient and their family and have a conversation about the possibility of offering an accurate prediction of the risks of SUDEP and effective interventions.

The study is published on the Proceedings of the National Academy of Sciences. 

 

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