Lung cancer can stay hidden for over 20 years

Doctor examining a lung radiography (stock image).
Credit: © Minerva Studio / Fotolia

Scientists have discovered that lung cancers can lie dormant for over 20 years before suddenly turning into an aggressive form of the disease.

UK scientists have discovered that lung cancers can lie dormant for over 20 years before suddenly turning into an aggressive form of the disease, according to a study published in Science* on the 9th of october 2014.
The team studied lung cancers from seven patients — including smokers, ex-smokers and never smokers. They found that after the first genetic mistakes that cause the cancer, it can exist undetected for many years until new, additional, faults trigger rapid growth of the disease.
During this expansion there is a surge of different genetic faults appearing in separate areas of the tumour. Each distinct section evolves down different paths — meaning that every part of the tumour is genetically unique.
This research — jointly funded by Cancer Research UK and the Rosetrees Trust — highlights the need for better ways to detect the disease earlier. Two-thirds of patients are diagnosed with advanced forms of the disease when treatments are less likely to be successful.
By revealing that lung cancers can lie dormant for many years the researchers hope this study will help improve early detection of the disease.
Study author Professor Charles Swanton, at Cancer Research UK’s London Research Institute and the UCL Cancer Institute, said: “Survival from lung cancer remains devastatingly low with many new targeted treatments making a limited impact on the disease. By understanding how it develops we’ve opened up the disease’s evolutionary rule book in the hope that we can start to predict its next steps.”
The study also highlighted the role of smoking in the development of lung cancer. Many of the early genetic faults are caused by smoking. But as the disease evolved these became less important with the majority of faults now caused by a new process generating mutations within the tumour controlled by a protein called APOBEC.
The wide variety of faults found within lung cancers explains why targeted treatments have had limited success. Attacking a particular genetic mistake identified by a biopsy in lung cancer will only be effective against those parts of the tumour with that fault, leaving other areas to thrive and take over.
Over 40,000 people are diagnosed with lung cancer each year and, despite some positive steps being made against the disease it remains one of the biggest challenges in cancer research, with fewer than 10 per cent surviving for at least five years after diagnosis.
Building on this research will be a key priority for the recently established Cancer Research UK Lung Cancer Centre of Excellence at Manchester and UCL. The Centre — where Professor Swanton is joint centre lead — is a key part of Cancer Research UK’s renewed focus to beat lung cancer; bringing together a unique range of internationally renowned scientists and clinicians to create an environment that catalyses imaginative and innovative lung cancer research.
Professor Nic Jones, Cancer Research UK’s chief scientist, said: “This fascinating research highlights the need to find better ways to detect lung cancer earlier when it’s still following just one evolutionary path. If we can nip the disease in the bud and treat it before it has started travelling down different evolutionary routes we could make a real difference in helping more people survive the disease.
“Building on this work Cancer Research UK is funding a study called TRACERx which is studying 100s of patient’s lung cancers as they evolve over time to find out exactly how lung cancers mutate, adapt and become resistant to treatments ”
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The above story is based on materials provided by Cancer Research UK. Note: Materials may be edited for content and length.

Multiple neurodevelopmental disorders have a common molecular cause

A large fraction of neurodevelopmental disorders are associated with variation in specific genes, but the genetic factors responsible for these diseases are very complex.
Credit: © agsandrew / Fotolia

Neurodevelopmental disorders such as Down syndrome and autism-spectrum disorder can have profound, lifelong effects on learning and memory, but relatively little is known about the molecular pathways affected by these diseases. A study shows that neurodevelopmental disorders caused by distinct genetic mutations produce similar molecular effects in cells, suggesting that a one-size-fits-all therapeutic approach could be effective for conditions ranging from seizures to attention-deficit hyperactivity disorder.

Neurodevelopmental disorders such as Down syndrome and autism-spectrum disorder can have profound, lifelong effects on learning and memory, but relatively little is known about the molecular pathways affected by these diseases. A study published by Cell Press October 9th in the American Journal of Human Genetics shows that neurodevelopmental disorders caused by distinct genetic mutations produce similar molecular effects in cells, suggesting that a one-size-fits-all therapeutic approach could be effective for conditions ranging from seizures to attention-deficit hyperactivity disorder.
“Neurodevelopmental disorders are rare, meaning trying to treat them is not efficient,” says senior study author Carl Ernst of McGill University. “Once we fully define the major common pathways involved, targeting these pathways for treatment becomes a viable option that can affect the largest number of people.”
A large fraction of neurodevelopmental disorders are associated with variation in specific genes, but the genetic factors responsible for these diseases are very complex. For example, whereas common variants in the same gene have been associated with two or more different disorders, mutations in many different genes can lead to similar diseases. As a result, it has not been clear whether genetic mutations that cause neurodevelopmental disorders affect distinct molecular pathways or converge on similar cellular functions.
To address this question, Ernst and his team used human fetal brain cells to study the molecular effects of reducing the activity of genes that are mutated in two distinct autism-spectrum disorders. Changes in transcription factor 4 (TCF4) cause 18q21 deletion syndrome, which is characterized by intellectual disability and psychiatric problems, and mutations in euchromatic histone methyltransferase 1 (EHMT1) cause similar symptoms in a disease known as 9q34 deletion syndrome.
Interfering with the activity of TCF4 or EHMT1 produced similar molecular effects in the cells. Strikingly, both of these genetic modifications resulted in molecular patterns that resemble those of cells that are differentiating, or converting from immature cells to more specialized cells. “Our study suggests that one fundamental cause of disease is that neural stem cells choose to become full brain cells too early,” Ernst says. “This could affect how they incorporate into cellular networks, for example, leading to the clinical symptoms that we see in kids with these diseases.”
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The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.

Mechanism that repairs brain after stroke discovered

A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.
Credit: Image courtesy of Lund University

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered by researchers. A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems. The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain.

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered at Lund University and Karolinska Institutet in Sweden. The findings have been published in the journal Science.
A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.
The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.
“This is the first time that astrocytes have been shown to have the capacity to start a process that leads to the generation of new nerve cells after a stroke,” says Zaal Kokaia, Professor of Experimental Medical Research at Lund University.
The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells.
“Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells,” says Zaal Kokaia.
“This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage.”
The new nerve cells were found to form specialized contacts with other cells. It remains to be shown whether the nerve cells are functional and to what extent they contribute to the spontaneous recovery that is observed in a majority of experimental animals and patients after a stroke.
A decade ago, Kokaia’s and Lindvall’s research group was the first to show that stroke leads to the formation of new nerve cells from the adult brain’s own neural stem cells. The new findings further underscore that when the adult brain suffers a major blow such as a stroke, it makes a strong effort to repair itself using a variety of mechanisms.
The major advancement with the new study is that it demonstrates for the first time that self-repair in the adult brain involves astrocytes entering a process by which they change their identity to nerve cells.
“One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson’s disease and Huntington’s disease,” says Olle Lindvall, Senior Professor of Neurology.
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The above story is based on materials provided by Lund University. Note: Materials may be edited for content and length.

Amputees discern familiar sensations across prosthetic hand

Medical researchers are helping restore the sense of touch in amputees.
Credit: Image courtesy of Case Western Reserve University

Amputees discern familiar sensations across prosthetic hand

Patients connected to a new prosthetic system said they ‘felt’ their hands for the first time since they lost them in accidents. In the ensuing months, they began feeling sensations that were familiar and were able to control their prosthetic hands with more — well — dexterity.

Even before he lost his right hand to an industrial accident 4 years ago, Igor Spetic had family open his medicine bottles. Cotton balls give him goose bumps.
Now, blindfolded during an experiment, he feels his arm hairs rise when a researcher brushes the back of his prosthetic hand with a cotton ball.
Spetic, of course, can’t feel the ball. But patterns of electric signals are sent by a computer into nerves in his arm and to his brain, which tells him different. “I knew immediately it was cotton,” he said.
That’s one of several types of sensation Spetic, of Madison, Ohio, can feel with the prosthetic system being developed by Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center.
Spetic was excited just to “feel” again, and quickly received an unexpected benefit. The phantom pain he’d suffered, which he’s described as a vice crushing his closed fist, subsided almost completely. A second patient, who had less phantom pain after losing his right hand and much of his forearm in an accident, said his, too, is nearly gone.
Despite having phantom pain, both men said that the first time they were connected to the system and received the electrical stimulation, was the first time they’d felt their hands since their accidents. In the ensuing months, they began feeling sensations that were familiar and were able to control their prosthetic hands with more — well — dexterity.
To watch a video of the research, click here: http://youtu.be/l7jht5vvzR4.
“The sense of touch is one of the ways we interact with objects around us,” said Dustin Tyler, an associate professor of biomedical engineering at Case Western Reserve and director of the research. “Our goal is not just to restore function, but to build a reconnection to the world. This is long-lasting, chronic restoration of sensation over multiple points across the hand.”
“The work reactivates areas of the brain that produce the sense of touch, said Tyler, who is also associate director of the Advanced Platform Technology Center at the Cleveland VA. “When the hand is lost, the inputs that switched on these areas were lost.”
How the system works and the results will be published online in the journal Science Translational Medicine Oct. 8.
“The sense of touch actually gets better,” said Keith Vonderhuevel, of Sidney, Ohio, who lost his hand in 2005 and had the system implanted in January 2013. “They change things on the computer to change the sensation.
“One time,” he said, “it felt like water running across the back of my hand.”
The system, which is limited to the lab at this point, uses electrical stimulation to give the sense of feeling. But there are key differences from other reported efforts.
First, the nerves that used to relay the sense of touch to the brain are stimulated by contact points on cuffs that encircle major nerve bundles in the arm, not by electrodes inserted through the protective nerve membranes.
Surgeons Michael W Keith, MD and J. Robert Anderson, MD, from Case Western Reserve School of Medicine and Cleveland VA, implanted three electrode cuffs in Spetic’s forearm, enabling him to feel 19 distinct points; and two cuffs in Vonderhuevel’s upper arm, enabling him to feel 16 distinct locations.
Second, when they began the study, the sensation Spetic felt when a sensor was touched was a tingle. To provide more natural sensations, the research team has developed algorithms that convert the input from sensors taped to a patient’s hand into varying patterns and intensities of electrical signals. The sensors themselves aren’t sophisticated enough to discern textures, they detect only pressure.
The different signal patterns, passed through the cuffs, are read as different stimuli by the brain. The scientists continue to fine-tune the patterns, and Spetic and Vonderhuevel appear to be becoming more attuned to them.
Third, the system has worked for 2 ½ years in Spetic and 1½ in Vonderhueval. Other research has reported sensation lasting one month and, in some cases, the ability to feel began to fade over weeks.
A blindfolded Vonderhuevel has held grapes or cherries in his prosthetic hand — the signals enabling him to gauge how tightly he’s squeezing — and pulled out the stems.
“When the sensation’s on, it’s not too hard,” he said. “When it’s off, you make a lot of grape juice.”
Different signal patterns interpreted as sandpaper, a smooth surface and a ridged surface enabled a blindfolded Spetic to discern each as they were applied to his hand. And when researchers touched two different locations with two different textures at the same time, he could discern the type and location of each.
Tyler believes that everyone creates a map of sensations from their life history that enables them to correlate an input to a given sensation.
“I don’t presume the stimuli we’re giving is hitting the spots on the map exactly, but they’re familiar enough that the brain identifies what it is,” he said.
Because of Vonderheuval’s and Spetic’s continuing progress, Tyler is hopeful the method can lead to a lifetime of use. He’s optimistic his team can develop a system a patient could use at home, within five years.
In addition to hand prosthetics, Tyler believes the technology can be used to help those using prosthetic legs receive input from the ground and adjust to gravel or uneven surfaces. Beyond that, the neural interfacing and new stimulation techniques may be useful in controlling tremors, deep brain stimulation and more.
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The above story is based on materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.

Manipulating memory with light: Scientists erase specific memories in mice

During memory retrieval, cells in the hippocampus connect to cells in the brain cortex.
Credit: Photo illustration by Kazumasa Tanaka and Brian Wiltgen/UC Davis

Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.
Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.
Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories — memories about specific places and events — involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.
“The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event,” Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.
But this model has been difficult to test directly, until the arrival of optogenetics.
Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.
They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a “fear response.”
Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.
“The cortex can’t do it alone, it needs input from the hippocampus,” Wiltgen said. “This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true.”
They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.
Co-authors are Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa and Jalina Graham, all at the Center for Neuroscience. The work was funded by grants from the Whitehall Foundation, McKnight Foundation, Nakajima Foundation and the National Science Foundation.