A genetic mutation caused by ultraviolet light is likely the driving force behind millions of human skin cancers, according to researchers at the Stanford University School of Medicine.

The mutation occurs in a gene called KNSTRN, which is involved in helping cells divide their DNA equally during cell division.

Genes that cause cancer when mutated are known as oncogenes. Although KNSTRN hasn’t been previously implicated as a cause of human cancers, the research suggests it may be one of the most commonly mutated oncogenes in the world.

“This previously unknown oncogene is activated by sunlight and drives the development of cutaneous squamous cell carcinomas,” said Paul Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology in the School of Medicine and chair of the Department of Dermatology. “Our research shows that skin cancers arise differently from other cancers, and that a single mutation can cause genomic catastrophe.”

Cutaneous squamous cell carcinoma is the second most common cancer in humans. More than 1 million new cases are diagnosed globally each year. The researchers found that a particular region of KNSTRN is mutated in about 20 percent of cutaneous squamous cell carcinomas and in about 5 percent of melanomas.

Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumour cells with those of normal skin and looked for mutations that occurred only in the tumours. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.

The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.

If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.

The mutation in the KNSTRN gene was caused by the replacement of a single nucleotide, called a cytosine, with another, called a thymine, within a specific, short stretch of DNA. The swap is indicative of a cell’s attempt to repair damage from high-energy ultraviolet rays, such as those found in sunlight.

“Mutations at this UV hotspot are not found in any of the other cancers we investigated,” said Khavari. “They occur only in skin cancers.”

The researchers found the UV-induced KNSTRN mutation in about 20 percent of actinic keratoses — a premalignant skin condition that often progresses to squamous cell carcinoma — but never in 122 samples of normal skin, indicating the mutation is likely to be an early event in the development of squamous cell carcinomas.

Furthermore, overexpression of mutant KNSTRN in laboratory-grown human skin cells disrupted their ability to segregate their DNA during cell division and enhanced the growth of cancer cells in a mouse model of squamous cell carcinoma.

Finally, Lee compared five patient-derived squamous cell carcinomas that had the KNSTRN mutation with five samples that did not have the mutation. Although both sets of cells were aneuploid, those with the mutation had the most severely abnormal genomes. Stanford University School of Medicine

New research from the University of Rochester Medical Center describes how exposure to air pollution early in life produces harmful changes in the brains of mice, including an enlargement of part of the brain that is seen in humans who have autism and schizophrenia.
As in autism and schizophrenia, the changes occurred predominately in males. The mice also performed poorly in tests of short-term memory, learning ability, and impulsivity.
The new findings are consistent with several recent studies that have shown a link between air pollution and autism in children. Most notably, a 2013 study in JAMA Psychiatry reported that children who lived in areas with high levels of traffic-related air pollution during their first year of life were three times as likely to develop autism.
‘Our findings add to the growing body of evidence that air pollution may play a role in autism, as well as in other neurodevelopmental disorders,’ said Deborah Cory-Slechta, Ph.D., professor of Environmental Medicine at the University of Rochester and lead author of the study, published in the journal Environmental Health Perspectives.
In three sets of experiments, Cory-Slechta and her colleagues exposed mice to levels of air pollution typically found in mid-sized U.S. cities during rush hour. The exposures were conducted during the first two weeks after birth, a critical time in the brain’s development. The mice were exposed to polluted air for four hours each day for two four-day periods.
In one group of mice, the brains were examined 24 hours after the final pollution exposure. In all of those mice, inflammation was rampant throughout the brain, and the lateral ventricles — chambers on each side of the brain that contain cerebrospinal fluid — were enlarged two-to-three times their normal size.
‘When we looked closely at the ventricles, we could see that the white matter that normally surrounds them hadn’t fully developed,’ said Cory-Slechta. ‘It appears that inflammation had damaged those brain cells and prevented that region of the brain from developing, and the ventricles simply expanded to fill the space.’
The problems were also observed in a second group of mice 40 days after exposure and in another group 270 days after exposure, indicating that the damage to the brain was permanent. Brains of mice in all three groups also had elevated levels of glutamate, a neurotransmitter, which is also seen in humans with autism and schizophrenia.
Most air pollution is made up mainly of carbon particles that are produced when fuel is burned by power plants, factories, and cars. For decades, research on the health effects of air pollution has focused on the part of the body where the damage is most obvious — the lungs. That research began to show that different-sized particles produce different effects. Larger particles — the ones regulated by the Environmental Protection Agency (EPA) — are actually the least harmful because they are coughed up and expelled. But many researchers believe that smaller particles known as ultrafine particles — which are not regulated by the EPA — are more dangerous, because they are small enough to travel deep into the lungs and be absorbed into the bloodstream, where they can produce toxic effects throughout the body.
That assumption led Cory-Slechta to design a set of experiments that would show whether ultrafine particles have a damaging effect on the brain, and if so, to reveal the mechanism by which they inflict harm
‘I think these findings are going to raise new questions about whether the current regulatory standards for air quality are sufficient to protect our children,’ said Cory-Slechta. University of Rochester Medical Center

Researchers at King’s College London have identified a genetic variant associated with an increased risk of stroke and heart attack.

Stroke and heart attack are caused when arteries, already clogged up by fatty substances (a condition known as atherosclerosis), become completely blocked by the formation of a blood clot. Risk factors for this include smoking, high blood pressure and high cholesterol.

The findings suggest a new genetic link caused by a variation in a protein known as ‘glycoprotein IIIa’. This genetic variant is found in platelets, a type of blood cell involved in the formation of blood clots.

These findings may, in future, allow clinicians to identify patients who are at particularly high risk of stroke or heart attack by looking for the genetic variant. This would represent advancement on current practice, which mainly addresses risk factors such as smoking and high blood pressure.

Previous findings surrounding this genetic variant have been inconsistent and the study at King’s represents the first large-scale meta-analysis of the literature, including over 50,000 participants from a combined total of 82 studies.

In the UK over 150,000 people have a stroke every year. Stroke is the third largest cause of death after heart disease and cancer. A stroke occurs when blood supply to part of the brain is cut off, leading to damage of brain cells. There are around 103,000 heart attacks in the UK each year, caused by blockage of a coronary artery that supplies blood to the heart and resulting in damage to heart muscles.

In the first research paper, which examined stroke patients, researchers found that carrying the PlA2 genetic variant of glycoprotein IIIa was associated with an increased risk of thrombotic stroke – that is, stroke caused by a blood clot. This equated to a higher risk of around 10-15 per cent, which was even stronger (amounting to a 70 per cent increase in risk) in people who carried two copies of this gene variant. The variant was not associated with haemorrhagic stroke, which is caused by bleeding into the brain.

The second research paper found that the same genetic variant was also associated with an increased risk of heart attack. This link was stronger in younger than in older patients, which is likely to reflect the greater influence of other cardiovascular risk factors in older patients (such as smoking and high cholesterol), according to the researchers.

Albert Ferro, Professor of Cardiovascular Clinical Pharmacology at King’s College London, said: ‘The genetic risk found in stroke and heart attack patients is likely to be caused by over-active platelets. Under normal circumstances, platelets help your body form clots to stop bleeding, but in these patients platelet activation has the undesired effect of causing their narrowed arteries to be blocked off completely. In future it may be possible to reduce the chances of this happening by examining patients for this variant on a blood test, so that if they carry the PlA2 form – and especially if they carry two copies of it – such patients could be identified for a more determined reduction of risk factors such as smoking, high blood pressure or high cholesterol.’ King’s College London

Influenza infection can enhance the ability of the bacterium Streptococcus pneumoniae to cause ear and throat infections, according to new research

 In the study, the investigators infected mice with either influenza alone, pneumococci alone, or both at once, and then monitored the populations of bacteria and virus over time. They also monitored the mice for development of middle ear infection.

Influenza infection enhanced the bacterium’s ability to colonize the nasopharynx, and to infect the normally sterile middle ear.

 “We learned that once influenza virus is introduced, all of the “rules” regarding phase variants are out the window,” says corresponding author W. Edward Swords of Wake Forest University, Winston-Salem, NC. Phase variation refers to the fact that the colonizing bacteria have transparent cell surfaces, while those that spread within the host have opaque surfaces.

 “However, in the presence of influenza, opaque variants can readily colonize the nasopharynx, and transparent variants can persist in the ear,” says Swords. “This indicates that the host environs are more permissive for infection by the entire bacterial population.”

 Furthermore, recent research had shown that influenza interferes with innate immunity in a way that enables pneumococci to flourish. In this research, Swords shows that that interference manifests as increased inflammatory responses at the mucosal surface in the influenza-infected mice, such as within the middle ear, and in the nasopharynx.

“As with most pneumococcal infections, it should be appreciated that localized nonlethal infections are much more common than the rapidly lethal presentations,” says Swords. “For example, influenza is a contributing factor in otitis media (middle ear infections) in children.”

 “If we can understand why and how viral infection causes bacteria to colonize privileged sites like the middle ear, we will better know what aspects of disease to focus on with preventive or therapeutic treatments,” says Swords. American Society for Microbiology