Researchers at UT Southwestern Medical Center have identified hyaluronon (HA) as a critical substance made by the body that protects against premature births caused by infection. Pre-term birth from infection is the leading cause of infant mortality in many countries according to the World Health Organization. The findings of the study are the first to identify the specific role that HA plays in the reproductive tract.

Dr. Yucel Akgul, first author and senior author Dr. Mala Mahendroo
“We found that HA is required to allow the epithelial lining of the reproductive tract to serve as the first line of defence against bacterial infections,” said senior author Dr. Mala Mahendroo, an Associate Professor in the Department of Obstetrics and Gynecology’s Cecil H. and Ida Green Center for Reproductive Biology Sciences. “Because of this action, HA offers cervical protection against the bacterial infections that cause 25 to 40 percent of pre-term births in women.”

Hyaluronon is a natural substance found in many tissues, and is both a lubricant and a beneficial component of eyes, joints, and skin. It has long been thought to play an essential role in increasing the cervix’s flexibility during the birth process; however, the study, which was conducted using mouse models, showed that HA is not essential for increased cervical pliability during late pregnancy. Rather, the substance plays an important barrier role in epithelial cells of the lower reproductive tract and in so doing protects against infection-related pre-term birth. The World Health Organization estimates that 1.09 million children under age 5 die from direct complications of being born prematurely, meaning before the 37th week of pregnancy.

Previous studies by UT Southwestern reproductive biology researchers showed that HA is present in both the cervix and cervical mucus of pregnant women. Next steps include determining the mechanism by which HA affects cervical protection against infection.

“This study demonstrates that HA plays a crucial role in the epithelial barrier as well as the cervix’s mucus,” said Dr. Yucel Akgul, first author of the study and research scientist in the Department of Obstetrics and Gynecology. “Our next step is to identify exactly how HA protects the cervix, which can have important clinical implications in the effort to reduce infection-mediated pre-term labour.” UT Southmwestern Medical Center

Genetic mutations may link smoking and alcohol consumption to destruction of the pancreas observed in chronic pancreatitis, according to a 12-year study led by researchers at the University of Pittsburgh School of Medicine. The findings provides insight into why some people develop this painful and debilitating inflammatory condition while most heavy smokers or drinkers do not appear to suffer any problems with it.

The process appears to begin with acute pancreatitis, which is the sudden onset of inflammation causing nausea, vomiting and severe pain in the upper abdomen that may radiate to the back, and is typically triggered by excessive drinking or gallbladder problems, explained senior investigator David Whitcomb, M.D., Ph.D., chief of gastroenterology, hepatology and nutrition, Pitt School of Medicine. Up to a third of those patients will have recurrent episodes of acute pancreatitis, and up to a third of that group develops chronic disease, in which the organ becomes scarred from inflammation.

“Smoking and drinking are known to be strong risk factors for chronic pancreatitis, but not everyone who smokes or drinks damages their pancreas,” Dr. Whitcomb said. “Our new study identifies gene variants that when combined with these lifestyle factors make people susceptible to chronic pancreatitis and may be useful to prevent patients from developing it.”

In the North American Pancreatitis Study II consortium, researchers evaluated gene profiles and alcohol and smoking habits of more than 1,000 people with either chronic pancreatitis or recurrent acute pancreatitis and an equivalent number of healthy volunteers. The researchers took a closer look at a gene called CTRC, which can protect pancreatic cells from injury caused by premature activation of trypsin, a digestive enzyme inside the pancreas instead of the intestine, a problem that has already been associated with pancreatitis.

They found that a certain variant of the CTRC gene, which is thought to be carried by about 10 percent of Caucasians, was a strong risk factor for alcohol- or smoking-associated chronic pancreatitis. It’s possible that the variant fails to protect the pancreas from trypsin, leaving the carrier vulnerable to ongoing pancreatic inflammation and scarring.

“This finding presents us with a window of opportunity to intervene in the diseases process,” Dr. Whitcomb said. “When people come to the hospital with acute pancreatitis, we could screen for this gene variant and do everything possible to help those who have it quit smoking and drinking alcohol, as well as test new treatments, because they have the greatest risk of progressing to end-stage chronic pancreatitis.” University of Pittsburgh Health Sciences

A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type.

There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that the majority of triple-negative tumours are of the basal-like subtype.

Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer.

The team looked at breast cancers from almost 3000 patients. Their search had a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A.

‘Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong,’ says Dr Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. ‘BCL11A activity stood out because it is so active in triple-negative cancers.

‘It had all the hallmarks of a novel breast cancer gene.’

Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished.

‘Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers,’ says Dr Walid Khaled, joint first author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. ‘We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells. Wellcome Trust Sanger Institute

Despite a strong suspected link between genetics and asthma, commonly found genetic mutations account for only a small part of the risk for developing the disease — a problem known as missing heritability.

Rare and low frequency genetic mutations have been thought to explain missing heritability, but it appears they are unlikely to play a major role, according to a new study led by scientists from the University of Chicago. Analysing the coding regions of genomes of more than 11,000 individuals, they identified mutations in just three genes that were associated with asthma risk. Each was associated with risk in specific ethnicities.

‘Previous studies have likely overestimated the heritability of asthma,’ said study senior author Carole Ober, PhD, Blum-Riese Professor and chair of the Department of Human Genetics at the University of Chicago. ‘This could be because those estimates are based on correlations between family members that share environment as well as genes, which could inflate the heritability. Gene-environment interactions are not considered in these large scale association studies, and we know that these are particularly important in establishing individual risks for asthma.’

Asthma affects more than 25 million adults and children of all ages and ethnicities in the US. Due to the widespread nature of the disease, most studies of its genetic underpinnings have focused on commonly occurring mutations, referred to as genetic variants. However, while numerous such variants have been identified, they are able to account for only a small proportion of the risk for inheriting or developing asthma. Rare mutations, found in less than five percent of the population, have been hypothesized to explain this disparity.

Graduate student Catherine Igartua led the analysis under the supervision of co-senior author Dan Nicolae, PhD, Professor in the Departments of Medicine, Statistics and Human Genetics. She evaluated nearly 33,000 rare or low frequency mutations in more than 11,000 individuals of a variety of ethnicities representing European, African and Latino backgrounds. She analysed mutations jointly across subjects, using a technique that allowed them to study mutations common in one ethnicity, but rare in others.

Only mutations in the genes GRASP, GSDMB and MTHFR showed a statistical link to asthma risk. Mutations in the first two genes were found primarily in Latino individuals, and mutations in the last gene in those with African ancestry. These genes, involved in protein scaffolding, apoptosis regulation and vitamin B9 metabolism respectively, have as yet unknown roles in asthma. The rarity and ethnic-specificity of these genes is insufficient to account for the widespread prevalence of asthma.

Although rare mutations might not contribute much to population asthma risk, these genes still have the potential to serve as targets for therapeutic development. Ober points to the discovery of rare mutations in the LDL receptor that eventually led to the development of statins to treat high cholesterol. She also notes that it is possible, but unlikely, that there are mutations with large effects on asthma risk outside of their screen as it looked at approximate 60 percent of mutations in coding regions of the genome.

‘It was assumed that there would be rare mutations with larger effect sizes than the common variants we have been studying,’ Ober said. ‘Surprisingly, we found that low frequency mutations explain only a very small amount of asthma risk.’ The University of Chicago Medicine

The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance.

The global research collaboration analysed 1612 samples from 15 locations in Southeast Asia and Africa finding 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in four other genes to support artemisinin resistance.

‘Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance – until mutations occurred in the kelch13 gene,’ explains Dr Roberto Amato, a first author and Research Associate in Statistical Genomics at the Wellcome Trust Sanger Institute and Oxford University’s Wellcome Trust Centre for Human Genetics. ‘It’s similar to what we see with pre-cancerous cells which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick-off growth.’

The variety of kelch13 mutations associated with artemisinin resistance, with new variants continually emerging, makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background – in this case, a fixed set of four well-defined mutations in the fd, arps10, mdr2, and crt genes – could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions even before resistant parasites take hold.

‘We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective,’ says Nick Day, Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. ‘We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.’

Researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar and Bangladesh, scientists found that the distribution of different kelch13 mutations are localised within relatively well-defined geographical areas.

Whilst artemisinin resistant parasites do appear to have migrated across national borders, this only happened on a limited scale and, in fact, the most widespread kelch13 mutation, C580Y, appeared to have emerged independently on several occasions. Notably parasites along the Thailand-Myanmar border appear to have acquired this mutation separately from those in Cambodia and Vietnam. Crucially, parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

There remain many unanswered questions. ‘We don’t yet know the role of these background mutations,’ says Dr Olivo Miotto, a first author and Senior Informatics Fellow at MORU and the Centre for Genomics and Global Health. ‘Some may not affect drug resistance directly, but rather provide an environment where drug resistance mutations are tolerated. Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.’

Mutations in the kelch13 gene were present, yet rare, in Africa but weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur. Wellcome Trust Sanger Institute