Researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.

Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.

“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”

In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.

The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.

“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.” University of Pennsylvania Health System

A study by researchers at Children’s Hospital Los Angeles (CHLA), Brigham and Women’s Hospital and the California Department of Public Health suggests that all babies with a known mutation for cystic fibrosis (CF) and second mutation called the 5T allele should receive additional screening in order to better predict the risk of developing CF later in life.

The results indicate that adding specific DNA sequencing to current newborn screenings would allow for early diagnosis in ethnically diverse populations and may increase the number of CF diagnoses in the U.S. over time. Such diagnoses could result in earlier treatment of CF, which could ultimately improve the outcome and prolong the life of a child with the disease.

Newborn screening programs, using a simple blood test taken within 24 to 48 hours of a child’s birth, allow for early detection and treatment of often devastating disorders. In the U.S., millions of newborns are screened each year, and early testing for CF – a progressive, genetic disease that causes persistent lung infections – has been implemented in all 50 states since 2010. CF is an autosomal recessive disorder, meaning that the child must inherit two copies of an abnormal gene in order for the disease to develop.

Each state uses a different screening algorithm to detect newborns with CF. California has implemented a unique algorithm which incorporates full sequencing of the gene responsible for CF, called the CF Transmembrane Conductance Regulator or CFTR.  Most other states perform a two-tier screen on the blood that first measures the concentration of the pancreatic enzyme that is elevated in CF.  In babies with the highest levels of this enzyme, called immunoreactive trypsinogen (IRT), a secondary screen looks at a selected list of 23 to 140 CFTR mutations known to cause the disease.

According to lead investigator Danieli Salinas, MD, Division of Pediatric Pulmonology at CHLA, these CFTR mutation panels were built based on the most prevalent mutations among severely affected individuals, most of whom were Caucasians.

“If only a commercial panel is applied, a large number of diagnoses are missed among African Americans and Hispanics,” Salinas said. “Missing these causal mutations during newborn screening has the devastating consequence of not detecting CF in these individuals until later in life, when lung damage is already irreversible.”

In California, after detection of one CFTR mutation, the blood sample is sent for CFTR-DNA sequencing to rule out presence of a second pathogenic mutation. California has screened over 4 million newborns for CF since 2007, discovering that – in babies with two mutations – only about one third had classic CF symptoms.  Two-thirds of the babies with sequence variants were not found to have CF as indicated by an abnormal chloride sweat test, considered to be the gold standard of CF diagnosis.

“The question became whether the babies in the second group (labeled CFTR-related metabolic syndrome or CRMS) really went on to develop CF, or if benign variants in CFTR were being detected that might never cause a clinical problem,” said  senior author Richard B. Parad, MD, MPH.

The researchers evaluated the effect of a specific, common mild CFTR gene variant that is carried by nearly one of 10 people, the 5T allele. They followed the cohort of babies detected through CF newborn screening with a variant detected in both of their CFTR gene copies: one severe CF-causing mutation and one 5T allele.  This cohort was followed over eight years to describe clinical outcomes. The researchers were able to generate risk predictions based on the “TG repeat” – a DNA repeating pattern of varying length found directly adjacent to 5T alleles.

Newborns with the 11 TG, a measurement of the length of the repeat, showed no signs of CF during eight years of follow-up. However, 6 percent of babies with the 12 TG developed the disease and nearly 40 percent of children with the 13 TG were considered to have CF within eight years of birth.

“The study’s conclusions show that, depending on the 5T-TG repeat length information, the risk of presenting a natural history consistent with CF can be anticipated,” said Parad. “Right now, these babies are not detected by CF newborn screening in states other than California. Instead of being detected in an asymptomatic state and followed closely, these babies later present with CF symptoms and may have missed an important opportunity to initiate early appropriate therapies during a window of protection that might improve their long term outcome.”

“Having CFTR-DNA sequencing as part of a newborn screening model can unveil the full spectrum of this disorder, through early detection of mild to severe cases in an ethnically diverse population,” added Salinas, who is also an assistant professor of Pediatrics and preventive medicine at the Keck School of Medicine at the University of Southern California. “Studies like this are important to better guide providers and families, by determining which individuals with which mutation combinations should be clinically monitored.”

Children’s Hospital Los Angeles www.chla.org/press-release/dna-sequencing-uncovers-latent-risk-developing-cystic-fibrosis

A new bioinformatic framework developed by researchers at University of California San Diego School of Medicine has identified key proteins significantly altered at the gene-expression level in biopsied tissue from patients with diabetic kidney disease, a result that may reveal new therapeutic targets.

In a recently published paper, researchers, led by Kumar Sharma, MD, professor of medicine at UC San Diego School of Medicine, revealed that the protein MDM2 was consistently down-regulated and played a key role in diabetic kidney disease progression. The researchers used the new “MetBridge Generator” bioinformatics framework to identify the relevant enzymes and bridge proteins that link human metabolomics data to the pathophysiology of diabetic kidney disease at a molecular level.

“MetBridge Generator allows for efficient, focused analysis of urine metabolomics data from patients with diabetic kidney disease, providing researchers an opportunity to develop new hypotheses based on the possible cellular or physiological role of key proteins,” said Sharma, senior author and director of the Institute for Metabolomic Medicine and the Center for Renal Translational Medicine at UC San Diego School of Medicine. “The framework may also be used in the interpretation of other metabolomic signatures from a variety of diseases. For example, MDM2 is also involved in regulating tumour protein p53, which is a target for cancer treatments.”

In a previous study, the authors identified 13 metabolites that were found to be altered in patients with diabetic kidney disease. Combining this information and publicly available data on metabolic pathways, the researchers tested an hypothesis that some proteins act as bridges creating less well-defined pathways. The framework then created a map of metabolic and protein-protein interaction (PPI) networks. This allowed the team to look deeper into relevant bridges with the greatest number of interactions with enzymes that regulate the 13-metabolite signature of diabetic kidney disease.

The authors already identified protein-RNA interactions as possible sources for additional key pathways underlying disease progression that could be added to the MetBridge Generator network. This growth will continue to add to possible therapeutic targets for disease treatment.

University of California – San Diego ucsdnews.ucsd.edu/pressrelease/new_bioinformatic_analysis_reveals_role_of_proteins_in_diabetic_kidney_dise

The presence of certain bacteria in the mouth may reveal increased risk for pancreatic cancer and enable earlier, more precise treatment. This is the main finding of a study led by researchers at NYU Langone’s Laura and Isaac Perlmutter Cancer Center.

Pancreatic cancer patients are known to be susceptible to gum disease, cavities, and poor oral health in general, say the study authors. That vulnerability led the research team to search for direct links between the makeup of bacteria driving oral disease and subsequent development of pancreatic cancer, a disease that often escapes early diagnosis and causes 40,000 U.S. deaths annually.

“Our study offers the first direct evidence that specific changes in the microbial mix in the mouth—the oral microbiome—represent a likely risk factor for pancreatic cancer along with older age, male gender, smoking, African-American race, and a family history of the disease,” says senior investigator and epidemiologist Jiyoung Ahn, PhD.

Specifically, researchers found that men and women whose oral microbiomes included Porphyromonas gingivalis had an overall 59 percent greater risk of developing pancreatic cancer than those whose microbiomes did not contain the bacterium. Similarly, oral microbiomes containing Aggregatibacter actinomycetemcomitans were at least 50 percent more likely overall to develop the disease. Doctoral student and lead investigator Xiaozhou Fan, MS, says both types of bacteria have been tied in the past to periodontitis, a disease characterized by inflammation of the gums.

“These bacterial changes in the mouth could potentially show us who is most at risk of developing pancreatic cancer,” adds Ahn, an associate professor at NYU Langone and associate director of population sciences at the Perlmutter Cancer Center.

In another study, Ahn and her colleagues showed that cigarette smoking was linked to dramatic, although reversible, changes in the amount and mix of bacteria in the oral microbiome. But she cautions that further research is needed to determine if there is any cause-and-effect relationship, or how or whether such smoking-related changes alter the immune system or otherwise trigger cancer-causing activities in the pancreas.

Laura and Isaac Perlmutter Cancer Center nyulangone.org/press-releases/pancreatic-cancer-risk-tied-to-specific-mouth-bacteria

Myeloid-derived suppressor cells (MDSCs) are a population of immune cells that have been implicated in tumour resistance to various types of cancer treatment, including targeted therapies, chemotherapy and immunotherapy. Polymorphonuclear (PMN) cells represent the largest population of MDSCs. However, fully understanding the biology and clinical importance of these cells has been hampered by a lack of markers that set them apart from normal neutrophils.

Now, scientists at The Wistar Institute have identified a marker that distinguishes PMN-MDSCs from neutrophils in the blood of patients with a variety of cancers. Study results showed that higher numbers of cells positive for the marker were associated with larger tumour size.

‘Before we started this work, the only way to isolate PMN-MDSCs was by density centrifugation of blood because they could not be properly identified in tumour tissue,’ said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and professor and program leader of the Translational Tumor Immunology program at Wistar, and senior author of the study. ‘Identifying a marker for PMN-MDSCs will allow us to study these cells in much more depth. In addition, if our clinical results are verified in larger studies, the marker could also be used to help physicians and patients make informed treatment decisions and, ultimately, it could be exploited to target PMN-MDSCs for therapeutic benefit.’

MDSCs are potent suppressors of immune responses. They naturally regulate immune responses in healthy individuals, but the population rapidly expands in patients with cancer, and the presence of these cells has been associated with poor patient outcomes. One of the few ways to know for sure that cells are MDSCs is by showing that they suppress immune responses in vitro.

Gabrilovich and colleagues used whole-genome analysis to compare the genes expressed by PMN-MDSCs and neutrophils from the blood of patients with non-small cell lung cancer and head and neck cancer. The researchers focused on the genes expressed at higher levels in PMN-MDSCs compared with neutrophils, in particular those genes that encoded proteins detectable on the surface of cells. This led them to the protein LOX-1, which was almost undetectable on the surface of neutrophils but detectable on the surface of about one-third of PMN-MDSCs.

When they tested the ability of LOX-1-positive and LOX-1-negative cells to suppress immune responses in vitro only the LOX-1-positive cells had this function. The results showed that LOX-1 was a marker of PMN-MDSCs.

Gabrilovich and colleagues speculated that the number of LOX-1-positive PMN-MDSCs in blood and tumour samples from patients with cancer might help predict disease severity and outcome. They had samples from only a few patients with non-small cell lung cancer to study, but found that patients with larger tumours had higher numbers of these cells in both blood and tumour samples.

‘Now that we have a specific marker for MDSCs, we can begin to ask new questions about the biology of these cells and their clinical significance,’ added Gabrilovich.

EurekAlert www.eurekalert.org/pub_releases/2016-08/twi-wsi080316.php