The term intellectual disability covers a large number of clinical entities, some with known cause and others of uncertain origin. For example Down syndrome is due to an extra copy of chromosome 21 and Rett syndrome is in part caused by a mutation in the control switch gene called MeCP2.

In other cases the mechanisms by which they are produced are not clearly identified. It is the case of most of those disorders classified under the large umbrella of autism. An study by Manel Esteller, director of the Program Epigenetics and Cancer Biology (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona , has discovered a mechanism that identifies a cause of intellectual disabilities in these puzzling cases.

‘We have analysed the genome of 215 patients with mental retardation, autism or Rett syndrome, in which they had not found any genetic alteration in the genes classically associated with these clinical conditions, to see if we could find a molecular cause. And this process has allowed us to detect a new mutated gene that could be causing these disorders. ‘He explained Manel Esteller.

‘Specifically, the identified gene is called JMJD1C (Jumonji Domain Containing 1C) and is an epigenetic gene which its normal function is to control the activity of other genes. Only a small percentage of mental retardation of unknown origin is due to mutation of this gene. This finding suggests that many genes with low frequency disturbance are responsible for cases with unknown cause. They have demonstrated that this gene joins the MeCP2 gene so it could also contribute to cases of atypical Rett Syndrome ‘says Esteller. IDIBELL

A database compiled by Ash Alizadeh and his team provides broad patterns that correlate with poor or good survival rates for a variety of cancers.

Physicians have long sought a way to accurately predict cancer patients’ survival outcomes by looking at biological details of the specific cancers they have. But despite concerted efforts, no such clinical crystal ball exists for the majority of cancers.

Now, researchers at the Stanford University School of Medicine have compiled a database that integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.

Combining the data from so many people and cancers allowed the researchers to overcome reproducibility issues inherent in smaller studies. As a result, the researchers were able to clearly see broad patterns that correlate with poor or good survival outcomes. This information could help them pinpoint potential therapeutic targets.

“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, an assistant professor of medicine and a member of the Stanford Cancer Institute. “The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”

In particular, the researchers found that high expression of a gene called FOXM1, which is involved in cell growth, was associated with a poor prognosis across multiple cancers, while the expression of the KLRB1 gene, which modulates the body’s immune response to cancer, seemed to confer a protective effect.

The new database, which will be available to physicians and researchers, is called PRECOG, an abbreviation for “prediction of cancer outcomes from genomic profiles.” Stanford’s Department of Medicine

A multidisciplinary team at Yale, led by Yale Cancer Center members, has defined a subgroup of genetic mutations that are present in a significant number of melanoma skin cancer cases. Their findings shed light on an important mutation in this deadly disease, and may lead to more targeted anti-cancer therapies.

The role of mutations in numerous genes and genomic changes in the development of melanoma — a skin cancer with over 70,000 new cases reported in the United States each year — is well established and continues to be the focus of intense research. Yet in approximately 30% of melanoma cases the genetic abnormalities are unclear. To deepen understanding of melanoma mutations, the Yale team conducted a comprehensive analysis using whole-exome sequencing of more than 200 melanoma samples from patients with the disease.

The multidisciplinary team — drawing on their expertise in genetics, cancer, computational biology, pharmacology, and other disciplines — also tested the response of tumour cells with specific mutations to anti-cancer drugs.

The researchers confirmed that a gene known as NF1 is a “major player” in the development of skin cancer. “The key finding is that roughly 45% of melanomas that do not harbour the known BRAF or NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing pathway,” said Dr. Michael Krauthammer, associate professor of pathology and the study’s corresponding author.

Additionally, researchers observed that melanoma patients with the NF1 mutation were older and had a greater number of mutations in the tumours. These include mutations in the same pathway, collectively known as RASopathy genes.

Yet mutations in NF1 are not sufficient to cause skin cancer, said Ruth Halaban, senior research scientist in dermatology, a member of Yale Cancer Center, and lead author of the study. “Loss of NF1 requires more accompanying changes to make a tumour,” she explained. “Our study identified changes in about 100 genes that are present only in the malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can be applied to personalized cancer treatment.”

By testing the response of the melanoma samples to two cancer drugs, the researchers also determined that, in addition to loss of NF1, multiple factors need to be tested to predict the response to the drugs. “It opens the door to more research,” said Halaban, who is also principal investigator at Yale SPORE in Skin Cancer.
Yale University

Study identifies ‘major player’ in skin cancer genes
A multidisciplinary team at Yale, led by Yale Cancer Center members, has defined a subgroup of genetic mutations that are present in a significant number of melanoma skin cancer cases. Their findings shed light on an important mutation in this deadly disease, and may lead to more targeted anti-cancer therapies.

The role of mutations in numerous genes and genomic changes in the development of melanoma — a skin cancer with over 70,000 new cases reported in the United States each year — is well established and continues to be the focus of intense research. Yet in approximately 30% of melanoma cases the genetic abnormalities are unclear. To deepen understanding of melanoma mutations, the Yale team conducted a comprehensive analysis using whole-exome sequencing of more than 200 melanoma samples from patients with the disease.

The multidisciplinary team — drawing on their expertise in genetics, cancer, computational biology, pharmacology, and other disciplines — also tested the response of tumour cells with specific mutations to anti-cancer drugs.

The researchers confirmed that a gene known as NF1 is a “major player” in the development of skin cancer. “The key finding is that roughly 45% of melanomas that do not harbour the known BRAF or NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing pathway,” said Dr. Michael Krauthammer, associate professor of pathology and the study’s corresponding author.

Additionally, researchers observed that melanoma patients with the NF1 mutation were older and had a greater number of mutations in the tumours. These include mutations in the same pathway, collectively known as RASopathy genes.

Yet mutations in NF1 are not sufficient to cause skin cancer, said Ruth Halaban, senior research scientist in dermatology, a member of Yale Cancer Center, and lead author of the study. “Loss of NF1 requires more accompanying changes to make a tumour,” she explained. “Our study identified changes in about 100 genes that are present only in the malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can be applied to personalized cancer treatment.”

By testing the response of the melanoma samples to two cancer drugs, the researchers also determined that, in addition to loss of NF1, multiple factors need to be tested to predict the response to the drugs. “It opens the door to more research,” said Halaban, who is also principal investigator at Yale SPORE in Skin Cancer. Yale University

Scientists of the Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München have identified a new mechanism which contributes to the development of idiopathic pulmonary fibrosis (IPF). They showed that the pathological changes of lung tissue are accompanied by an increase in protein turnover by the central protein degradation machinery of the cell – the proteasome.

Idiopathic pulmonary fibrosis is a very aggressive form of pulmonary fibrosis and has a particularly poor prognosis. This fatal disease, for which so far no causal therapies exist, is characterized by a massive deposition of connective and scar tissue in the lung, which leads to a progressive loss of lung function and ultimately death. Connective tissue is mainly produced by myofibroblasts. The research group led by PD Dr. Silke Meiners of the Institute of Lung Biology and the CPC showed now for the first time that the activation of these myofibroblasts depends on increased protein turnover by the 26S proteasome.

In the recently published study, the Helmholtz scientists were able to demonstrate an activation of the 26S proteasome during the transformation of normal fibroblasts into myofibroblasts both in vitro and in vivo using two different experimental models of pulmonary fibrosis. Moreover, increased protein turnover was also detected in fibrotic lung tissue of IPF patients. “Conversely, we were able to show that targeted inhibition of the 26S proteasome prevents the differentiation of primary human lung fibroblasts into myofibroblasts, confirming the essential role of enhanced proteasomal protein degradation for this pathological process,” said Silke Meiners.

“Understanding the mechanisms that lead to a disease such as IPF helps us identify innovative approaches that allow therapeutic intervention,” comments Professor Oliver Eickelberg, director of the Institute of Lung Biology and scientific director of the CPC. In further studies, the Helmholtz scientists want to test the therapeutic use of substances which specifically inhibit the 26S proteasome, but do not affect other proteasome complexes in the cell. Helmholtz Zentrum München

New research from the University of Alberta shows that body fluids such as saliva may hold the keys to understanding a person’s likelihood of developing Alzheimer’s, even among those who don’t yet have memory and thinking problems associated with the disease.

Knowing that Alzheimer’s typically coexists with certain metabolic disorders, Shraddha Sapkota, a neuroscience PhD student at the U of A, along with psychology professor Roger Dixon and chemistry professor Liang Li, as well as colleagues from the Faculty of Medicine & Dentistry, reported success in identifying substances in saliva that could differentiate people with Alzheimer’s from those who were aging normally.

“Saliva is easily obtained, safe and affordable, and has promising potential for predicting and tracking cognitive decline, but we’re in the very early stages of this work and much more research is needed,” says Sapkota.

Early detection of Alzheimer’s symptoms is critically important for people with the disease and for clinical studies seeking to slow or stop its progression. However, many diagnosis techniques can be costly or invasive. Saliva is simple to obtain and easy to transport, and has been successfully used to help identify a variety of diseases and conditions. And because multiple samples can be readily obtained, saliva testing is particularly useful for performing repeated assessments that span days, weeks, months or longer.

“There is now consensus that Alzheimer’s disease begins with changes in the brain that are happening while people are still cognitively normal, decades before memory and thinking problems begin, which then accelerate as the disease progresses,” says Maria Carrillo, chief science officer of the Alzheimer’s Association. “Still, diagnosis of Alzheimer’s usually happens fairly late in the progression of the disease, typically not until symptoms are severe enough to prompt a visit to the doctor.”

The researchers conducted their study using saliva samples, clinical diagnoses and cognitive data from the Victoria Longitudinal Study, a long-term, large-scale investigation of human aging. Liquid chromatography-mass spectrometry was used to analyse the saliva samples and identify which substances were predominant in the saliva of three types of individuals: people with normal aging (NA), those with an earlier phase of dementia known as mild cognitive impairment (MCI), and those with Alzheimer’s disease (AD).

Linking that data back to each participant’s clinical diagnosis, researchers reported strong associations between certain substances and a person’s cognitive abilities. For example, higher levels of one substance in the MCI group and another in the Alzheimer’s group were observed. When these were examined in NA, higher levels of both predicted worse episodic memory performance. Another substance with higher levels in the Alzheimer’s group predicted slower speed in processing information.

“Equally important is the possibility of using saliva to find targets for treatment to address the metabolic component of Alzheimer’s, which is still not well understood,’ Sapkota notes. ‘This study brings us closer to solving that mystery.” University of Alberta