University of Adelaide researchers have uncovered a genetic signal common to both cerebral palsy and autism.
The finding comes from the first large-scale study of gene expression in children with cerebral palsy.
The researchers, from the University’s Australian Collaborative Cerebral Palsy Research Group in the Robinson Research Institute, also showed common underlying molecular pathways in clinically diverse cerebral palsy. They say both findings add significantly to the weight of evidence for underlying genetic causes of cerebral palsy.
“Cerebral palsy is the most common motor disability of childhood with a frequency of around two in every 1000 live births,” says lead researcher Dr Clare van Eyk, Postdoctoral Research Fellow, Adelaide Medical School, University of Adelaide. “We know that, like autism, it’s a disorder of brain development primarily during pregnancy. But the underlying causes of cerebral palsy are still poorly understood.”
In this study, the researchers use new RNA sequencing technology to measure the gene messengers (RNA) in cells from children with cerebral palsy.
Cell lines from 182 individuals with cerebral palsy were studied and many showed disruption of cell signalling and inflammatory pathways, as seen in some children with autism.
“The results showed that the neurological or signalling pathways being disrupted in children with cerebral palsy overlap with those disruptions seen in autism,” says Dr van Eyk. “This supports a common biological change in both cerebral palsy and autism. Autism and cerebral palsy do sometimes co-exist, which further underlines common causation in some individuals.”
This is the latest in a series of studies from the University of Adelaide which have found increasing numbers of genetic mutations that are the likely cause of cerebral palsy. Using this data together with existing DNA sequencing results increases the proportion of individuals with a likely genetic cause to around 25%.
The University’s Cerebral Palsy Research Group is led by Emeritus Professor Alastair MacLennan and Professor Jozef Gecz, Channel 7 Children’s Research Foundation Chair for the Prevention of Childhood Disability. They are leading the world in discovering an increasing genetic basis to cerebral palsy.
“This research continues to refute the historical assumption that cerebral palsy is often due to difficulties at birth,” says Professor MacLennan.

University of Adelaidewww.adelaide.edu.au/news/news99822.html

When researchers at the University of São Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy.
According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets.
“Previous research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,” said Érica Aparecida de Oliveira, a postdoctoral scholar at USP’s School of Pharmaceutical Sciences (FCF).
As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism.
DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by José Agustín Pablo Quincoces Suárez, a professor at Bandeirantes University (UNIBAN).
“Experiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,” Oliveira said.
To unpack DM-1’s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker’s and brewer’s yeast.
“This yeast’s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,” Oliveira said.
The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment.
The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP.
“We then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,” Oliveira said.
The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR).
The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients.
“We performed a data mining exercise to find genes with altered expression during melanoma progression,” Oliveira said. “We identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.”
In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells.
In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells.
“Like curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,” Oliveira said.
EurekAlerthttps://tinyurl.com/ya7hhwwk

Two decades ago, oncologists realized that molecular biologists could see medically important differences between tumours that looked identical to pathologists. Molecular biologists could read information in the genome that helped to increase the precision of diagnoses, guide treatment strategies, and improve health outcomes.
Now, a research team from Columbia University has taken the first steps toward bringing such a genomic strategy into dermatology.
Their findings represent an initial step towards developing a molecular taxonomy for hair disorders. The taxonomy will be useful for diagnostic sequencing of patients with diseases affecting their hair follicles. It will also improve the characterization of hair follicle biology and pave the way for new precision medicine treatments for hair diseases.  
“Genome sequencing is changing the nature of disease diagnosis, and we saw an opportunity with rare hair diseases, since these disorders tend to be poorly annotated in catalogues of genetic diseases,” says Lynn Petukhova, an assistant professor in the Department of Dermatology at the College of Physicians & Surgeons and an affiliate of the Data Science Institute, where she’s a member of the Health Analytics Center.  “We thus started to organize genetic data for diagnostic sequencing in patients with rare diseases involving hair and were excited by what we discovered.”
After sifting through several databases the team found more than 600 genes, Petukhova said. Once the team saw all that data, they realized they had an opportunity to gain a deeper understanding of the biology that helps maintain a healthy hair follicle.
The team then mined more databases to understand relationships among the genes, collecting data about how the genes function in cells and tissues. In the end, they identified nearly 5,000 biological terms shared by groups of hair genes, amassing a matrix of more than three million data points. Andreas Mueller, a lecturer at the Data Science Institute, guided the team’s analysis of the big data, helping them to understand the underlying causal structure of hair disorders. The researchers discovered that the 684 genes could be grouped into 35 clusters based on their molecular functions. And these genetically-derived biological modules provided a foundation for the development of the new hair-disease taxonomy.
Disease classification systems have historically been based solely on disease symptoms. And oncologists have shown that incorporating molecular data into diagnostic algorithms helps to provide better care for cancer patients. Now, the same hope holds forth for the field of dermatology, Petukhova says.
“We felt that big data and data science could be used to gain a deeper understanding of the biology that renders hair susceptible to disease,” says Petukhova. “And it’s our hope that this new taxonomy will help scientists, doctors and researchers develop precision-medicine treatments for people with hair disorders.”

Data Science Institutehttps://tinyurl.com/yczd7e6h

Several patients with recurring glioblastoma, a deadly brain cancer, survived for more than a year in a clinical trial believed to be the first to use comprehensive DNA and RNA sequencing of a patient’s tumour to inform treatment for these patients in real-time. The study was led by the Translational Genomics Research Institute (TGen), UC San Francisco (UCSF) and the Ivy Foundation Early Phase Clinical Trials Consortium.
"To our knowledge, this is the first report of a prospective profiling study in recurrent glioblastoma to show patients with extended time to progression following treatment with genomics-informed therapy," said Dr. Sara Byron, Research Assistant Professor in TGen’s Integrated Cancer Genomics Division and the study’s lead author. "This is a primary example of the benefits of genomics-driven precision medicine being applied for patients with aggressive and refractory tumours."
Fifteen of 16 glioblastoma patients in the study conducted at UCSF received TGen’s genomics-informed treatment recommendations, in which the therapeutics suggested by a medical review panel (UCSF’s Molecular Tumor Board) were matched to each patient’s particular genetic code. Of those 15, seven patients were treated by their physicians using the genomic-based recommendations.
Key to this study was the fact that all genomic sequencing (the spelling out of the chemical DNA and RNA bases for more than 20,000 genes in the human genome), genetic analysis, and recommendations for treatment were completed in less than 35 days after surgery, ensuring that suggested therapies could begin within "a clinically acceptable time frame."

Timely administration of therapeutics is critical
Glioblastoma is an aggressive disease, with a median overall survival of only 15 months for newly diagnosed patients. One of the major difficulties in treating glioblastoma is its intrusive penetration into adjoining tissues, which prevents the complete surgical removal of the tumours from the brain, even with follow-up radiation and chemotherapy. As a result, nearly all glioblastomas recur. Patients whose brain cancer returns are often encouraged to enter experimental clinical trials. However, even on clinical trials, further progression of the disease is seen, on average, within 4 months.
"Notably, two of the patients experienced progression-free survival – meaning their tumour did not return or increase in size – for more than a year, with one of these patients progression-free at 21 months, three times longer than the time to progression on their previous therapy," said Dr. Michael D. Prados, the Charles B. Wilson Endowed Chair in Neurological Surgery at UCSF, and the study’s senior author.
Another major challenge in treating brain tumours is finding drugs that can penetrate the blood-brain barrier, which buffers the brain from the rest of the body’s blood-circulatory system. Located along small capillaries, the blood-brain barrier protects the brain from rapid changes in the body’s metabolic conditions and minimizes exposure to large molecules that are toxic to neurons in the brain.
The only FDA-approved standard-of-care drugs to treat glioblastoma are temozolomide, nitrosoureas, and bevacizumab.
In this study, more than 180 FDA-approved agents were reviewed, including all FDA-approved oncology drugs and a selection of repositioned agents that are approved by the FDA for other indications but show promising activity against cancer pathways. The tumor board considered the drugs supported by the genomic data for each patieunt, and discussed each drug’s ability to penetrate the blood-brain barrier, potential opportunities to combine treatments, drug-to-drug interactions and drug-safety profiles.
One of the patients was a 58-year-old woman with recurrent glioblastoma. Genomic sequencing showed several alterations with potential therapeutic relevance. Based on mutations in her NF1 and PALB2 genes, the UCSF Molecular Tumor Board recommended treatment with a combination of trametinib, olaparib and carboplatin. "This patient continued on treatment without disease progression (for more than) 665 days after surgery," according to the new paper, which adds, "Additional preclinical and clinical studies will be needed to determine the role of genomic context and combination therapy in the response observed for this patient."
"This precision-medicine study provides one of the first prospective demonstrations of using genome-wide molecular profiling to guide treatment recommendations for patients with recurrent glioblastoma within a clinically actionable time frame," said Dr. Michael Berens, TGen Deputy Director for Research Resources, and Professor and Director of TGen’s Cancer and Cell Biology Division.
"These findings provide a rationale and framework for larger prospective studies to further assess the efficacy of employing genomics-guided treatment for patients with recurrent glioblastoma," said Dr. Berens, one of the study’s authors.
TGen
tgen.org/home/news/2017-media-releases/tgen-ucsf-genomics-guided-brain-tumor-treatment.aspx#.WfJJcGKCxz8