Moffitt Cancer Center researchers have found that breast and lung cancer patients who have low levels of a protein called tristetraprolin (TTP) have more aggressive tumours and a poorer prognosis than those with high levels of the protein. 

Cancer arises through the increased activity of oncogenes, proteins that drive cancer growth, and the decreased activity of tumour suppressors, proteins that block malignant growth and progression. TTP is a recently discovered tumour suppressor protein, and scientists at Moffitt have found that this protein can prevent lymphoma growth in mice.

Researchers wanted to further investigate the importance of TTP in cancer patients and what other genes it is associated with in cancer. Using a detailed catalogue of genetic changes in cancer developed by the National Institutes of Health, called The Cancer Genome Atlas, Moffitt scientists compared patients who had low levels of TTP to those with high levels of the protein.

These researchers found a network of 50 different genes associated with low levels of TTP in breast, lung and colon tumours. This genetic network was also present in other tumour types, including prostate, pancreatic and bladder cancer.  This demonstrates that TTP is involved in a variety of mechanisms important for tumour development and growth, and suggests that developing agents that target this network may be an effective therapeutic strategy across a wide spectrum of tumours.

They also reported that low levels of TTP were associated with poor prognosis in certain cancers, including a higher rate of relapse in breast cancer patients and lower rates of survival in lung adenocarcinoma patients.  Additionally, breast and lung cancer patients with low levels of TTP tended to have more aggressive types of tumors.

“Identifying this network allows us to set up future research projects focused on understanding how TTP functions as a tumor suppressor with the ultimate goal of developing treatments specific for patients that have low levels of TTP,” explained Robert Rounbehler, Ph.D., research scientist at Moffitt. Moffitt Cancer Center

Scientists have been labouring to detect cancer and a host of other diseases in people using promising new biomarkers called “exosomes.” Indeed, Popular Science magazine named exosome-based cancer diagnostics one of the 20 breakthroughs that will shape the world this year. Exosomes could lead to less invasive, earlier detection of cancer, and sharply boost patients’ odds of survival.

“Exosomes are minuscule membrane vesicles — or sacs — released from most, if not all, cell types, including cancer cells,” said Yong Zeng, assistant professor of chemistry at the University of Kansas. “First described in the mid-’80s, they were once thought to be ‘cell dust,’ or trash bags containing unwanted cellular contents. However, in the past decade scientists realized that exosomes play important roles in many biological functions through capsuling and delivering molecular messages in the form of nucleic acids and proteins from the donor cells to affect the functions of nearby or distant cells. In other words, this forms a crucial pathway in which cells talk to others.”

While the average piece of paper is about 100,000 nanometers thick, exosomes run just 30 to 150 nanometers in size. Because of this, exosomes are hard to separate out and test, requiring multiple-step ultracentrifugation — a tedious and inefficient process requires long stretches in the lab, according to scientists.

“There aren’t many technologies out there that are suitable for efficient isolation and sensitive molecular profiling of exosomes,” said Zeng.  “First, current exosome isolation protocols are time-consuming and difficult to standardize. Second, conventional downstream analyses on collected exosomes are slow and require large samples, which is a key setback in clinical development of exosomal biomarkers.”

Now, Zeng and colleagues from the University of Kansas Medical Center and KU Cancer Center have just published a breakthrough paper in the Royal Society of Chemistry journal describing their invention of a miniaturized biomedical testing device for exosomes. Dubbed the “lab-on-a-chip,” the device promises faster result times, reduced costs, minimal sample demands and better sensitivity of analysis when compared with the conventional bench-top instruments now used to examine the tiny biomarkers.

“A lab-on-a-chip shrinks the pipettes, test tubes and analysis instruments of a modern chemistry lab onto a microchip-sized wafer,” Zeng said. “Also referred to as ‘microfluidics’ technology, it was inspired by revolutionary semiconductor electronics and has been under intensive development since the 1990s. Essentially, it allows precise manipulation of minuscule fluid volumes down to one trillionth of a litre or less to carry out multiple laboratory functions, such as sample purification, running of chemical and biological reactions, and analytical measurement.”

Zeng and his fellow researchers have developed the lab-on-a-chip for early detection of lung cancer — the number-one cancer killer in the U.S. Today, lung cancer is detected mostly with an invasive biopsy, after tumours are larger than 3 centimetres in diameter and even metastatic, according to the KU researcher.

Using the lab-on-a-chip, lung cancer could be detected much earlier, using only a small drop of a patient’s blood.

“Most lung cancers are first diagnosed based on symptoms, which indicate that the normal lung functions have been already damaged,” Zeng said. “Unlike some cancer types such as breast or colon cancer, no widely accepted screening tool has been available for detecting early-stage lung cancers. Diagnosis of lung cancer requires removing a piece of tissue from the lung for molecular examination. Tumour biopsy is often impossible for early cancer diagnosis as the developing tumour is too small to see by the current imaging tools. In contrast, our blood-based test is minimally invasive, inexpensive, and more sensitive, thus suitable for large population screening to detect early-stage tumours.”

Zeng said the prototype lab-on-a-chip is made of a widely used silicone rubber called polydimethylsiloxane and uses a technique called “on-chip immunoisolation.”

“We used magnetic beads of 3 micrometres in diameter to pull down the exosomes in plasma samples,” Zeng said. “In order to avoid other interfering species present in plasma, the bead surface was chemically modified with an antibody that recognizes and binds with a specific target protein — for example, a protein receptor — present on the exosome membrane. The plasma containing magnetic beads then flows through the microchannels on the diagnostic chip in which the beads can be readily collected using a magnet to extract circulating exosomes from the plasma.”

Beyond lung cancer, Zeng said the lab-on-a-chip could be used to detect a range of potentially deadly forms of cancer.

“Our technique provides a general platform to detecting tumour-derived exosomes for cancer diagnosis,” he said. “In addition to lung cancer, we’ve also tested for ovarian cancer in this work. In theory, it should be applicable to other types of cancer. Our long-term goal is to translate this technology into clinical investigation of the pathological implication of exosomes in tumour development. University of Kansas

The discovery of new genetic mutations associated with childhood blindness, achieved through a collaboration between teams led by Michel Cayouette at the IRCM, Robert K. Koenekoop at McGill University and Doris Kretzschmar at Oregon Health and Science University has recently been published. The researchers identified a novel link between retinal degeneration and lipid metabolism. Results of their study could pave the way to new treatments for retinal degenerative diseases like Olive McFarlane syndrome (OMS) and Leber’s congenital amaurosis (LCA).

By attempting to uncover the genetic causes of OMS, a rare disease characterized by a degeneration of the retina that causes vision loss at a very young age, the researchers identified mutations in the gene PNPLA6 that are involved in lipid metabolism.

“This breakthrough is important because it represents the first discovery of a genetic mutation associated with this disease,” says Michel Cayouette, PhD, Director of the Cellular Neurobiology research unit at the IRCM. “In addition, we discovered that this same gene also affects patients with LCA.”

“We found that the gene plays an important role in the survival of photoreceptors, a specialized type of light-sensing neurons found in the retina,” explains Vasanth Ramamurthy, PhD, co-first author of the study in Dr. Cayouette’s laboratory. “More specifically, our results show that mutations in the gene lead to photoreceptor death, which, in turn, causes blindness in children with OMS and LCA.”

The scientists also discovered the lipid metabolism was altered in photoreceptors, thereby identifying a potential new target for the development of drugs that could treat retinal degeneration in patients with OMS and LCA.

“At the IRCM, we started a new research project to produce a mouse model of the mutation in order to better understand the molecular causes of these pathologies,” adds Dr. Cayouette. “This model will also allow us to test different therapeutic approaches to determine, for example, whether manipulating lipid metabolism could prevent retinal degeneration.” IRCM

TAU researchers discover that a genetic form of deafness is due to absence of thyroid hormone

Fatigue, weight gain, chills, hair loss, anxiety, excessive perspiration — these symptoms are a few of the signs that the thyroid gland, which regulates the body’s heart rate and plays a crucial role in its metabolism, has gone haywire. Now, new research from Tel Aviv University points to an additional complication caused by thyroid imbalance: congenital deafness.

The study, was conducted by Prof. Karen B. Avraham and Dr. Amiel Dror of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine. Using state-of-the-art imaging, the researchers found that congenital deafness can be caused by an absence of a thyroid hormone during development.

‘Since our laboratory mainly focuses on the system of the inner ear, the study of a system such as the thyroid gland was new to us and therefore challenging,’ said Dr. Dror. ‘My curiosity as to how these two systems interact together to develop normal hearing led to this multidisciplinary study.’

The researchers used mouse populations to study a form of congenital deafness that affects humans. Harnessing electron microscopy at the Sackler Cellular & Molecular Imaging Center, researchers tracked the inner hair cells of the cochlea (the auditory portion of the inner ear) in two groups — control (wild) mice and mutant (congenitally deaf) mice.

Examination of the inner ear showed a spectrum of structural and molecular defects consistent with hypothyroidism or disrupted thyroid hormone action. The researchers’ analysis of the images revealed defective formation of the mice’s thyroid glands: labelled thyroid follicles did not grow or grew incompletely.

‘Our work demonstrated that normal hearing fails to develop when thyroid hormone availability is insufficient as a result of a genetic mutation,’ said Dr. Dror. ‘Our model provides a platform to test therapeutic approaches in order to prevent hearing loss before it occurs. There is still long way ahead before we get to the point of practical treatments with our research, but we believe we are moving in the right direction.’ American Friends of Tel Aviv University

A study involving scientists from the University of Leicester has established a link between hypoglycaemia and increased risk of cardiovascular events and mortality in patients with diabetes.

Professors Kamlesh Khunti and Melanie Davies, scientists from the University of Leicester’s Diabetes Research Centre, have confirmed an association between hypoglycaemia and an increased risk of cardiovascular events and mortality in insulin-treated patients with diabetes, which could lead to changes in the way some patients’ treatment is managed.

As part of an international collaboration with scientists from Imperial College London, the QIMR Berghofer Medical Research Institute and Novo Nordisk A/S – using data from the UK Clinical Practice Research Datalink database – Professors Khunti and Davies demonstrated that, following hypoglycaemia, insulin-treated patients with diabetes had an ~60% higher risk of cardiovascular events, and were between 2–2.5 times more likely to die over the same period as patients who did not experience hypoglycaemia.

Kamlesh Khunti, Professor of Primary Care Diabetes & Vascular Medicine at the University of Leicester, who led the research, said:  “This is one of the first studies to report the risk of cardiovascular events and mortality in people with both type 1 and type 2 diabetes. The risks are very significant and we need to identify these patients early with a view to implementing strategies to reduce their risk of hypoglycaemia.”

Patients with diabetes are at higher risk of cardiovascular disease due to the formation of atherosclerotic plaques in blood vessels; this is a major cause of early death in these patients. The results of the study show that hypoglycaemia, which occurs when a patient’s blood glucose becomes dangerously low, can trigger potentially fatal cardiovascular events.

Melanie Davies, Professor of Diabetes Medicine at the University of Leicester and Honorary Consultant at Leicester’s Hospitals,  commented: “The data from this important and large piece of research confirms what we already know in people with type 2 diabetes and extends our knowledge in those with type 1 diabetes. It also confirms the significance of hypoglycaemia and the link with an increased risk of cardiovascular events, a risk that persists over a long time period. Going forward we need to focus on management strategies that help patients minimise their risk of having hypoglycaemic events.” University of Leicester