University of Utah scientists have identified two microRNA molecules that control chronic inflammation, a discovery that one day may help researchers prevent certain fatal or debilitating conditions before they start.

‘We’re living at a time where the aging population is growing,’ said Ryan O’Connell, D.Phil., assistant professor of pathology, whose lab made the discovery. ‘The question is: how can we predict and prevent the onset of disorders that emerge upon growing older?’

After three years of research and building on previous studies, the scientists determined that if a particular microRNA is genetically removed from mice, the animals will develop chronic inflammation spontaneously and die early from subsequent ailments such as cancer or an autoimmune disorder. However, mice that also lack a second type of microRNA don’t develop chronic inflammation. So one microRNA prevents the condition while the other promotes it, identifying a key system in the body that modulates this harmful state.

Certain types of immune cells, called T follicular helper cells, are known to promote the production of antibodies that attack our own tissues and contribute to chronic inflammation. O’Connell and colleagues found that the microRNAs at issue are produced by and act to control these important cell types.

‘Now we know which cells in the body we need to get miRNA inhibitors delivered to if we want to reduce chronic inflammatory conditions,’ said O’Connell, noting that the next step is human research. One question would be whether patients with chronic inflammation who received an inhibitor of a certain microRNA would see their chronic inflammation indicators decrease, preventing fatal conditions from emerging.

Previous studies have shown that chronic inflammation is linked to the development of certain conditions including diabetes, lupus, arthritis, obesity, cancer, neurodegeneration and cardiovascular disease along with a shortened life span. The challenge is that chronic inflammation happens at a low level and is typically not detected by doctors. But certain biomarkers such as elevated levels of cytokines or antibodies can indicate the condition.

‘Everyone waits until they have bad symptoms to go see the doctor,’ he said. ‘However, the goal of medicine is to take a person who is not sick yet and be able to analyze something we can test that can help predict whether they’re going to be sick in the future — and take appropriate measures to prevent terrible outcomes.’ EurekAlert

A new comprehensive analysis of thyroid cancer from The Cancer Genome Atlas Research Network has identified markers of aggressive tumours, which could allow for better targeting of appropriate treatments to individual patients.
The finding suggests the potential to reclassify the disease based on genetic markers and moves thyroid cancer into a position to benefit more from precision medicine.

“This understanding of the genomic landscape of thyroid cancer will refine how it’s classified and improve molecular diagnosis. This will help us separate those patients who need aggressive treatment from those whose tumour is never likely to grow or spread,” says Thomas J. Giordano, M.D., Ph.D., professor of pathology at the University of Michigan Medical School.

Giordano is the project co-lead for TCGA thyroid cancer analysis along with Gad Getz, Ph.D., director of Cancer Genome Computational Analysis at the Broad Institute of MIT and Harvard.

Thyroid cancer incidence has increased three-fold over the last 30 years and is the most rapidly increasing cancer in the United States. While the tumours are often slow-growing and easily treated with a combination of surgery, thyroid hormone and radioactive iodine, some patients will develop more aggressive and deadly thyroid cancers.

In this TCGA study the researchers analysed nearly 500 thyroid cancer samples to identify all genetic mutations that play a role. They found several new cancer genes as well as new variations of existing genes.

Overall, the thyroid cancer genome is relatively quiet, with fewer genetic mutations involved than in other common cancers, the researchers found. This may explain why the disease is often slow-growing.

Fewer mutations meant the researchers were able to look at the signalling pathways involved and understand what drives thyroid tumours. This approach helped them understand the genetic drivers of more of these cancers, reducing the percentage of “dark matter” cases – those with unknown genetic drivers – from 25 percent to 3.5 percent.

Those drivers can be broken down into two primary oncogenic groups: BRAF plus similar mutations and RAS plus similar mutations. But within these two primary groups, especially the BRAF group, several different subtypes of thyroid cancer exist. Currently, all thyroid cancers associated with BRAF, for example, had been considered essentially the same. That’s not the case.

“This study integrated a wide variety of genomic data to not only identify cancer drivers, but to compare how these different drivers behave,” said Getz, who is also director of the Bioinformatics Program at the Massachusetts General Hospital Cancer Center and an associate professor of pathology at Harvard Medical School. “Interestingly, we found that subsets of BRAF-mutated thyroid cancers are driving cancer through distinct mechanisms, and that some of these subsets are associated with higher risk and less differentiated cancers.”

The researchers used this understanding to create measures or scores that can determine how a tumour signals and how aggressive a thyroid tumour is. These scores are being tested in a clinical trial to assess if it can lead to more targeted treatment recommendations.

“These findings are a major step forward in how doctors and patients will address thyroid cancer diagnosis and treatment. Researchers around the world will be using this data, coming back to it and asking other scientific questions,” says Carolyn Hutter, Ph.D., M.S., program director in the division of genomic medicine at the National Human Genome Research Institute.

An initial recommendation is for the pathology and scientific communities to consider reclassifying thyroid cancer based on molecular subtypes to better reflect their underlying molecular properties. This would allow doctors to identify the slow-growing tumours from the aggressive tumours and recommend appropriate treatments. Broad Institute

Researchers at Okayama demonstrate that injection of a virus solution followed by tumour removal can eradicate cancer metastasis in lymph nodes without the need for preventative surgery.
While early-stage gastrointestinal cancers can be treated non-surgically, once the cancer has invaded to a particular depth, preventative – ‘prophylactic’ – surgery is routine. The frequency of lymph node metastasis increases significantly once the cancer has penetrated the submucosal layers, and as there is no way of determining whether the cancer has metastasized in the lymph nodes they will be surgically removed just in case. Now researchers at Okayama University and the University of California in San Diego have demonstrated that injection of a viral solution can eradicate lymph node metastasis making prophylactic surgery unnecessary.
To treat early stage cancers a saline solution is injected creating a fluid cushion, which raises and isolates the tumour. The tumour is then readily removed by equipment through a standard endoscopic viewing tube inserted in the gastrointestinal tract. However if the cancer has already penetrated the submucosal layer it will be prone to relapse in the lymphatic system.
Toshiyoshi Fujiwara and his colleagues adapted the standard endoscopic treatment by injecting a solution of Telomelysin – a virus known to kill epithelial and mesenchymal malignant cells – instead of saline solution.  They tested the treatment in a mouse model, injecting green-fluorescent-protein-labelled cancer cells into the submucosal layers of the rectum, which developed lymph node metastasis. Fluorescence imaging showed that cancer cells were successfully eliminated by the treatment with virus solution, in contrast to mice treated with saline solution instead. In addition, treated mice showed no relapse four weeks after the treatment
In their report of the results the researchers conclude, “From a clinical view point, this new, simple, and robust strategy is a more realistic and promising bench-to-bedside translation than prophylactic surgery for ablation of potential lymph node metastases in early gastrointestinal cancer patients.”
Early stage gastrointestinal cancers are defined by the level of the cancer invasion reaching no further than the submucosa. Endoscopic treatment removes these tumours by dissecting the submucosal layers.
For esophageal gastric and colorectal submucosally invaded cancers, the frequency at which the cancer is found to metastasize in the lymph nodes is approximately 10 to 20%. The lymphatic system distributes fluids, proteins, chemicals, cells and drugs. This makes it a major pathway for the spread of metastatic cancers so that cancerous invasion of the lymphatic system is particularly problematic. It is very difficult to determine whether the cancer has metastases in the lymph nodes. As a result lymph node surgery just in case is routine when treating esophageal gastric and colorectal submucosal cancers, even though in many cases it may not have been necessary.
Previous research has demonstrated that certain viruses replicate in cancer cells and break them down, and may be developed for cancer treatments. The researchers further exploited the role of the lymph system in mediating proteins and fluids, a function which makes it more prone to exposure to a virus injected in the surrounding area. They experimented with Telomelysin – a telomerase-dependent, tumour-killing replicating adenoviral agent (OBP-301). The virus is known to kill epithelial and mesenchymal malignant cells.  
The researchers first tested the virus on green-fluorescent-protein-labelled colorectal cancer cell lines with. Using fluorescence imaging, they observed rapid cell death in response to injection with the virus while there was no such response in cell lines treated with mutant strains of the virus that had replication deficiencies.
The researchers demonstrated how their treatment exploited the lymph node function using mouse models injected with red-fluorescent-protein-labelled lymph node metastasized cancer cells. After six days the virus labelled with green fluorescent protein was injected and fluorescence images showed the position of the virus coincided with the metastatic foci in the lymph nodes.

Kikuchi S, Kishimoto H, Tazawa H, Hashimoto Y, Kuroda S, Nishizaki M, Nagasaka T, Shirakawa Y, Kagawa S, Urata Y, Hoffman RM, Fujiwara T: Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer. Mol Ther. 2014 Dec 19.

A Dartmouth study suggests that it may be possible to use Diffuse Optical Spectroscopic Tomographic imaging (DOST) to predict which patients will best respond to chemotherapy used to shrink breast cancer tumours before surgery. These findings could eliminate delays in effective early treatment for tumours unlikely to respond to neoadjuvant chemotherapy (NAC).

Breast cancer is the most common non-skin cancer in women worldwide, and the second leading cause of women’s cancer mortality in the United States. A common treatment strategy after diagnosis is to shrink breast cancer tumours larger than 3 centimetres with a 6- to 8-month course of NAC prior to surgery. Clinical studies have shown that patients who respond to NAC have longer disease-free survival rates, but only 20 to 30 percent of patients who receive NAC fit this profile.

‘Our work represents the first clinical evidence that tumour total haemoglobin (estimated from DOST images) is different in the women with locally advanced breast cancer who respond to neoadjuvant chemotherapy,’ said lead author Shudong Jiang, associate professor of Engineering at the Thayer School of Engineering at Dartmouth. ‘We were able to predict breast tumour response to NAC based on image data acquired before the initiation of therapy.’
DOST imaging is used to measure tumour tissue for haemoglobin and oxygen saturation levels—key indicators of the presence the tiny blood vessels cancer tumours need to grow. This study suggests that biomarkers obtained through DOST imaging could help physicians determine the best treatment strategy for patients.
‘The implication of this information is that certain tumours are pre-disposed to responding to neoadjuvant chemotherapy, and that this predisposition could be known prior to choosing the therapy,’ says Jiang. ‘The study also could dramatically accelerate future randomized clinical trials on optimal NAC regimes. By using a validated imaging surrogate as an outcome measure, we could potentially reduce the number of patients required, and the length of time they need to be followed.’
Jiang says the next step will be to develop a portable and compact system to more accurately measure changes in the breast prior or/and during neoadjuvant chemotherapy. This system could be integrated into the workflow of clinical oncology practice to maximize patient participation, and determine whether additional prognostic information could be obtained that would influence patient management. Norris Cotton Cancer Center at Dartmouth-Hitchcock

New Penn Medicine research has found that elevated levels in the blood of the brain-enriched protein calpain-cleaved αII-spectrin N-terminal fragment, known as SNTF, shortly after sports-related concussion can predict the severity of post-concussion symptoms in professional athletes.

This new study builds on previous research from this group showing that elevated blood levels of SNTF on the day of a mild traumatic brain injury treated in the emergency room predicted those patients who would go on to suffer diffuse axonal injury and long-term cognitive dysfunction.

“We extended this biomarker research to the domain of professional sports to test its merit as an objective and rapid way to determine players’ severity of brain injury,” says lead author, Robert Siman, PhD, Research Professor of Neurosurgery at Penn. “This blood test may aid neurobiologically-informed decisions on suitability for return to play following a sports-related concussion.”

The study, conducted in collaboration with Henrik Zetterberg, MD, PhD and Kai Blennow, MD, PhD, of the Sahgrenska Academy at University of Gothenburg, Sweden, and their colleagues, enrolled 288 players in the top Swedish professional ice hockey league.  Each of the 28 players who suffered a concussion during the first half of the 2012-2013 season received serial blood draws and was evaluated daily for symptom resolution using the latest guidelines for treatment of sports concussions. Eight of the concussed players were symptom-free within a few days of their injury, but 20 of the players had persistent post-concussion symptoms requiring they be withheld from play six days or longer.  An additional 45 players were evaluated during the preseason, 17 of whom were also tested before and after a concussion-free training game.

Compared to those players who were not concussed, or whose concussion symptoms resolved rapidly, the researchers found an increase in the blood SNTF concentration from one hour up to 144 hours post-concussion in those players experiencing persisting post-concussion symptoms.  SNTF is a protein that is present at undetectable levels in healthy human brains, but is produced under conditions where nerve cells are traumatized and begin to die.  Concussions that lead to lasting brain dysfunction cause SNTF to accumulate in vulnerable long axon tracts of the brain, and its blood elevation is a measure of this diffuse axonal injury.

“These results show that SNTF has promise as a blood biomarker for sports-related concussion and beyond. High blood levels of SNTF appear to identify acute brain damage that corresponds with persisting symptoms after concussion.  These observations lend further support to the growing awareness that concussion is not trivial, since it can induce permanent brain damage in some individuals,” agree Siman and senior author, Douglas H. Smith, MD, professor of Neurosurgery and director of the Center for Brain Injury and Repair at Penn. Penn Medicine