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

An international team of researchers led by KU Leuven has developed a new test to help doctors diagnose ovarian tumours and choose the most appropriate treatment. The researchers have recently described the test called ADNEX `

Existing predication models for ovarian cancer discriminate between benign and malignant tumours but lack accuracy and are unable to sub-classify different types of malignant tumour. This makes determining the appropriate treatment difficult, since some ovarian tumours require more serious treatment than others.

The new test developed by Professor Ben Van Calster (KU Leuven) in cooperation with the International Ovarian Tumour Analysis group (IOTA) not only discriminates between benign and malignant tumours but also makes it possible to accurately identify and classify malignant tumours into four types: borderline, stage 1 invasive, stage II-IV invasive and secondary metastatic.

The test is based on the patient’s clinical information, a simple tumour marker blood test and features that can be identified on an ultrasound scan. In addition to identifying the type of tumour, the test also expresses the confidence of the diagnosis as a percentage.

Doctors can use the test in a clinical database or by entering the patient’s details into a smartphone app, which was demonstrated to gynaecologists at the International Society for Ultrasound in Obstetrics and Gynecology World Congress in Barcelona last month. The authors of the study say doctors could start using ADNEX straight away.

Successful treatment depends in large part on the correct identification of the type of tumour, but this can be difficult. As a result, many women with ovarian cancer are not referred to the right specialist and some undergo more serious operations than necessary. A benign ovarian tumour often does not even need treatment at all.

But for malignant tumours especially, determining the tumour type is crucial to selecting the right specialist surgeon and treatment.

The researchers developed the test using data from almost 6,000 ovarian cancer patients, which were gathered and analysed by the IOTA group led by Professor Dirk Timmerman of UZ Leuven (University Hospitals Leuven), KU Leuven’s network of research hospitals. University of Leuven

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

Researchers at the University of Connecticut have found a new way to identify protein mutations in cancer cells. The novel method is being used to develop personalized vaccines to treat patients with ovarian cancer.

“This has the potential to dramatically change how we treat cancer,” says Dr. Pramod Srivastava, director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health and one of the principal investigators on the study. “This research will serve as the basis for the first ever genomics-driven personalised medicine clinical trial in immunotherapy of ovarian cancer, and will begin at UConn Health this fall,” Srivastava says.

 Dr. Angela Kueck, a gynecological oncologist at UConn Health, will run the initial clinical study, once it is approved by the FDA. The research team will sequence DNA from the tumours of 15 to 20 women with ovarian cancer, and use that information to make a personalized vaccine for each woman.

The researchers focused their clinical trial on patients with ovarian cancer because the disease usually responds well to surgery and chemotherapy in the short term, but often returns lethally within a year or two. That gives researchers the perfect window to prepare and administer the new therapeutic vaccines, and also means they may be able to tell within two years or so whether the vaccine made a difference. If the personalized vaccines prove to be safe and feasible, they’ll design a Phase II trial to test its clinical effectiveness by determining whether they prolong patients’ lives.

In order for the immune system to attack cancers, it first has to recognize them. Every cell in the body has a sequence of proteins on its exterior that acts like an ID card or secret handshake, confirming that it’s one of the good guys. These protein sequences, called epitopes, are what the immune system ‘sees’ when it looks at a cell. Cancerous cells have epitopes, too. Since cancer cells originate from the body itself, their epitopes are very similar to those of healthy cells, and the immune system doesn’t recognize them as bad actors that must be destroyed.

But just as even the best spy occasionally slips up on the details, cancer cell epitopes have tiny differences or mistakes that could give them away, if only the immune system knew what to look for.

“We want to break the immune system’s ignorance,” Srivastava says. For example, there could be 1,000 subtle changes in the cancer cell epitopes, but only 10 are “real,” meaning significant to the immune system. To find the real, important differences, Mandoiu, the bioinformatics engineer, took DNA sequences from skin tumours in mice and compared them with DNA from the mice’s healthy tissue.

Previous researchers had done this but looked at how strongly the immune system cells bound to the cancer’s epitopes. This works when making vaccines against viruses, but not for cancers. Instead, Srivastava’s team came up with a novel measure: they looked at how different the cancer epitopes were from the mice’s normal epitopes. And it worked. When mice were inoculated with vaccines made of the cancer epitopes differing the most from normal tissue, they were very resistant to skin cancer.

Theoretically, this approach could work for other cancers, although the research has yet to be done. University of Connecticut

A new study led by researchers at King’s College London in collaboration with the University of Manchester and the University of Dundee has found a strong link between exposure to peanut protein in household dust during infancy and the development of peanut allergy in children genetically predisposed to a skin barrier defect.

Around 2% of school children in the UK and the US are allergic to peanuts. Severe eczema in early infancy has been linked to food allergies, particularly peanut allergy. A major break-through in the understanding of eczema developed with the discovery of the FLG gene which codes for the skin barrier protein filaggrin. Mutations in the FLG gene result in an impaired skin barrier which is thought to allow allergens to penetrate the skin and predispose the body towards an allergic response.

Immunology, looked at the amount of peanut protein children were exposed to in household dust in their first year of life by vacuuming dust from the living room sofa and measuring peanut in the dust. A group of 577 children were assessed at 8 and 11 years of age for peanut allergy and their DNA was checked for FLG mutations. The study was conducted in children recruited to the Manchester Asthma and Allergy Study.

A strong link was found between early-life exposure to peanut protein in household dust and peanut allergy in children with FLG mutations. A three-fold increase in house dust peanut exposure during infancy was associated with a three-fold increase in risk of school-age peanut allergy. One in five children with peanut allergy had an FLG mutation. There was no significant effect of environmental peanut exposure in children without FLG mutations.

Dr Helen A Brough, first author from the Department of Paediatric Allergy, Division of Asthma, Allergy & Lung Biology, King’s College London, said: “Our findings provide evidence that peanut allergy may develop via the skin in children with mutations in the gene that codes for filaggrin which damage the function of this important skin protein. These findings are also an example of how an individual’s response to their environment can be modified by their genes. Our study raises the possibility of being able to identify a group of children with FLG mutations through genetic testing in the future, and altering their environmental exposure to peanut early in life to reduce the risk of developing peanut allergy.” King’s College London