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Salivary Cortisol Biomarker May Improve Glucocorticoid Therapy Management

In patients with adrenal insufficiency, salivary cortisol rhythm may serve as a useful biomarker to evaluate the adequacy of glucocorticoid replacement, according to findings from a proof-of-concept study reported in Clinical Endocrinology.

The well-being of patients with adrenal insufficiency depends on optimized glucocorticoid therapy, as undertreatment could induce chronic fatigue and lead to life-threatening adrenal crisis, and overtreatment may have negative, long-term metabolic and cardiovascular consequences, Filippo Ceccato, MD, a doctoral student at the University Hospital of Padova, Italy, and colleagues wrote in the study background.

Early Indicators of Lung Cancer Probed in New Study

Many of the critical processes underlying cancer formation and eventual metastasis to other organs remain mysterious. In the quest for earlier diagnoses and more effective treatment, intensive research efforts have been applied to the search for biomarkers—presymptomatic signs of disease detectable in blood, saliva, or other biofluids.

Chad Borges, an analytical biochemist working at Arizona State University’s Biodesign Institute has been studying a particularly promising class of potential biomarkers known as glycans. His new study, appearing in the journal Analytical Chemistry, investigates the formation of aberrant glycan molecules, which have been clinically implicated in a range of deadly cancers including ovarian, prostate, pancreatic, liver, multiple myeloma, breast, lung, gastric, thyroid and colorectal.

Indeed, as the authors note, nearly every known type of tumor cell displays abnormal glycans, making them a particularly attractive candidate for biomarker discovery and validation. Until now, however, detecting the source of aberrant glycans has been frustratingly difficult.

Borges is a member of Biodesign’s Molecular Biomarkers Unit, where proteins and protein modifications are examined for their potential as markers of human disease. “Our primary work has to do with extracting proteins from blood samples or other biofluids, purifying them and examining them in an intact state through mass spectrometry,” Borges says. “We look for variants in these proteins, which in many cases include glycosylation—the focus of this paper—except in this case we looked at global changes across all blood serum proteins.”

Glycans are biological sugar polymers, made up of several different types of sugar units—glucose, mannose, galactose and others. Glycans typically adorn the surfaces of cells and can act to modify proteins. Unlike other biological polymers like DNA and proteins, however, glycans are made “on-the-go,” without a preset template. This makes their formation and behavior trickier to predict.

As Borges explains, “glycans are assembled by enzymes through a first come, first build process. In cancer, the protein enzymes that form glycans—known as glycotranserases—get overexpressed. When that happens, you get these weird glycan structures that aren’t normal.” The study found, for the first time, at least two glycotransferases displaying aberrant activity in lung cancer samples, with other abnormal glycotransferase activity strongly implied as well.

The assembly of glycans is schematically similar to a tinker toy set in which glycotransferase enzymes act to connect various wheel-like sugar units via spoke-like branching elements. Overexpression of glycotransferases produces aberrant glycans, which tend to display bushier, more profuse branching patterns when compared with their normal counterparts. (see Figure 1).

These abnormal glycans can help facilitate metastasis of cancerous cells, because their presence on cell surfaces is differentially recognized by the immune system. Instead of destroying diseased cells, the immune system leaves them alone. The abnormal glycans can also help cancer cells traverse non-native tissues, i.e. metastasize.

In the current proof-of-concept study, archived plasma samples from 30 lung cancer patients were examined, along with 29 non-cancerous control samples matched by age, gender and smoking status. The study attempted to track the immediate upstream cause of aberrant glycans, namely the glycotransferase enzymes that build them—a process that takes place in the endoplasmic reticulum and Golgi apparatus of the cell.

“Most glycomics efforts look at intact glycans, but often this is not a good molecular surrogate for the activity of glycotranferases because glycotranferases work on hundreds of growing glycan polymers,” Borges notes. “Our new, bottom-up approach looks at glycans in a different way.” To evaluate glycotranferase activity, the study pooled together the glycan polymer branching points or nodes for all of the aberrant glycan structures observed. Specific sugar subunits and linkage types characterize these glycan nodes.

A technique known as gas chromatography/mass spectrometry was used to detect glycan node levels, which were then combined to infer glycotransferase activity. The study demonstrated that a number of glycan nodes exhibited a 1:1 molecular correspondence with particular glycotranferases. The technique was used to accurately pinpoint lung cancer in blood samples with 76-88 percent reliability.

While a number of hurdles must be addressed in future research, the new technique holds the promise of a simple test capable of analyzing multiple glycotransferases simultaneously and linking abnormal activity with the aberrant glycans formed by these enzymes. The test can be carried out without the need for enzyme or antibody reagents and provides a potential means of finally harnessing aberrant glycans as useful disease biomarkers.

The method’s effectiveness is expected to further improve once information from large data sets of known patient outcome are applied and analyzed. This will hopefully permit the development of disease-specific biomarkers for a range of ailments including cancers and other inflammation-related diseases.

Applying the glycan-node strategy directly to cancerous fluids or tissues, rather than plasma/serum (where normal glycans tend to dilute the desired signal) may further enhance the test’s sensitivity. “The interesting thing is that we see widely different glycan profiles for different biofluids and different tissues, suggesting that they will be able to provide information above and beyond what blood serum alone can provide,” Borges says.

The method, once refined, may offer clinicians an extra piece of evidence on which to base decisions concerning invasive procedures (like lung biopsy or pancreatectomy) for confirming cancer diagnosis and charting appropriate treatment.

Source: Multiplexed surrogate analysis of glycotransferase activity in whole biospecimens.

Source: Arizona State University Biodesign Institute

Virus-like Particles Provide Vital Clues About Brain Tumors

“Current wisdom says that cells are closed entities that communicate through the secretion of soluble signalling molecules. Recent findings indicate that cells can exchange more complex information – whole packages of genetic material and signalling proteins. This is an entirely new conception of how cells communicate”, says Dr Mattias Belting, Professor of Oncology at Lund University and senior consultant in oncology at Skåne University Hospital, Lund, Sweden.

Exosomes are small vesicles of only 30 nm. They are produced inside cells and act as “transport vehicles” of genetic material that can be transferred to surrounding cells. Since their first discovery, exosomes have been found in blood, saliva, urine, breast milk and other body fluids.

Mattias Belting’s research group has investigated exosomes released from tumour cells of patients with gliomas.

The tiny exosome particles are delivered from the tumour to healthy cells of the brain and may prime normal tissue for efficient spreading of the tumour. The researchers in Lund have now shown that the aggressiveness of the tumour is reflected in the exosome molecular profile.

“We have succeeded in developing a method for the isolation of exosomes from brain tumour patients through a relatively simple blood test. Our analyses indicate that the content of exosomes mirrors the aggressiveness of the tumour in a unique manner”, says postdoctoral researcher Paulina Kucharzewska.

Exosomes could thus be utilised as biomarkers, i.e. to provide guidance on how the patient should be treated and to monitor treatment response. This possibility is particularly attractive with brain tumours that are not readily accessible for tissue biopsy. However, analysis of exosomes from the blood may also prove important with other tumour types. The value of conventional tumour biopsies is limited by the heterogeneity of tumour tissue, i.e. the tissue specimen may not be fully representative of the biological characteristics of a particular tumour. Exosomes, however, may offer more comprehensive information, according to the researchers.

The second international meeting on exosomes has just opened in Boston, and Mattias Belting and members of his team are there.

“It is very exciting to be part of the emergence of a novel research field. It can be anticipated that the most influential researchers in this area may one day be awarded the Nobel Prize”, says Dr Belting.

Study: Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development

Source: EurekAlert!

Inform Genomics Transplant Product Shown to Predict Oral Mucositis with a High Degree of Accuracy in Patients Undergoing Conditioning Regimens Prior to Hematopoetic Stem Cell Transplant

Inform Genomics, Inc., a private company focused on developing novel platforms of genomic-based personalized medicine products for cancer supportive care, presented results that demonstrate the ability of its Transplant Product to predict a patient’s risk for developing oral mucositis (OM) prior to high dose chemotherapy as part of conditioning regimens for stem cell transplant in patients with hematologic malignancies.

UCLA Dentistry Receives Major Grant to Develop Saliva Test to Predict Onset of PTSD

Each year, more than a million Americans are at-risk of developing serious mental health problems after experiencing a terrifying event or serious physical injury. Once manifested, these psychiatric illnesses, such as post-traumatic stress disorder and depression, can be extremely crippling and difficult to treat and are a leading cause of disability in civilian, military and minority populations.

Recognizing these emerging disorders early on provides health care professionals the best opportunity for preventive interventions. Now, a team of researchers, led by Dr. Vivek Shetty, a professor at the UCLA School of Dentistry, has received a $3.8 million research grant to develop a salivary-biomarker approach for identifying individuals at future risk of developing post-traumatic stress disorder and depression following a traumatic event.