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Are e-Cigarettes ‘Safer’ than Regular Cigarettes?

E-cigarettes appear to trigger unique immune responses as well as the same ones triggered by regular cigarettes, according to new research published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

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

Low Levels of Serum Bilirubin Spell Higher Lung Cancer Risk for Male Smokers

Elevated levels of bilirubin in the blood get attention in the clinic because they often indicate that something has gone wrong with the liver. Now researchers have found that male smokers with low levels of the yellow-tinged chemical are at higher risk for lung cancer and dying from the disease.

A team led by researchers at The University of Texas MD Anderson Cancer Center reported its findings in a late-breaking abstract at the AACR Annual Meeting 2013 in Washington, D.C.

“Our study indicates male smokers with low levels of bilirubin are a high-risk group that can be targeted with smoking cessation help, low-dose spiral CT screening of their lungs and other preventive measures,” said senior author Xifeng Wu, M.D., Ph.D., professor and chair of MD Anderson’s Department of Epidemiology and the Betty B. Marcus Chair in Cancer Prevention.

Lung cancer usually is diagnosed at a late stage, when tumors are inoperable and treatments largely ineffective. The overall five-year survival rate is 15 percent, but it falls to 5 percent for stage 3 lung cancer patients and 1 percent for those with stage 4 disease.

Spiral CT scans catch cancer early, biomarker could reduce false positives

The National Lung Screening Trial found that low-dose spiral computed tomography screening reduces mortality among heavy smokers by 20 percent. However, 95 percent of growths found by spiral CT are false positives, a barrier to large-scale screening.

“Validated biomarkers are urgently needed to improve risk prediction for lung cancer and to reduce false positives, shifting the balance toward more effective and efficient CT screening for cancer detection,” Wu said.

The researchers started with an objective analysis of levels of metabolites — substances produced during metabolism. Bilirubin is produced during the breakdown of old blood cells.

They analyzed 60 samples divided into three groups known as “trios” — normal controls, early stage and late stage non-small cell lung cancer patients. The top three metabolites were validated in two more groups of 50 and 123 trios.

When bilirubin emerged as the most significant metabolite, another validation study was done in a prospective cohort of 435,985 people with 208,233 men in Taiwan.

Men were divided into four groups according to their serum bilirubin levels. Lower bilirubin level was associated with significantly higher rates of both lung cancer incidence and mortality.

In the Taiwanese cohort, the incidence rate per 10,000 person-years in men was 7.02 for those in the lowest bilirubin quartile (.68 mg/dL or less), compared to 3.73 in the highest quartile of bilirubin level (1.12 mg/dL or more). The mortality rate per 10,000 person-years was 4.84 for the lowest level compared with 2.46 in the highest bilirubin quartile.

Next step: Establish a risk prediction model in heavy smokers

Bilirubin makes sense as a protective agent because of its anti-oxidant, anti-inflammatory and anti-proliferative effects. “It’s plausible that bilirubin protects against lung cancer by scavenging free radicals and carcinogens associated with smoking,” said study presenter Fanmao Zhang, a doctoral candidate in epidemiology.

Indeed, a Belgian study showed that bilirubin in the high normal range lowered cancer mortality in men. A study in the United Kingdom showed higher bilirubin levels in the normal range were associated with lower risks of chronic obstructive pulmonary disease, lung cancer and all-cause mortality. Neither of those studies stratified their analysis of bilirubin by smoking status.

“We expected that bilirubin might be protective, but our finding that bilirubin levels affect only smokers was somewhat of a surprise,” Wu said. “Our discovery that low levels increase lung cancer risk is unique.”

Smokers in the two middle cohorts of bilirubin levels also had higher lung cancer risk than those in the highest quartile. As an objective risk index for lung cancer and all-cause mortality, low levels of bilirubin should send an urgent message to quit smoking, said Chi Pang Wen, M.D., Ph.D., co-lead author from National Health Research Institutes, Taiwan.

The next step, Wu said, is to evaluate the predictive value of serum bilirubin in heavy smokers and to establish a risk prediction model that incorporates bilirubin and other biomarkers with clinical and epidemiological data to improve the efficiency of lung cancer risk prediction.

Source: EurekAlert!

Advances in Molecular Testing Offer New Hope for Lung Cancer Patients

The emergence of molecular diagnostic testing in lung cancer offers new hope for patients battling the number one cancer killer in the United States and abroad. Now, for the first time after a decade of biomarker testing in lung cancer, a uniform approach for testing for the EGFR mutation and ALK rearrangement along with the availability of targeted therapies offer lung cancer patients the chance for improved quality of life and more time with their loved ones.

The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) have developed an evidence-based guideline, “Molecular Testing Guideline for the Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors,” which establishes recommendations for EGFR and ALK testing, helping to guide targeted therapies. The guideline was released on April 3, 2013, in Archives of Pathology & Laboratory Medicine (APLM), Journal of Thoracic Oncology, and The Journal of Molecular Diagnostics.

“The key recommendation of the guideline, and perhaps most important to lung cancer patients, is that all patients with advanced lung adenocarcinoma should be tested for EGFR and ALK abnormalities, that would qualify them for tyrosine kinase inhibitor therapy, regardless of their clinical variables, such as smoking history, gender, or ethnicity,” said Marc Ladanyi, MD, attending pathologist in the Molecular Diagnostics Service at Memorial Sloan-Kettering Cancer Center in New York, and IASLC member.

Similar to the testing done in breast cancer, matching a cancer patient’s molecular profile with the appropriate targeted therapy provides individualized treatment options. The guideline answers important clinical questions, including:

  • When should testing be performed?
  • How should testing be performed?
  • Should other genes be routinely tested in lung cancer?
  • How should molecular testing of lung cancer be implemented?

“In the U.S. up to 20 percent of patients with lung adenocarcinoma, the most common type of lung cancer, will test positive for one of the two biomarkers,” said Philip T. Cagle, MD, FCAP, medical director of Pulmonary Pathology in the Department of Pathology and Genomic Medicine at The Methodist Hospital in Houston, Texas, APLM editor, and CAP member. “It is critical to identify these patients because they stand to benefit more from new targeted drugs than from conventional chemotherapy, and with fewer side effects.”

For lung cancer survivor Richard Heimler, molecular diagnostic testing has meant five additional years with his family, including his daughter and son. After his initial diagnosis in 2004, Heimler had surgery to remove cancer tumors in his lungs and brain. When multiple tumors returned in 2008, Heimler participated in a clinical trial to determine if he was a candidate for targeted therapies.

“After testing positive for the abnormal ALK gene, I began taking a targeted drug in the form of a pill,” said Heimler. “It was wonderful to not experience the debilitating side effects that I had with chemotherapy. This new world of science has given me hope that I will have more time to create memories with my children and watch them grow up.”

In an era of precision medicine, the guideline provides recommendations for pathologists, oncologists, and other cancer health professionals on the current state-of-the-art recommendations for the molecular testing of lung cancer.

“The three organizations came together to address the variance in practice around the world about how this testing should performed,” said Neal I. Lindeman, MD, director of Molecular Diagnostics at Brigham and Women’s Hospital and associate professor of Pathology at Harvard Medical School in Boston, and AMP member. “Pathologists who specialize in molecular diagnostics and lung cancer collaborated to create the guideline to minimize variation and provide greater precision in the care of patients.”

The CAP Pathology & Laboratory Quality Center, (the Center,) a forum for developing evidence-based guidelines and consensus recommendations, provided the process for creating the guideline. Expert panels made up of renowned worldwide leaders in the field collaborated to develop the recommendations.

“The guideline is an important step in making sure that patients benefit from the new molecular understanding of lung cancer,” said Dr. Ladanyi. “As new studies lead to further evidence-based recommendations, we hope to develop additional guidelines for other biomarkers related to this disease.”

In conjunction with the publishing of the guideline, CAP, IASLC, and AMP have developed clinical tools and resources for pathologists and oncologists that summarize the findings and recommendations. In addition, the organizations have developed a patient guide for further understanding, including questions for patients to ask their physicians. A series of videos featuring three of the guideline authors and a lung cancer survivor can be found on the CAP, IASLC, and AMP YouTube Channels.

Source: EurekAlert!

A Simpler Way to Predict Heart Failure

The most widely used models for predicting heart failure rely on a complex combination of lifestyle, demographic, and cardiovascular risk factor information. But recently Vijay Nambi, M.D., Ph.D., and Christie Ballantyne, M.D., of The Methodist Hospital Center for Cardiovascular Disease Prevention and the Baylor College of Medicine presented new data that show two biomarkers can improve heart failure risk prediction as part of a simpler model. Their presentation was part of the American Heart Association’s Scientific Sessions 2012 in Los Angeles.