Molecular Marker of Human Aging
A team from the University of North Carolina have demonstrated that a biomarker that appears to be correlated with chronological age is present in human blood
Back in 2004, researchers from the University of North Carolina (NC, USA) made a crucial discovery; the expression of a key protein called p16INK4a was found to radically increase in most mammalian organs as cells and tissues age.
p16INK4a is a regulator of the retiboblastoma protein pathway. Genetic loss of p16INK4a is observed in a wide variety of human cancers, including nonsmall-cell lung cancer, glioblastoma, melanoma and pancreatic cancer. The scientists from from the University of North Carolina study genetic and epigenetic events that cooperate with loss of these important tumor suppressors in murine cancer, but are also interested in understanding the regulation and function of these pathways in nascent cancers and under normal physiologic conditions.
Since p16INK4a is a tumor suppressor protein, cancer researchers are interested in its role in cellular aging and cancer prevention. Recently, the team have demonstrated that this protein can be found in human blood, and that it is strongly correlated both with chronological age and with behaviors that are known to accelerate the aging process, including tobacco use and physical inactivity.
The researchers believe that they have overcome all the technical hurdles and developed a simple blood test that can detect p16INK4a expression, which is present in peripheral blood T lymphocytes.
University of North Carolina Lineberger member Norman Sharpless, the senior author of the study, and associate professor of medicine and genetics at University of North Carolina‘s School of Medicine stated the significance of the test, “This is a major step toward a practical tool to clinically determine a person‘s actual molecular, as opposed to just their chronological age.”
The test was validated by collecting blood samples from 170 healthy volunteers who also filled out a questionnaire regarding their current and past health status and behaviors. The results were very promising, with the expression of the biomarker correlating with the subjects‘ chronological age. In fact, p16INK4a expression increased exponentially with age. Increased levels were also independently associated with physical activity and tobacco use, as well as with plasma IL-6 concentration, a biomarker of human frailty.
Sharpless explained that several of the results came as quite a surprise, “We found a very weak correlation between the biomarker and obesity – as measured by BMI – despite other data suggesting that caloric restriction slows aging. The data suggest the possibility that reduced exercise may actually be worse with regard to molecular age than a higher BMI.”
Sharpless went on to explain how this work can influence the clinic, “Although we do not know whether this test is a good reflection of cellular age in all types of human tissues, we believe it is a first step toward a better understanding of issues like the suitability of organs for transplantation, how well patients are likely to recover after surgery or the future toxicity of chemotherapy for cancer patients”.
Critical Marker of Response to Pancreatic Cancer Drug Identified
A protein expressed in pancreatic tumor cells can be used to predict the response to the chemotherapeutic drug gemcitabine (Gemzar™), results from a recently published report suggest. The findings of the study indicate that this protein could serve, not only as a marker of the likely clinical utility of gemcitabine, but also as a potential target for pancreatic cancer therapy.
Hu antigen R (HuR) is a stress response protein found in the cytoplasm of pancreatic tumor cells. The new study found that in certain experimental situations, HuR-overexpressing pancreatic cancer cells, when compared with control cells, were approximately 30-times more sensitive to gemcitabine, which is the main chemotherapy component of treatment regimens for pancreatic ductal adenocarcinoma (PDA).
The authors of the study also undertook a clinical correlate study of gemcitabine treatment in PDA patients, finding patients with low levels of cytoplasmic HuR to have a sevenfold increased risk of mortality compared with those with high cytoplasmic HuR levels.
“This marker appears to tell us upfront whether a patient will respond to treatment with gemcitabine, which is the routine treatment for pancreatic cancer,” said Jonathan Brody, senior author of the study.
Pancreatic cancer is an extraordinarily deadly disease and is responsible for over 220,000 deaths worldwide each year. It is hoped that using HuR, better treatment plans can be developed for patients with the disease.
Interestingly, HuR is related to aggressive cancers, yet this protein appears to actually improve the efficacy of gemcitabine. “Normally, patients with higher HuR cytoplasmic levels have a worse prognosis, since HuR expression is associated with advanced malignancies,” said Brody. “However, in our study, they did better than patients with low HuR levels when they were treated with gemcitabine.”
The authors propose that not only do HuR levels in PDA cells modulate the therapeutic efficacy of gemcitabine, thereby serving as a marker of the likely clinical utility of the drug, but also that targeting this protein could be a valid approach for the treatment of pancreatic cancer. Indeed, according to Brody, research is already underway to find a means of activating HuR expression in patients with low levels of the protein, with the aim of increasing the efficacy of subsequent gemcitabine treatment in these patients.
An Anorexia Biomarker?
Anorexia is an eating disorder that that mostly affects women and is often fatal. Eating disorders are usually viewed as psychological or societal diseases but, perhaps, there is an underlying biological cause.
Scientists are yet to fully understand the physical causes of anorexia; however, a number of studies have proposed a link to low levels of a brain protein known as BDNF.
Cynthia Bulik, a member of Faculty of 1000 Medicine, and leading expert in the field of psychiatry and eating disorders has recommended a study demonstrating that BDNF levels are higher in women who have recovered from anorexia. This implies that the low BDNF levels found in patients with anorexia may be reversible.
The study was carried out by researchers at Chiba University in Japan who discovered that women with anorexia have lower levels of BDNF in their blood than healthy women or those who have recovered from the disorder. It was also found that women who had low BDNF also had the lowest self-image, performed badly on certain cognitive ability tests and experience anxiety and depression.
Although continued research is required to see what role BDNF plays in anorexia and whether or not it is predictive of risk, Bulik expects that, “BDNF may emerge as a useful biomarker of (anorexia) and of recovery from (anorexia).”
Earlier Detection of Alzheimer‘s Disease
“The earlier we can catch Alzheimer's disease, the more we can do for the patient.”
In a recent study, Swedish scientists have suggested that Alzheimer‘s disease can be detected in cerebrospinal fluid at very early stages of the disease
Researchers from the University of Gothenburg took (Sweden) cerebrospinal fluid (CSF) samples from 168 patients from seven different European countries, and analyzed them. They discovered that a pattern of biomarkers known as the ‘CSF Alzheimer‘s disease (AD) profile‘ was present in patients who simply had mild memory problems. This is earlier than the illness could be detected by existing tests.
“The earlier we can catch AD, the more we can do for the patient,” stated Kaj Blennow. “The patients who had the typical changes in biomarker profile of the CSF had a risk of deterioration that was 27 -times higher than the control group. We could also see that all patients with mild cognitive impairment who deteriorated and developed AD had these changes in the biomarker profile of their CSF.”
In a further development, the researchers discovered a relationship between the CFS AD profile and other typical Alzheimer‘s signs. This included the deterioration of the area of the brain that controls memory and the presence of the gene APOEε4.
Blennow explained the significance of the study, “If the new type of pharmaceutical that can directly slow the progression of the disease proves to have a clinical effect … It is important in this case to start treatment before the changes in the brain have become too severe.”
Promising Colorectal Cancer Biomarker Discovered
“The results implied that NDRG4 promotor methylation was more prevalent in colorectal cancer than in noncancerous colon tissue."
A team of researchers led by Manon van Engeland from the department of pathology at Maasrtricht University Medicial Centre (The Netherlands) studied the NDRG4 gene as a novel tumour suppressor and a biomarker in stool samples.
NDRG4 promoter methylation was analyzed in human colorectal cancer cell lines, colorectal tissue and noncancerous colon mucosa using methylation-specific PCR and bisulfite sequencing. NDRG4 mRNA and protein expression were measured using real-time PCR and immunohistochemistry, respectively. Quantitative methylation-specific PCR enabled NDRG4 to be examined as a biomarker in fecal DNA from 75 colorectal cancer patients and 75 control subjects.
The results implied that NDRG4 promotor methylation was more prevalent in colorectal cancer than in noncancerous colon tissue. mRNA and protein expression of NDRG4 was found to be decreased in the cancerous tissue compared with the healthy mucosa. The authors concluded that, “to our knowledge, this is the first study to describe a tumor suppressor role for NDRG4 in cancer. Our data indicate that NDRG4 promoter methylation is potentially useful as a sensitive and specific noninvasive pre-selection modality for identifying individuals at risk for colorectal cancer for whom colonoscopy is recommended.”
Early B-Type Natriuretic Peptide Response Predicts Outcome in Acute Heart Failure
Reduced levels of B-type natriuretic peptide (BNP) following treatment for acutely decompensated heart failure may indicate a better prognosis, according to new research carried out by Alain Cohen-Solal (Université Denis Diderot, Paris, France) and colleagues. The new data suggest that lower levels of BNP over the first 5 days following treatment are associated better survival at 1 and 6 months.
The researchers retrospectively analyzed data for 1038 patients enrolled in the Survival of Patients with Acute Heart Failure in Need of Intravenous Inoptropic Support (SURVIVE) trial, which aimed to examine the effect of levosimendan and dobutamine on 1- and 6-month mortality in severe acutely decompensated heart failure patients. Criteria for enrollment in the trial included a left ventricular ejection fraction of 30% or below and being in need of inotropic support, as indicated by an insufficient response to intravenous diuretics and/or vasodilators, with at least one of: oliguria; dyspnea at rest or on mechanical ventilation; and pulmonary-capillary wedge pressure above 18 mmHg or cardiac index below 2.2 l/min.
Patients classified as responders (follow-up BNP level at least 30% lower than baseline) at days 1, 3 and 5 had lower all-cause mortality than nonresponders (p ≤ 0.001), whereas those with an increase in BNP between baseline and day 5 had three- or more times higher 1-month mortality than responders. Responders at day 5 had a 67% reduction in 1-month and 47% reduction in 6-month all-cause mortality compared with nonresponders (both p < 0.001).
Mihai Georghiade and Peter Pang (Northwestern University Feinberg School of Medicine, IL, USA), believe the study “raises an important hypothesis that remains to be tested: in patients hospitalized with severe heart failure, a significant decrease in BNP over a few days irrespective of any specific therapy is a better predictor of prognosis than the baseline BNP measurement.”