The health risks and mortality associated with pre-diabetes seem to increase at the lower cut-off point for blood sugar levels recommended by some guidelines, finds a large study published.

Pre-diabetes is a ‘pre-diagnosis’ of diabetes — when a person’s blood glucose level is higher than normal, but not high enough to be considered diabetes. If left untreated, pre-diabetes can develop into type 2 diabetes. An estimated 79 million people in the US and 7 million people in the UK are thought to be affected.

Doctors define pre-diabetes as impaired fasting glucose (higher than normal blood sugar levels after a period of fasting), impaired glucose tolerance (higher than normal blood sugar levels after eating), or raised haemoglobin levels.

But the cut-off points vary across different guidelines and remain controversial.

For example, the World Health Organization (WHO) defines pre-diabetes as fasting plasma glucose of 6.1-6.9 mmol/L, while the 2003 American Diabetes Association (ADA) guideline recommends a cut-off point of 5.6-6.9 mmol/L.

Results of studies on the association between pre-diabetes and risk of cardiovascular disease and all cause mortality are also inconsistent. Furthermore, whether raised haemoglobin levels for defining pre-diabetes is useful for predicting future cardiovascular disease is unclear.

So a team of researchers from the affiliated Hospital at Shunde, Southern Medical University in China analysed the results of 53 studies involving over 1.6 million individuals to shed more light on associations between different definitions of pre-diabetes and the risk of cardiovascular disease, coronary heart disease, stroke, and all cause mortality.

They found that pre-diabetes, defined as impaired fasting glucose or impaired glucose tolerance, was associated with an increased risk of cardiovascular disease and all cause mortality.

The risk increased in people with a fasting glucose concentration as low as 5.6 mmol/L – the lower cut-off point according to ADA criteria.

Raised haemoglobin levels were also associated with an increased risk of cardiovascular disease and coronary heart disease, but not with an increased risk of stroke and all cause mortality.

The authors point to some study limitations that could have influenced their results, and say pulling observational evidence together in a systematic review and meta-analysis is a good way to consider all the evidence at once, ‘but we cannot make statements about cause and effect. We would need to look at experimental evidence for that.’

However, they say their findings ‘strongly support’ the lower cut-off point for impaired fasting glucose and raised haemoglobin levels proposed by the ADA guideline.

And they conclude that lifestyle change — eating a healthy balanced diet, keeping weight under control, and doing regular physical activity — is the most effective treatment.

EurekAlert www.eurekalert.org/pub_releases/2016-11/b-ssl112216.php

Scientists at the Wellcome Trust Sanger Institute and their collaborators have discovered genetic markers in malaria parasites linked with resistance to the anti-malarial drug piperaquine. This research will allow health officials to monitor the spread of resistance, and help doctors and public health officers decide where the treatment is most likely to be effective.

Resistance to this key anti-malarial drug has recently emerged in Cambodia, leading to complete treatment failure there, threatening global efforts to treat and eliminate malaria.

Malaria is caused by Plasmodium parasites and in 2015, the World Health Organisation estimated that more than 200 million people were infected and nearly half a million people died worldwide from the disease. Children under the age of five made up 70 percent of these deaths. Malaria is a treatable disease when caught early enough, but is a huge problem in many areas due to drug resistance.

Piperaquine is a powerful drug, which is used in combination with another anti-malarial, artemisinin, as a first-line treatment in many areas of the world. Resistance to artemisinin emerged more than seven years ago in South East Asia, but until recently the combination of the drugs still successfully killed the malaria parasites there.  Now, the development of piperaquine resistance has led to complete failure of treatment in Cambodia.

Researchers carried out a genome-wide association study on approximately 300 Plasmodium falciparum samples from Cambodia to study the genetic basis behind piperaquine resistance. They looked at thousands of variations in the DNA sequence of the parasites, comparing these across samples with different levels of resistance to piperaquine.

“By studying the genomes of these parasites we found two genetic markers that are linked with piperaquine resistance. Not only can we now use these markers to monitor the spread of the drug resistant malaria, they will also help towards understanding as much as possible about the biology and evolution of the parasite.”

Dr Roberto Amato, lead author from the Wellcome Trust Sanger Institute
The scientists found that extra copies of the genes encoding two proteins of a family called plasmepsin, were linked with piperaquine resistance. Plasmepsins are part of a biological pathway that is targeted by other anti-malarial drugs, so this marker could also help the researchers understand the mechanism of the drug resistance. In addition to this, a mutation on chromosome 13 was found to be a second genetic marker linked with the resistance. Both markers were observed in parasites infecting patients who were not responding to treatment.

“The emergence of piperaquine resistance in these Cambodian parasites has led to complete treatment failure there. These malaria parasites are now resistant to both drugs, and since they are no longer being killed, resistance to both drugs will spread. This will threaten global attempts to eliminate malaria.”

Sanger Institute www.sanger.ac.uk/news/view/genetic-marker-found-resistance-malaria-treatment-cambodia

Twenty to forty percent of the patients with the type of leukemia known as multiple myeloma have a defect in the ‘protein factory’ of the cell: the ribosome. These patients have a poorer prognosis than patients with intact ribosomes. At the same time, they respond better to a drug that already exists. These are the findings of a study by the KU Leuven Laboratory for Disease Mechanisms in Cancer, led by Professor Kim De Keersmaecker.
Multiple myeloma (MM, also known as Kahler’s disease) is a blood cancer whereby the plasma cells in the bone marrow start proliferating malignantly. MM cannot be cured and is most common among older people. Various treatments exist to temporarily suppress the disease, but the challenge is determining to which treatment the patient will respond best.
Doctoral student Isabel Hofman discovered defects in the ribosome of MM patients. “The ribosome is the protein factory of a cell. In MM patients, one part of the ribosome is produced less in 20 to 40 percent of the patients, depending on how aggressive the cancer is. We suspect that their cells are still producing protein, but that the balance is somewhat disrupted. In any case, we found that these people have a poorer prognosis than MM patients with an intact ribosome,” explains Professor De Keersmaecker.
One possible treatment for MM is the use of proteasome inhibitors. “The proteasome is the protein demolition machine in a cell. There’s a type of drugs, including Bortezomib, that inhibits its functioning. How the defects in the ribosome influence the proteasome is not quite clear yet. But we discovered that patients with a defective ribosome respond better to Bortezomib. In other words, their poorer prognosis can be offset by this treatment. On the basis of these findings, we can now develop tests to identify defects in the ribosome and thus determine which therapy will have most effect in a specific patient.”
The notion that cancer is related to ribosome defects is a relatively new concept in science. “A few years ago, we discovered defects in the ribosome of patients with acute lymphatic leukemia. Now we know that the same applies to MM. In all likelihood, this will also hold true for other types of cancer.

KU Leuven http://tinyurl.com/jnubnm7

Why do some breast cancers respond to treatment while others resist it? A study led by researchers at the University of North Carolina Lineberger Comprehensive Cancer Center may provide insight into this important question.
The researchers report at the San Antonio Breast Cancer Symposium they have identified biomarkers they believe can be used as part of a larger model to predict how patients with HER2-positive operative breast cancer will respond to the targeted treatment trastuzumab, commercially known as Herceptin, and chemotherapy. “We’re trying to find biomarkers for resistance to trastuzumab treatment and chemotherapy,” said the study’s first author Maki Tanioka, MD, PhD, a postdoctoral research associate at UNC Lineberger. “What’s the cause of response? What’s the cause of resistance? That’s what we are trying to identify in this genomic study.”
Tanioka and his colleagues analysed multiple biologic features of cancer cells from 213 patients treated for HER2-positive breast cancer through a National Cancer Institute cooperative group clinical trial, CALGB 40601. The biologic features included multiple kinds of genetic information such as DNA mutations, DNA copy number and RNA gene expression data. The researchers found that certain gene signatures, and either having too many, or too few, of certain genes were predictive of whether patients responded to treatment, and that combining those two features was the most effective method of predicting response.
Examining features like mutations, amplifications or deletions of genes in tumour cells, the overall subtype of the tumour, as well as indicators of immune responses helped the researchers predict response. The researchers also determined that amplification of a specific chromosome, and a particular gene called MAPK14 on that chromosome, may be a predictor of sensitivity to treatment, while deletions of other genes predicted resistance.
The researchers say the next step is to identify another set of data to validate and broaden their findings.
“HER2-positive breast cancer is genomically heterogeneous,” Tanioka said. “Therefore, we need a model that incorporates all these different features. We are actively seeking a set of patient data that we can use to validate the biomarkers we have identified so we can create a comprehensive predictive model of response to allow us to better tailor treatment.”

University of North Carolina Lineberger Comprehensive Cancer Center http://tinyurl.com/grk84cg

People with head and neck cancers with evidence of human papillomavirus (HPV) infection generally have a better prognosis than people without evidence of infection. A new study suggests that to produce a strong, reliable prognostic signal, all that’s needed is a blood serum test for two specific HPV antibodies, rather than lab work on a biopsy. Further, the researchers said, the study shows that this blood-based biomarker is predictive of outcome for all types of head and neck cancer.
“What this adds is that it helps us know how best to measure clinically the HPV contribution to this disease,” said study senior author Karl Kelsey, a professor of epidemiology and of pathology and laboratory medicine at Brown University. Kelsey collaborated with lead author Heather Nelson of the University of Minnesota Masonic Cancer Center in making the findings.
Moreover, Nelson, Kelsey and their colleagues wrote, referring to the common HPV16 strain of the virus: “These data are among the first to demonstrate a convincing relationship between HPV16 and improved patient survival for tumours of the larynx and oral cavity.”
The study examined blood serum samples and five-year survival rates among more than 1,000 Boston-area head and neck cancer patients diagnosed between 1999 and 2011. Overall, those who tested positive for antibodies to the oncogenic HPV proteins E6 or E7 were less likely to die during the five year follow-up period after diagnosis compared to those who tested negative for the antibodies. Based on the analysis, the researchers estimated that those with evidence of an immune response to HPV were 25% less likely to die during the course of follow-up compared to those with no immune response to HPV.
The study’s purpose was to determine whether the antibodies provide a reliable indication of prognosis. In ongoing trials, doctors are testing whether patients with HPV-associated cancers can be treated less aggressively — and hopefully with fewer negative side effects — than people with non-HPV-associated cancers, Kelsey said. If trials prove successful, then it will be particularly important to determine whether cancers are HPV-associated.
“The assessment of a patient’s HPV status likely will affect treatment,” he said. “That’s why there’s real interest in getting it right; for instance, how do you test?”
Prior studies have focused primarily on the role of HPV in the oropharynx — the area of the throat right behind the mouth. An important contribution of the current study, Nelson said, is demonstration that an immune response to HPV is important for all forms of head and neck cancer, although the benefit does show some variance based on the exact cancer location. Those patients with an HPV immune response with tumours located in the oropharynx and larynx had a similar risk of dying during the follow-up period, though the reduced risk was slightly attenuated for those patients with tumours located in the oral cavity.
The results didn’t depend significantly on whether people had high or low levels of the antibodies, so long as they had some, the researchers found, though testing positive for both E6 and E7 was better than for just one.
The reduced chance of dying by five years carried through for people who tested positive for the antibodies even if they consumed tobacco and alcohol. But the worst prognoses in the study were among smokers whose cancers could not be traced to HPV.
In all, the findings controlled for the statistical influences not only of tobacco and alcohol exposure, but also of age, race, gender, education and how far advanced the cancer was.
Kelsey said the findings could help bring head and neck cancer treatment closer into line with two emerging practices of fighting the disease: personalized medicine and immunotherapy.

Brown University http://tinyurl.com/z3n94a4