Scientists have developed an ultra-sensitive test that should enable them to detect signs of a disease in its earliest stages.
The scientists, from Imperial College London and the University of Vigo, have created a test to detect particular molecules that indicate the presence of disease, even when these are in very low concentrations. There are already tests available for some diseases that look for such biomarkers using biological sensors or ’biosensors’. However, existing biosensors become less sensitive and predictable at detecting biomarkers when they are in very low concentrations, as occurs when a disease is in its early stages.
In this study, the researchers demonstrated that the new biosensor test can find a biomarker associated with prostate cancer, called Prostate Specific Antigen (PSA). However, the team say that the biosensor can be easily reconfigured to test for other diseases or viruses where the related biomarker is known.
Professor Molly Stevens, senior author of the study from the Departments of Materials and Bioengineering at Imperial College London, said: ‘It is vital to detect diseases at an early stage if we want people to have the best possible outcomes – diseases are usually easier to treat at this stage, and early diagnosis can give us the chance to halt a disease before symptoms worsen. However, for many diseases, using current technology to look for early signs of disease can be like finding the proverbial needle in a haystack. Our new test can actually find that needle. We only looked at the biomarker for one disease in this study, but we’re confident that the test can be adapted to identify many other diseases at an early stage.’
The team demonstrated the effectiveness of their biosensor by testing PSA biomarker samples in solutions containing a complex mixture of blood derived serum proteins. Monitoring the levels of PSA at ultralow concentrations can be crucial in the early diagnosis of the reoccurrence of prostate cancer, but classic detection approaches are not sensitive enough to carry out this analysis with a high degree of accuracy. The new test could enable more reliable diagnosis, but more research will need to be done to further explore its potential.
In their study, the team detected PSA at 0.000000000000000001 grams per millilitre, which is at the limits of current biosensor performance. By comparison, an existing test called an Enzyme-Linked Immunosorbent Assay (ELISA) test can detect PSA at 0.000000001 grams per millilitre, which is nine orders of magnitude more concentrated.
The biosensors used in today’s study consist of nanoscopic-sized gold stars floating in a solution containing other blood derived proteins. Attached to the surface of these gold stars are antibodies, which latch onto PSA when they detect it in a sample. A secondary antibody, which has an enzyme called glucose oxidase attached to it, recognises the PSA and creates a distinctive silver crystal coating on the gold stars, which is more apparent when the PSA biomarkers are in low concentrations. This silver coating acts like a signal that PSA is present, and it can be easily detected by scientists using optical microscopes.
The next stage of the research will see the team carrying out further clinical testing to assess the efficacy of the biosensor in detecting a range of different biomarkers associated with conditions such as HIV and other infections. They will also explore ways of commercialising their product. Imperial College London

HER2 and its epidermal growth factor receptor cousins mobilise a specialised protein to activate a major player in cancer development and sugar metabolism, scientists report.
This chain of events, the scientists found, promotes Herceptin resistance in breast cancer and activation of glucose metabolism (glycolysis), which cancer cells primarily rely on to fuel their growth and survive.
Their research focused on Skp2 E3 ligase, a protein that binds to and tags other proteins with molecules called ubiquitins, in this case to activate the Akt kinase.
‘We discovered a novel function of Skp2 E3 ligase that makes it an important player in cancer development and also identified a crucial role for it as a regulator of the glycolysis pathway,’ said senior author Hui-Kuan Lin, Ph.D., associate professor in MD Anderson’s Department of Molecular and Cellular Oncology.
‘This is potentially important for understanding and addressing Herceptin resistance in breast cancer,’ Lin said. ‘The effect on glucose metabolism also could have implications for other types of solid tumour cancers, including prostate, because they rely so heavily on glycolysis.’
The team also found that Skp2 over-expression is associated with poor prognosis for breast cancer patients and its spread to other organs.
Lin and colleagues are studying potential inhibitors of Skp2 that might be developed for treatment.
The EGFR family of proteins includes HER2, which abundantly coats cancer cells in about a third of breast cancers, making these tumours prime targets for the targeted drug Herceptin.
The Akt kinase relays signals by growth factors from outside of the cell into the cell. It regulates cell proliferation and survival, metabolism and tumour development, the authors noted.
To do its work, whether normal or oncogenic signalling, it must move from the cytosol to the plasma membrane. To do that, Lin and colleagues had previously shown that Akt must be ubiquitinated – and those ubiquitins must be attached in a specific chain formation, the K63-linked polyubiquitin chains.
That earlier finding involved the insulin-like growth factor receptor (IGF-1) and a different E3 ligase. ‘Finding that the epidermal growth factor receptors also ubiquitinate Akt, and that they do so through the Skp2 E3 ligase, was quite unexpected,’ Lin said.
Finding two paths to ubiquitination implies that there might be more, Lin said. University of Texas M. D. Anderson Cancer Center

A collaborative group of investigators has joined together to identify five genetic variations associated with Crohn’s disease (CD) and Jewish individuals of Eastern and Central European descent, who are also known as Ashkenazi Jews.
CD causes inflammation of the lining of the digestive tract and can be both painful and debilitating, and sometimes may lead to life-threatening complications. CD is two-to-four times more prevalent among individuals of Ashkenazi Jewish descent compared to non-Jewish Europeans. The study conducted at multiple institutions across the world, including the Feinstein Institute for Medical Research, was an important step toward understanding the genetic reasons for this higher prevalence.
‘This large collaborative study made it possible to define more precisely the genetic contributions to Crohn’s disease that are enriched in the Ashkenazi Jewish population, which has carried a higher risk for this disorder.’ said Peter K. Gregersen, head of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute. ‘The study identified genetic regions that hadn’t been discovered before, and if additional studies of these regions are conducted there is a chance that biological pathways affecting susceptibility to Crohn’s disease could be found and novel treatments could be developed.’
Seventy-one genetic variants had already been identified in patients who had Crohn’s disease (CD) and were of European descent. A collaborative group of investigators, including some from the Feinstein Institute for Medical Research, led by Inga Peter at Mt Sinai School of Medicine took a step further and conducted a genome-wide association study (GWAS) aimed at exploring genetic variation associated with CD in Jewish individuals of Eastern and Central European decent (Ashkenazi Jews). The study was conducted by combining raw genotype data across 10 Ashkenazi Jew cohorts consisting of 907 cases and 2,345 controls in the discovery stage followed up by a replication study in 971 cases and 2,124 controls. The study confirmed 12 of the known variants and identified five novel genetic varation regions not previously found. These five novel genetic regions were mapped to chromosomes 5q21.1, 2p15, 8q21.1, 10q26.3, and 11q12.1. The Feinstein Institute

Roche and Panasonic Healthcare partner for novel Point of Care system to improve diagnosis in metabolic syndrome.

Roche and Panasonic Healthcare have allied for a new medical testing solution to combine early diagnosis and control of blood lipid and average glucose concentration (HbA1c) levels. The new designed system will pioneer with a unique approach, as it enables healthcare professionals to early detect metabolic syndrome and to improve overall therapy guidance for patients with diabetes at point of care.

Manufactured by Panasonic Healthcare in Japan and marketed worldwide by Roche, the novel solution will respond to the growing needs of today’s cost conscious healthcare environment in primary care combining ease of use, reliability and cost effectiveness.

“I am convinced that the partnership with Panasonic Healthcare enables us to provide some pioneering improvements for healthcare professionals to early identify people with a metabolic syndrome, and to enhance overall therapy management for patients with chronic cardiovascular disease”, states Colin Brown, head of Roche Professional Diagnostics.

Starting at the end of 2012 [1], the novel blood glucose and lipid monitoring system will aid healthcare professionals with a rapid on-the-spot test for the two most important cardiovascular disease risk factors, as it also supports doctors with a user-friendly and failsafe handling for near patient testing.

“The new system will allow healthcare professionals to fully concentrate on their patients, as it will imply a convenient and safe handling of samples combined with a user friendly graphic interface for rapid and explicit result reporting. Seamless connectivity to the laboratory’s information system will allow consistent data management in established IT environments”, comments Kazuya Nakaya, Executive Managing Director of Panasonic Healthcare.

Metabolic syndrome affects 20 to 25% of the global adult population and it is a cluster of the most dangerous cardiovascular disease (CVD) risk factors: diabetes and elevated plasma glucose, abdominal obesity, high cholesterol and high blood pressure. [2]

In 2011, about 366 million people worldwide suffered from diabetes. According to the World Health Organization (WHO), this will increase to 552 million by 2030 and, the number of deaths will double to about 6 million annually. [3, 4] It is estimated that more than half of all people with diabetes type 2 remain undiagnosed. [4] As undiagnosed diabetes may affect serious cardiovascular problems it is important to be aware of its very early symptoms.

In the US, Japan and Europe there are more than 240 million people with abnormal lipoprotein levels and the prevalence is constantly increasing. [5] Dyslipidemia is a disorder of the lipoprotein metabolism, manifested by elevated low-density lipoprotein (LDL) cholesterol and triglyceride concentrations in the blood. The WHO estimates that this situation accounts for 18% of ischemic heart disease (IHD) and 56% of stroke and more than four million of deaths annually. [6]

Besides the chronic impact to the patients, dyslipidemia and diabetes have a financial impact for the healthcare systems worldwide as the global healthcare expenditures to treat and to prevent diabetes and its side effects were estimated at USD 376 billion in 2010 alone.

The alliance with Panasonic Healthcare will continue to expand Roche’s global leading position with innovative products and services to enable healthcare professionals for improved management of chronic cardiovascular disease at the point of care.

References
1. initially outside the US
2. www.idf.org/metabolic-syndrome, accessed 08/02/2012
3. IDF Diabetes Atlas 2011
4. Diabetes WHO Fact sheet N°312. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/
5. Smith DG Am J Managed Care 2007; 13 (3): 69-71
6. Lozano et al. Miscoding and misclassification of ischaemic heart disease mortality. Global Programme on Evidence for Health Policy Working Paper No. 12. World Health Organization, September 2001.

A Yale University-led research team has developed a way to measure the loss of insulin-producing islet cells in the human pancreas. The death of those beta cells leads to diabetes. The finding is a crucial step in developing therapies to preserve insulin production and slow or halt the progress of diabetes.
Until now there has been no effective method for imaging pancreatic islet beta-cell mass in a non-invasive manner. Based on the work of Paul Harris and colleagues at Columbia University, the Yale team focused on the genetically expressed protein known as vesicular monoamine transporter type 2 (VMAT2). This protein facilitates the storage and release of some neurotransmitters, and is expressed simultaneously with insulin in pancreatic beta cells.
The Yale team infused both healthy patients and those with type-1 diabetes with a radioactive tracer that targets VMAT2. Patients were then scanned with a PET camera to calculate the radioactivity concentration in the pancreatic cells and measure the binding of the tracer.
Adjusting for dosage and body weight, the radiotracer binding among pancreatic cells was 40 percent less in type-1 diabetes patients than in healthy patients.
Senior author Gary W. Cline, associate professor of endocrinology at Yale School of Medicine, explained, ‘This tells us that we can now measure the loss of the pancreatic islet cells that produce insulin in diabetic patients. Being able to make these measurements will help in the development of a drug that can stop or slow the death of these cells, and thus prevent the damaging effects of type 1 diabetes.’ Yale University