A discovery sheds light on how cancerous cells differ from healthy ones, and could lead to the development of new strategies for therapeutic intervention for difficult-to-treat cancers in the future.
An international team of investigators found a “stop sign”—a modified protein researchers named a PIP-stop—inside cells that are overused by cancerous cells that effectively prevents healthy ones from sorting material in the way they were designed to.
“We have discovered that breast cancer, leukaemia, lymphoma and neuroblastoma cells have too many PIP-stops. This would upset protein function, and opens up a new avenue for developing drugs that block PIP-stop formation by kinase enzymes,” said Michael Overduin, a University of Alberta cancer researcher and professor of biochemistry, who led the research project.
The team named the modification a PIP-stop because it stops proteins from interacting with lipid molecules called PIP.
Before making their discovery, the researchers first solved the 3-D structure of a sorting nexin protein, which is key to sorting proteins to their proper locations within the cell. Powerful magnets in the U.K. and in the National High Field Nuclear Magnetic Resonance Centre (NANUC), Canada’s national magnet lab based in Edmonton, were then used to detect signals from within individual atoms within the protein structure.
By focusing on the protein structure, the team was able to discover the PIP-stop and see how it blocked the protein’s function. The PIP-stop is a phosphate which is added to the protein surface that binds the PIP lipid, and normally controls how proteins attach to membranes.
Samples from cancer patients have too many PIP-stops, which could lead to the unregulated growth seen in tumour cells. Similar PIP-stops were found to be overused in a large number of other proteins involved in other cancer types, where they could also influence tumour growth.
“Our goal now is to design inhibitors for the overactive kinases that create PIP-stops, and to use this information to design drug molecules that block the progression of cancers, particularly those which lack effective treatments,” said Overduin.
University of Alberta Faculty of Medicine & Dentistrywww.folio.ca/medical-researchers-find-protein-that-marks-difference-between-cancer-and-non-cancer-cells/

A group of researchers from Mayo Clinic and Exact Sciences Corporation have completed a phase II study comparing a set of DNA markers to alpha fetoprotein as a method to test for liver cancer.
“We currently test for liver cancer using ultrasound and a blood protein marker called alpha fetoprotein,” says John Kisiel, M.D., a gastroenterologist at Mayo Clinic. “Unfortunately, these tests are not very sensitive for curable stage liver cancers, and most patients who need this testing do not have it easily available or [are] not able to receive it often enough to be effective.”
Dr. Kisiel and his colleagues developed a simple blood test using abnormal DNA markers that are known to exist in liver cancer tissues. They were able to confirm that the abnormal DNA markers were present in the overwhelming majority of blood samples that came from people with primary liver cancers. Simultaneously, these markers were absent in healthy individuals and individuals with cirrhosis of the liver but no evidence of tumours on their clinical follow-up.
“We were most excited that our DNA markers were able to detect more than 90 percent of patients with curable stage tumours,” says Dr. Kisiel. “This is the main reason why we think a DNA test will make difference, compared to currently available tests.” Dr. Kisiel says the next step will be to validate these markers in blood testing on much larger patient cohorts.

Mayo Clinic Cancer Center
newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-take-a-step-closer-to-developing-a-dna-test-for-liver-cancer/

The field of immunotherapy – the harnessing of patients’ own immune systems to fend off cancer – is revolutionizing cancer treatment today. However, clinical trials often show marked improvements in only small subsets of patients, suggesting that as-yet unidentified variations among tumours result in distinct paths of disease progression and response to therapy.
Now, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) have demonstrated that genetic variations driving prostate cancer determine the composition of the immune cells that have been found to infiltrate primary prostate tumours. These immune cells, in turn, dictate tumour progression and response to treatment. The data suggest that profiling patients’ tumours based on this new information could lead to more successful clinical trials and tailored therapies for patients.
“We observed that specific genetic events resulted in striking differences in the composition of immune cells present in and around the tumour – results with important therapeutic implications,” said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. “Our data may be especially relevant for tailoring immunological therapies and for identifying responsive-patient population.”
The third leading cause of cancer-related death in U.S. men, prostate cancer, is linked to a number of diverse genetic mutations that drive the disease. For example, the loss of the tumour suppressor gene PTEN is a frequent event in prostate cancer and is well known to promote the disease in combinations with a plethora of other mutations. Researchers also know that the tumour’s microenvironment – the blood vessels, immune cells, signalling molecules and other factors that surround the tumour – plays an important role in tumour progression and response to therapy.
Pandolfi’s team – including lead author, Marco Bezzi, a post-doctoral fellow in Pandolfi’s lab – engineered mice models to represent four distinct known genetic variations of human prostate cancer. The models lacked either Pten alone or in combination with other genetic alterations known to drive the disease. When the team analysed the tumours from these mice, they saw profound differences in the types and relative numbers of the immune cells that had accumulated in and around the tumour, what they call the tumours’ “immune landscape”.
For example, specific immune landscapes tumours from the genetic model lacking both Pten and the tumour suppressor gene called Trp53 demonstrated an increased accumulation of myeloid cells, the immune cells that mediate immunosuppression. In stark contrast, tumours from the genetic model lacking Pten and a different tumour suppressor gene called PML lacked intratumoral immune infiltration; that is, the researchers observed no immune cells at all in these tumours, which the scientists dubbed “cold,” or “immune-deserts.” All four mouse models analysed presented very distinctive immune landscapes and these differences were maintained and exacerbated over time.
The research team also demonstrated that these differences in immune cell composition were directly dictated by the tumours themselves because of their genetic variations. Different tumours, they observed, secreted distinct chemical attractants, which in turn recruited – or didn’t recruit, in the case of the immune-desert tumours – different immune cell types into the tumour. Pandolfi and colleagues further demonstrated that these differences hold true in human prostate cancer. Critically, the immune cells recruited to the tumours were found to be essential in supporting the growth and progression of these tumours.
“We observed that when present, these infiltrating immune cells were required for the tumour to thrive and found therapies to block their recruitment to be effective,” said Bezzi. “On the other hand, the cancer genotype characterized by the so-called ‘immune desert’ phenotype, did not respond to such therapies. On this basis, we can predict the tumour response to immunotherapies and tailor treatment modalities to effectively impact tumors that are otherwise extremely aggressive,” he said. 
Thus, because immune cells interact with and also affect tumour response to therapy, these findings may be especially relevant for the development of more precise and effective combinations of immunotherapies and targeted therapies on the basis of the cancer genetic makeup.
Beth Israel Deaconess Medical Centerwww.bidmc.org/News/PRLandingPage/2018/January/Pandolfi-Bezzi.aspx

A new study has found that genes cause about 1 in 10 cases of chronic kidney disease in adults, and that identifying the responsible genes has a direct impact on treatment for most of these patients.
“Our study shows that genetic testing can be used to personalize the diagnosis and management of kidney disease, and that nephrologists should consider incorporating it into the diagnostic workup for these patients,” says Ali Gharavi, MD, chief of nephrology at Columbia University Vagelos College of Physicians and Surgeons and a co-senior author of the study.
It’s estimated that 1 in 10 adults in the United States have chronic kidney disease. Yet, for 15 percent of patients with chronic kidney disease, the underlying cause of kidney failure is unknown.
“There are multiple genetic causes of chronic kidney disease, and treatment can vary depending on the cause,” says Gharavi. “And because kidney disease is often silent in the early stages, some patients aren’t diagnosed until their kidneys are close to failing, making it more difficult to find the underlying cause.”
DNA sequencing has the potential to pinpoint the genetic culprits, but has not been tested in a wide range of patients with chronic kidney disease.
“Our study identifies chronic kidney disease as the most common adult disease, outside of cancer, for which genomic testing has been demonstrated as clinically essential,” says David Goldstein, PhD, director of Columbia University’s Institute for Genomic Medicine and a co-senior author of the study.
Nearly 1 in 10 patients have a genetic kidney disorder
In this study, researchers used DNA sequencing to look for genetic kidney disorders in 3,315 individuals with various types of chronic or end-stage kidney disease. For 8.5 percent of these individuals, clinicians had not been able to identify the cause of disease.
The researchers found that a genetic disorder was responsible for about 9 percent of the participants’ kidney problems, and DNA testing reclassified the cause of kidney disease in 1 out of 5 individuals with a genetic diagnosis. In addition, DNA testing was able to pinpoint a cause for 17 percent of participants for whom a diagnosis was not possible based on the usual clinical workup.
DNA results had a direct impact on clinical care for about 85 percent of the 168 individuals who received a genetic diagnosis and had medical records available for review. “For several patients, the information we received from DNA testing changed our clinical strategy, as each one of these genetic diagnoses comes with its own set of potential complications that must be carefully considered when selecting treatments,” Gharavi says.
About half of the patients were diagnosed with a kidney disorder that also affects other organs and requires care from other specialists. A few (1.5 percent) individuals learned they had medical conditions unrelated to their kidney disease, In all of these cases, the incidental findings had an impact on kidney care. “For example, having a predisposition to cancer would modify the approach to immunosuppression for patients with a kidney transplant,” adds Gharavi.
“These results suggest that genomic sequencing can optimize the development of new medicines for kidney disease through the selection of patient subgroups most likely to benefit from new therapies,” says Adam Platt, PhD, Head of Global Genomics Portfolio at AstraZeneca and a co-senior author of the study.
Irving Medical Centerhttps://tinyurl.com/y2xct8uo

IDTechEx Research has recently released a new market report ‘Technology for Diabetes Management, 2019-2029: Technology, Players and Forecasts’, including details of glucose test strips, continuous glucose monitoring (CGM), insulin pumps, insulin pens, digital health / digital therapeutics, side effect management and diagnosis.

The report covers the entire landscape for diabetes management devices, including mature, emerging and future options. The report has been researched via primary interviews with companies, physicians and diabetic individuals to characterize and predict the technology landscape for diabetes devices over the coming decade. In total, activities of 75 companies are covered throughout the report, ranging from the largest players to technology developers and startups developing the next generation of device options.

Historically, diabetics have monitored their blood glucose concentration by using disposable biosensors; following a finger prick, a drop of blood is placed onto a glucose test strip, which is inserted into a reader to provide the result. Whilst billions of test strips are produced each year, this sector as seen profitability shrink due to changing medical subsidies and increased competition. Alternative options have been developed to enable continuous glucose monitoring. These involve devices that are typically worn on the skin, using a sensor on a small needle to test glucose in interstitial fluid. There are now approved devices from several key players, with this industry growing each year.

However, challenges still remain with glucose monitoring devices, with the ultimate aim of providing the best experience for diabetics. CGM devices in the past have been reliant on test strips for calibration, as well as still being invasive or implantable, leading to discomfort. This has led to many players investigating glucose monitoring options which are less invasive, whilst maintaining the required accuracy and reliability. In addition, the possibility of pairing CGM devices with insulin pumps for increasingly automated "closed-loop" systems is becoming increasingly closer. These goals have been in place for decades, and the report follows all the latest news, trends and outlook in each of these technology frontiers around diabetes management devices.

However, managing diabetes is about more than just monitoring glucose levels. The report also covers other aspects of diabetes technology landscape, including insulin delivery, the role of digital health in diabetes, technology for managing side effects, technology for diagnosis and reimbursement, funding and investment examples. The report then includes detailed market forecast following two different methodologies. The first involves the collection of revenue data from companies throughout the space, with historic data back to 2010 by company and by sector. This is then projected given a series of assumptions based on IDTechEx’s primary research efforts. The second forecast scenario involves looking at data for the diabetic population, including number of diabetics, split by type, percentage diagnosis, and then adoption rates by device type for each group. The two forecasts are then discussed and compared, providing with the reader with ample content from which to base business decisions and understand the dynamics in the space.

As discussed, the report is split into 8 main chapters, discussing each aspect of diabetes management technology (not including pharmaceutical options). Following an executive summary, detailing the main conclusions and discussion of the report, the report introduces the challenges and opportunities in diabetes management, as well as going through the main patent holders and filing trends in the space. Then, topic chapters of the report are as follows:

• Sensors for diabetes management: This chapter includes coverage of glucose sensing, from test strips and glucometers, to continuous glucose monitoring (CGM), and through to a discussion of emerging options in this space. In total, 37 different companies are mentioned in this section, ranging from the largest players in tests strips and CGM (e.g. Abbott, Roche, Medtronic, Dexcom, etc.) through to many emerging players or innovators attempting new approaches to glucose monitoring.
• Insulin delivery: This chapter covers techniques from traditional vial-and-syringe and insulin pens, to insulin pumps and towards closed loop insulin delivery alongside CGM. Key trends discussed in this section include the integration of different connectivity and technology integrated alongside both insulin pump and insulin pens, the links from these devices into wider digital health ecosystems and the adoption of newer devices (particularly insulin pumps) by territory and demographic.
• Digital health: Chronic diseases are a prominent early target for those in the digital health ecosystem, and digital health options for diabetes have been prominent. This chapter discusses activities from both the small and larger players, including major acquisitions and collaborations, in areas including diabetes management systems, device companion software and digital therapeutics.
• Side effect management: The majority of the costs associated with diabetes are around managing side effects. This section focuses on new technology options emerging around areas such as diabetic neuropathy, foot ulcers and ketoacidosis. This includes various wearable, flexible and textile-based technology options.
• Diabetes diagnosis: discussing the use of emerging technologies to aid the early detection of diabetes, thereby preventing long hospital stays and other complications.
• Reimbursement options, funding and investment examples: These final elements to the report fill in details which are important for the broader space. Reimbursement, whether through insurers, national healthcare initiatives or otherwise, is still critical for the majority of diabetes devices. Funding and investment are also present, as with any large, transforming industry.

Over 75 companies are mentioned in the report, including many primary interviews, a patent analysis of the key patent-holders, and revenue data where relevant.