Cyanide exposure can happen occupationally or in low levels from inhaling cigarette smoke — or from being poisoned by someone out to get you. The effects are fast and can be deadly. But because cyanide is metabolized quickly, it can be difficult to detect in time for an antidote to be administered. Now, in an animal study, researchers report a new precise and accurate biomarker of cyanide exposure.
To treat cyanide poisoning, physicians first have to properly diagnose the condition. But symptoms such as dizziness, headaches and low blood pressure could indicate many different illnesses. And current tests for the condition have disadvantages. Directly measuring cyanide levels in samples is not possible in many cases, since it is rapidly cleared from the body. Some indirect markers of the compound are almost as short-lived, while others are also present in foods, such as broccoli, which can confound the analysis. Cyanide is known to react with thiols, which contain sulphur. In addition, evidence suggests that glutathione, an abundant sulphur-containing molecule in the body, could be a first-line of defence against cyanide poisoning. So, Brian Logue and colleagues wondered if a metabolite of glutathione could be a good indication that someone has been around cyanide.
The researchers reacted glutathione with cyanide and found that 2-aminothiazoline-4-oxoaminoethanioc acid (ATOEA) was produced. They then developed a rapid mass spectrometry method to analyze ATOEA in plasma, and saw that they could accurately detect the compound within minutes of exposure in animals. As the level of cyanide increased, so did the level of ATOEA. And when an antidote was given, ATOEA levels decreased. The researchers say that ATOEA also lasts longer in the body than cyanide, allowing more time for detection of this marker following exposure.

American Chemical Society https://tinyurl.com/y3hrz8zm

Scientists have identified a mutation that gives cancer cells resistance to the breakthrough cancer treatment olaparib and other PARP inhibitors.
The study findings could help predict which patients will develop resistance to PARP inhibitors and allow doctors to alter treatment at the earliest possible opportunity.
A team at The Institute of Cancer Research, London, used gene editing to identify a specific mutation in the PARP1 protein that prevents PARP inhibitors from working.
Testing for this mutation could add another level of personalisation to an already targeted treatment – helping guide decisions about whether to use PARP inhibitors in the first place, and when to switch to other drugs, such as platinum-based therapies.
PARP1 is crucial for the repair of damaged DNA and is an important target for olaparib and other PARP inhibitors. These drugs are especially effective in patients who already have weaknesses in DNA repair because of inherited errors in the BRCA genes – a discovery that was made at the ICR.
The scientists used new ‘CRIPSR-Cas9’ gene editing technology to generate mutations in small, targeted sections of the PARP1 gene, and tagged the mutant protein with a fluorescent protein so their effects could be tracked.
This approach allowed the researchers to observe the effect of specific mutations on PARP1 and on the sensitivity of cancer cells to PARP inhibitors, such as olaparib and talazoparib.
Olaparib is available on the NHS for women with ovarian cancer who have inherited BRCA mutations, and is currently being evaluated for breast cancer. It was the first ever cancer drug to be approved that is targeted against an inherited genetic fault.
The study identified specific PARP1 mutations which disrupt the ability of the protein to bind to DNA, which means PARP inhibitors can no longer trap them at the site of DNA damage.
The researchers found that, contrary to their original predictions, cancer cells with certain mutations in the BRCA1 gene could survive this loss of PARP1’s DNA repair function – making them resistant to PARP inhibitors.
It is thought that in these cases the BRCA1 gene retains some function, providing some residual ability to repair DNA despite the loss of PARP1.
The scientists emphasised that further research needs to be carried out to examine more PARP1 mutations in patients as only one example in humans was found in this study.
The team is looking to apply this same gene editing approach to study how resistance arises to other drugs, and if it is possible to predict how quickly this resistance will progress.

Institute of Cancer Researchwww.icr.ac.uk/news-archive/scientists-identify-cause-of-resistance-to-breakthrough-breast-and-ovarian-cancer-drug

Scientists have discovered a new gene variation that causes motor neurone disease (MND) in a novel biological pathway that until now hasn’t been linked with neurodegeneration.
The findings for the pioneering study, conducted by a team of researchers from the Sheffield Institute for Translational Neuroscience (SITraN) and the NIHR Sheffield Biomedical Research Centre (BRC), could potentially help to identify completely new ways of treating MND which currently affects over 5,000 people in the UK.
MND, also known as Amyotrophic Lateral Sclerosis (ALS), is a devastating neurodegenerative disorder that affects the nerves – motor neurones – that form the connection between the brain and the muscles. The messages from these nerves gradually stop reaching the muscles, causing them to weaken, stiffen and eventually waste. The progressive disease affects a person’s ability to walk, talk, eat and breathe. Approximately 10 per cent of MND cases are inherited but the remaining 90 per cent are caused by complex genetic and environmental interactions which are not well understood – this is known as sporadic MND. There is currently no curative therapy.

Dr Johnathan Cooper-Knock, NIHR Clinical Lecturer at the University of Sheffield’s Institute for Translational Neuroscience (SITraN), explained the impact of the ground-breaking research which is helping scientists to understand the fundamental genetic basis of MND.
“This new gene does not fit into a biological function that we already know is associated with MND,” said Dr Cooper-Knock.
“That means that this finding has potential to identify completely new ways of treating MND.
“The mutations found in patients were shown to be toxic to neurons and, when expressed in zebrafish they produced muscle weakness consistent with MND. This work strongly suggests that the mutations are the cause of MND in the patients where they were identified.”
During the study, researchers genetically sequenced tissue from two related patients with an unknown familial form of MND and found a mutation in the substrate binding region of a glycosyltransferase enzyme called GLT8D1. They went on to screen a larger sample of 103 patients, five of whom had this mutation. The study revealed a new genetic subtype of MND.

University of Sheffieldhttps://tinyurl.com/y4bwpra4

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.