National Institutes of Health (NIH) scientists have developed an ultrasensitive new test to detect abnormal forms of the protein tau associated with uncommon types of neurodegenerative diseases called tauopathies. This advance gives them hope of using cerebrospinal fluid, or CSF – an accessible patient sample – to diagnose these and perhaps other, more common neurological diseases, such as Alzheimer’s disease.
Scientists have linked the abnormal deposition of tau in the brain to at least 25 different neurodegenerative diseases. However, to accurately diagnose these diseases, brain tissue often must be analysed after the patient has died. For their study, the researchers used the same test concept they developed when using postmortem brain tissue samples to detect the abnormal tau types associated with Pick disease, Alzheimer’s disease and chronic traumatic encephalopathy (CTE). They adapted the test to use CSF for the detection of abnormal tau of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other less common tauopathies.
They detected abnormal tau in CSF from both living and deceased patients. In one case, the test led to a corrected diagnosis in a patient who had died from CBD, but who was initially diagnosed with PSP. The new test is called 4R RT-QuIC – which stands for 4-repeat tau protein amplified in a real-time, quaking-induced conversion process.
The researchers plan to continue evaluating the clinical performance of 4R RT-QuIC by analysing larger sets of CSF samples. One focus will be to compare test results from tauopathy patients who agree to provide CSF samples both before and after death. The scientists hope this type of evaluation will help them better understand how abnormal tau in CSF evolves during brain disease.
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Precision cancer medicine requires personalized biomarkers to identify patients who will benefit from specific cancer therapies. In an effort to improve the accuracy of predictions about prognosis for patients with breast cancer and the efficacy of personalized therapy, University of North Carolina Lineberger Comprehensive Cancer Center researchers have developed a method to precisely identify individual patients who have aggressive breast cancer. The new approach involves sorting and characterizing invasive breast cancer cells by epigenetic characteristics – a method that involves analysing how particular regulatory proteins interact with DNA to control their expression – as well as by how the genes are amplified or abnormally expressed. The researchers reported that they used this technique to identify potential new prognostic markers to predict distinct clinical outcomes for two major subtypes of breast cancer.
“This paper describes a ground-breaking multi-omics technology to discover drivers of proliferative and invasive breast tumours,” said Xian Chen, PhD, professor in the UNC School of Medicine Department of Biochemistry & Biophysics. “We think that eventually, these tools could help doctors better predict which particular patients have a good response, or acquire resistance to treatment.” Doctors often rely on information about tumour size, whether the cancer has spread and the tumour subtype to make treatment decisions. In addition to clinical subtypes of breast cancer, researchers have discovered molecular subtypes that have been used to help make treatment decisions. However, Chen argues that existing markers do not adequately distinguish breast cancer patient sub-populations with different clinical outcomes.
“Single ‘omics’ approaches, which rely on either genomics, transcriptomics, or proteomics alone, fail to dissect the heterogeneity that contributes to individual patients’ variability in terms of their rates of tumour growth, metastasis, or susceptibility to anti-cancer therapies,” he said. “Because biomarkers are not available to distinguish distinct patient sub-populations that are either responsive or resistant to particular drugs, doctors do not have all the tools they need to predict patient response to treatment and outcomes.”
In their study, the researchers wanted to see if they could stratify patients beyond existing molecular subtypes. Their goal was to develop a method to determine which patients within a single subtype would develop resistance or invasive cancer. There are five major molecular subtypes of breast cancer, which are classified based on how genes are expressed in a tumour.
Chen and his colleagues analysed luminal breast cancer and basal-like breast cancer, which is more commonly known as triple negative breast cancer, using breast cancer samples from two large international studies, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium.
To move beyond subtype for identifying exactly which patients might develop resistance, they first sorted the most invasive tumour cells in frozen tissue using a molecular probe that was able to distinguish tumour from adjacent non-malignant cells or tissue by binding to an epigenetic regulator, or a histone methylase, called G9a. This enzyme has been reported by other scientists to be abnormally upregulated in many cancer types, including breast cancer.
They then identified select proteins that were working with G9a as partners-in-crime, and worked backwards from there to identify the genetic abnormalities linked to those partner proteins in the cancer cell. They found in many instances the genes for these interactor proteins were amplified in multiple copies, or abnormally overexpressed, rather than mutated.
“Nowadays, people think somatic mutations of select genes are the primary drivers of tumorigenesis,” Chen said. “We didn’t see many mutations on our identified driver genes. We actually found the genes encoding those interactors have a high frequency amplification in breast cancer patients with poor prognosis.”
They then used this information to generate sets of genes that encoded these “interactor proteins,” and identified those linked to poor prognosis in patients. Looking ahead, Chen and his colleagues plan to determine the specificity and sensitivity of multi-omic aberrations of particular interactor gene sets as new systems biomarkers to predict cancer patient prognosis.
University of Northern Carolina
www.med.unc.edu/biochem/news/
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Researchers at the University of California, Berkeley, have identified biomarkers – genes and specific brain circuits in mice – associated with a common symptom of depression: lack of motivation.
The finding could guide research to find new ways to diagnose and potentially treat individuals suffering from lack of motivation and bring closer the day of precision medicine for psychiatric disorders like depression.
Depression is the most prevalent mental health disorder in the world, affecting around 9% of the American population each year, and is among the top causes of disability in the workplace. Depression symptoms can differ significantly between patients who have the same depression diagnosis, and the lack of a connection between symptoms and treatments is a main reason that about half of all people with depression fail to respond to medication or other therapies, and that side effects of these medications are common.
“If we had a biomarker for specific symptoms of depression, we simply could do a blood test or image the brain and then identify the appropriate medication for that patient,” said Stephan Lammel, a UC Berkeley assistant professor of molecular and cell biology. “That would be the ideal case, but we are far away from that situation right now.”
Now, for the first time, Lammel and his team have identified genes in a brain region – the lateral habenula – that are strongly turned on, or upregulated, in mice that show reduced motivation as a result of chronic stress. This brain region in mice is not associated with other depression symptoms, including anxiety and anhedonia, the inability to feel pleasure.
“We think that our study not only has the potential to transform how basic scientists study depression in animals, but the combination of anatomical, physiological and molecular biomarkers described could lay the foundation for guiding the development of the next generation of antidepressants that are tailored to specific depression symptoms,” Lammel said.
Lammel is senior author of a paper describing the discovery that appears this week in the journal Neuron. The study was led by first author Ignas Cerniauskas, who is a UC Berkeley graduate student.
Lammel and Cerniauskas work on mouse models of depression that have been a mainstay of basic research on this disorder for the past 60 years. Putting mice under constant stress produces at least three common symptoms of human depression – anxiety, lack of motivation and loss of pleasure – that scientists study to try to understand the disorder in humans.
Until now, however, researchers have sought answers by disregarding the variability of symptoms and instead categorizing all mice as either stressed (“depressed”) or non-stressed (“not depressed”). Cerniauskas and Lammel wanted to try to find changes in the brain that were associated with each specific symptom.
“Unfortunately, depression treatment is currently often based on guesswork. No one treatment works for everyone, and no one has objective data on how to differentiate the enormous variability of depression symptoms and subtypes,” Lammel said. “If we understand specifically how the brain changes in those animals with one certain type of symptom, there may be a way we can specifically reverse these symptoms.”
In response to a recent small clinical study in which doctors electrically stimulated the lateral habenula and found symptom improvement in depressed patients who were resistant to other therapies, Lammel and Cerniauskas decided to investigate that area of the brain. The lateral habenula has received increasing attention in the last few years, in part because it is connected to the dopamine and serotonin systems in the brain, both of which are known to be involved in depression. The most common drugs currently used to treat depression are serotonin reuptake inhibitors (SRIs) such as Zoloft and Prozac.
“After chronic stress, there is an increase in the neural activity of the lateral habenula cells – they fire more, they become overactive – and we found that this overactivity was present only in mice that showed very strong deficits in motivated behaviour, but not in animals that showed anxiety or animals that showed anhedonia,” Lammel said.
His team subsequently identified the specific synapses, cells and circuits in the lateral habenula that are altered by chronic stress in these particular mice, and in collaboration with Csaba Földy and colleagues at the University of Zürich, they found genes that are overexpressed as well.
University of California – Berkley
news.berkeley.edu/2019/10/28/new-findings-could-improve-diagnosis-treatment-of-depression/
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Researchers at the Bellvitge Biomedical Research Institute (IDIBELL) have just described for the first time the crucial involvement of a cell membrane protein in the development and progression of liver cancer. This protein, called clathrin, is known for its key role in the process of internalization of molecules from the extracellular space into the cell, called endocytosis. In this process, the cell membrane folds creating vesicles with a cladded structure. Thanks to the new results, analysing the levels of clathrin expression in biopsies of hepatocellular carcinoma patients will help select those patients who will benefit from a much more targeted and personalized therapy.
The research team, led by Dr Isabel Fabregat, who is a professor at the Faculty of Medicine and Health Sciences of the University of Barcelona and a researcher at the CIBER of Hepatic and Digestive Diseases, has shown that liver cells with invasive features have high levels of clathrin, a protein whose involvement in liver cancer was unknown until now. Specifically, researchers showed that high expression levels of clathrin correlate with the activation of the pro-tumorigenic pathway of a known hepatic carcinogenesis actor: TGF-β. In this sense, the work provides completely new and clinically valuable knowledge when it comes to understanding the complex and controversial role of TGF-β in this type of cancer.
TGF-β, which belongs to a large group of proteins called cytokines, has a dual role: in normal conditions, or in early stages of carcinogenesis, it plays a tumour suppressive role, promoting cell death and reducing tumour growth. But in advanced stages of liver cancer, where this signalling pathway is highly activated, tumour cells have acquired capabilities to escape its suppressor functions and respond to TGF-β by inducing cell migration and invasion, and thus contributing to tumour spreading.
Previous work by the Fabregat group had shown that for this change in cellular behaviour to take place, TGF-β activates the EGF receptor pathway (EGFR) in tumour cells, whose overexpression and hyperactivity has been associated with a large number of cancers. The new results have shown that clathrin is essential in the endocytosis of EGFR, a decisive step for the activation of this pathway by TGF-β. In vitro experiments of this recent work have allowed the IDIBELL researchers to demonstrate that clathrin cell levels determine, via EGFR, the function of TGF-β. If the expression of clathrin is eliminated, the cells die. On the contrary, high levels of clathrin promote the pro-invasive and tumorigenic character of the cells. The reason for this effect must be found in the functionality of the EGFR pathway: the elimination of clathrin results in an inhibition of this signalling pathway. Researchers have also shown that TGF-β is capable of inducing clathrin synthesis, ultimately encouraging a self-stimulation loop.
It is interesting to mention that the study also demonstrates that clathrin expression increases during hepatic tumorigenesis both in humans and mice, and its expression changes the response to TGF-β in favour of anti-apoptotic / pro-tumorigenic signals. There is a positive correlation between the expression of TGF-β and clathrin in samples of hepatocellular carcinoma patients. Patients expressing high levels of TGF-β and clathrin showed a worse prognosis and reduced survival. According to Dr. Fabregat, "determining the levels of clathrin expression in samples of hepato-cellular carcinoma patients can be of great help in selecting those who can be given a therapy based on inhibitors of the TGF-β pathway”.
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In symptom-free individuals, the detection of misfolded amyloid-β protein in the blood indicated a considerably higher risk of Alzheimer’s disease – up to 14 years before a clinical diagnosis was made. Amyloid-β folding proved to be superior to other risk markers evaluated, as shown by scientists from the German Cancer Research Center (DKFZ), Ruhr University Bochum (RUB), the Saarland Cancer Registry, and the Network Aging Research at Heidelberg University.
There is currently still no effective treatment for Alzheimer’s disease. For many experts, this is largely due to the fact that the disease cannot be clinically diagnosed until long after the biological onset of disease when characteristic symptoms such as forgetfulness appear. However, the underlying brain damage may already be advanced and irreversible by this stage.
"Everyone is now pinning their hopes on using new treatment approaches during this symptom-free early stage of disease to take preventive steps. In order to conduct studies to test these approaches, we need to identify people who have a particularly high risk of developing Alzheimer’s disease," explained Hermann Brenner from DKFZ. In patients with Alzheimer’s disease, misfolding of the amyloid-β protein may occur 15–20 years before the first clinical symptoms are observed. The misfolded proteins accumulate and form amyloid plaques in the brain. A technique devised by Klaus Gerwert from RUB can determine whether amyloid proteins are misfolded in blood plasma.
In a previous study, Gerwert and Brenner showed that the amyloid-β changes in the blood can be demonstrated many years before the clinical onset of disease. They also showed that demonstration of misfolded amyloid-β in the blood correlates with plaque formation in the brain. The researchers now wanted to investigate whether analysis of amyloid-β can be used to predict the risk of developing Alzheimer’s disease and how the risk marker performs in comparison to other known and suspected risk factors. To do so, they re-examined blood samples collected as part of ESTHER, a cohort study led by Hermann Brenner and conducted in collaboration with the Saarland Cancer Registry. The cohort study was initiated back in the year 2000.
In the current study, the researchers looked at the initial blood samples of 150 ESTHER participants in whom dementia was subsequently diagnosed during the 14-year follow-up period. These samples were compared with those of 620 randomly selected control participants not known to have been diagnosed with dementia who correlated with the dementia participants in terms of age, sex, and level of education.
Participants with Aβ misfolding had a 23-fold increased odds of Alzheimer’s disease diagnosis within 14 years. In patients with other types of dementia, such as those caused by reduced blood supply to the brain, the study did not demonstrate an increased risk, supporting Alzheimer’s disease specificity.
The researchers also included a number of other possible risk predictors in their analysis, including a particular variant of the gene for apolipoprotein E (APOE Ɛ4) and pre-existing diseases (diabetes, high blood pressure, de-pression) or lifestyle factors (bodyweight, level of education). With the exception of the APOE4 status, which showed a 2.4 times higher risk in those people who later went on to develop Alzheimer’s disease, none of the factors studied correlated with the risk of disease.
In predicting the risk of disease, it was largely irrelevant whether 0–8 or 8–14 years had passed between the time the blood sample was obtained and the clinical onset of dementia.
"This work was not about the use of amyloid-β folding as a diagnostic marker. Instead, we wanted to examine whether this marker could be used for risk stratification in the Alzheimer’s disease therapeutic development setting. Amyloid-β misfolding proved to be a far superior risk marker compared to the other potential risk factors," explained lead author Hannah Stocker from DKFZ and the University of Heidelberg’s Network Aging Research.
The German Cancer Research Center (DKFZ)
www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-46-Protein-misfolding-as-a-risk-marker-for-Alzheimers-disease-up-to-14-years-before-the-diagnosis.php
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Working with model mice, post-mortem human brains, and people with schizophrenia, researchers at the RIKEN Center for Brain Science in Japan have discovered that a subtype of schizophrenia is related to abnormally high levels hydrogen sulfide in the brain.
Experiments showed that this abnormality likely results from a DNA-modifying reaction during development that lasts throughout life. In addition to providing a new direction for research into drug therapies, higher than normal levels of the hydrogen sulfide-producing enzyme can act as biomarker for this type of schizophrenia.
Diagnosing disorders of thought is easier when a reliable and objective marker can be found. In the case of schizophrenia, we have known for more than 30 years that it is associated with an abnormal startle response. Normally, we are not startled as much by a burst of noise if a smaller burst – called a prepulse – comes a little bit earlier. This phenomenon is called prepulse inhibition (PPI) because the early pulse inhibits the startle response. In people with schizophrenia, PPI is lowed, meaning that their startle response is not dampened as much as it should be after the prepulse.
The PPI test is a good behavioural marker, and although it cannot directly help us understand the biology behind schizophrenia, it was the starting point that led to current discoveries.
The researchers at RIKEN CBS began first looked for differences in protein expression between strains of mice that exhibit extremely low or extremely high PPI. Ultimately, they found that the enzyme Mpst was expressed much more in the brains of the mouse strain with low PPI than in the strain with high PPI. Knowing that this enzyme helps produce hydrogen sulfide, the team then measured hydrogen sulfide levels and found that they were higher in the low-PPI mice.
"Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia," says team leader Takeo Toshikawa. "Once we discovered this, we had to figure out how it happens and if these findings in mice would hold true for people with schizophrenia."
First, to be sure that Mpst was the culprit, the researchers created an Mpst knockout version of the low-PPI mice and showed that their PPI was higher than that in regular low-PPI mice. Thus, reducing the amount of Mpst helped the mice become more normal. Next, they found that MPST gene expression was indeed higher in postmortem brains from people with schizophrenia than in those from unaffected people. MPST protein levels in these brains also correlated well with the severity of premortem symptoms.
Now the team had enough information to look at MPST expression as a biomarker for schizophrenia. They examined hair follicles from more than 150 people with schizophrenia and found that expression of MPST mRNA was much higher than people without schizophrenia. Even though the results were not perfect-indicating that sulfide stress does not account for all cases of schizophrenia-MPST levels in hair could be a good biomarker for schizophrenia before other symptoms appear.
Whether a person develops schizophrenia is related to both their genetics and the environment. Testing in mice and postmortem brains indicated that high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. So, the next step was for the team to search for environmental factors that could result in permanently increased MPST production.
Because hydrogen sulfide can actually protect against inflammatory stress, the group hypothesized that inflammatory stress during early development might be the root cause. "We found that anti-oxidative markers – including the production of hydrogen sulfide – that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia," says Yoshikawa.
He proposes that once excess hydrogen sulfide production is primed, it persists throughout life due to permanent epigenetic changes to DNA, leading to "sulfide stress" induced schizophrenia.
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New insights into how the colon functions and actually expels its contents have been revealed for the first time following decades of study by Flinders University researchers.
It promises new diagnostics tools and treatments for gastrointestinal disorders to address problems with bowel movements leading to constipation, diarrhoea and pain, affecting hundreds of millions of people worldwide.
Propulsion of intestinal contents is controlled by millions of neurons within the wall of the gut, known as the enteric nervous system. Capable of operating independently of the brain, a functioning enteric nervous system is essential for life – but exactly how it functions has been a mystery.
By unravelling the neural circuits of the enteric nervous system in guinea pigs and humans Professor Marcello Costa and colleagues are able to understand how the enteric nervous system ensures that food is slowly mixed and propelled along the digestive tube, allowing for absorption of nutrients and excretion of waste.
“For the first time we have combined video recording intestinal movements with a pressure-measuring manometric probe, enabling movements, pressures and electrical activities to be recorded all at the same time within the colon.
“This powerful combination of techniques applied to a guinea pig colon identified several distinct neural mechanisms involved in the propulsion of colonic contents.
“This answers the deceptively simple question of how neural mechanisms within the colon manage the propulsion of bowel contents” Professor Costa says.
“The findings also show how studies in human and animals can be complementary, identifying fundamental mechanisms that are shared across species – in this case guinea pigs and humans. “Currently we treat intestinal disorders by addressing the symptoms, such a stopping-up diarrhoea or softening stools to ease constipation, but as a result of this new understanding of the neural networks of the enteric system, clinicians may be able to develop treatments that treat the cause of the problems” Professor Costa says.
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A recently published study examines the evolutionary and epidemiologic history of an epidemic strain of extensively drug-resistant tuberculosis (XDR-TB) – called LAM4/KZN – in KwaZulu-Natal, South Africa. This strain was first reported in a 2005 outbreak in Tugela Ferry, KwaZulu-Natal, where it was associated with 90 % mortality among predominantly HIV infected individuals, and has since become widespread throughout the province. A new study identifies key host, pathogen and environmental factors that facilitated the success of this XDR-TB strain and steps that can be taken for early identification and containment of future epidemics.
The study, led by Columbia University, involved a multi-institutional team of researchers from South Africa, the United States, and Norway, used genomic, spatial and protein modelling to answer when and where this strain emerged, and how and why it became widespread. The study utilized data and TB strains collected in the prospective XDR-TB transmission study (TRAX) from 2011 to 2014 led by Emory University, the University of KwaZulu-Natal, and the U.S. Centers for Disease Control and Prevention.
Researchers localized the geographic origin of the strain to a rural district, bordering Mozambique and eSwatini, with high pre-existing rates of drug-resistant TB located 400 hundred kilometres away from where the first outbreak of LAM4/KZN was reported. Results also indicate that the strain emerged in the early 1990s, acquiring key advantageous mutations prior to undergoing marked expansion concurrent with the onset of the generalized HIV epidemic. In addition, the study suggests cyclical rural-urban migration in the rapid and widespread dissemination of this strain.
"Our results indicate that this strain of XDR-TB emerged approximately 12 years before it was identified by public health activities," said lead researcher Barun Mathema, PhD, assistant professor of epidemiology at Columbia University Mailman School of Public Health. "Our research highlights multiple environmental and pathogen-specific factors must align in order for these pathogens to establish sustained transmission and disperse into geographically separated populations. These processes take place in the so-called ‘pre-detection’ period, years before the pathogens are first noticed as public health threats," said Mathema.
"From our findings, we learned the importance of HIV coinfection, high pre-existing rates of drug-resistant TB, human migration, and adaptive evolution in the emergence and dispersal of this critical public health threat," noted first author Tyler S. Brown, MD, research fellow in the Infectious Diseases Division at Massachusetts General Hosptial.
"Routine integration of whole-genome sequencing into public health surveillance can address any knowledge gaps and enable us to better understand the pre-detection period and inform strategies for early identification and local containment of AMR pathogens," observed Mathema. "Surveillance, enabled by the rapidly decreasing cost of pathogen sequencing, can provide a powerful strategy for public health practitioners."
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Grey Wolf Therapeutics, a drug discovery biotechnology company focused on developing first-in-class therapies for immuno- oncology (IO), has completed a £2.5 million ($3.3 million) Series A2 financing round with existing healthcare investors Andera Partners and Canaan.
The new funding will allow the company to accelerate development of therapies targeting endoplasmic reticulum aminopeptidase 2 (ERAP2), following many positive signals of its potential. Funds will also be used to continue to drive the lead endoplasmic reticulum aminopeptidase 1 (ERAP1) modulator program.
Both of Grey Wolf’s novel ERAP approaches are aimed at directly altering tumour cells, illuminating them for attack and destruction by the immune system. The goal is to exploit this increased tumour visibility in monotherapy and to extend the therapeutic benefit of already approved immunotherapies to many more cancers. The company is developing small molecule modulators of ERAP1 and ERAP2, two key proteins in the antigen presentation pathway, to change the antigen repertoire of tumours and thereby increase the number and range of cancer-related antigens, including neoantigens, presented on tumour cells available to engage an immune response. Grey Wolf is expanding efforts around ERAP2 for two reasons. First, clinical data continues to demonstrate that tumours which are more visible to the immune system show improved responses to checkpoint inhibitors. Second, the company has developed unique insight into the targeting of the ERAP enzymes through the lead program ERAP1 and validated the role for ERAP inhibition in modulating the cancer-related antigen repertoire.
“We have continued to generate data showing that modulation of both ERAP pathways drives change to the cancer-related antigen repertoire,” said Tom McCarthy, Executive Chairman and Co-Founder of Grey Wolf Therapeutics. “Data clearly demonstrates that modulation of ERAP2 drives an altogether different change to the antigen repertoire, when compared with ERAP1 modulation, due to ERAP2’s clearly differentiated peptide substrate specificities. With this investment and the prior knowledge base within Grey Wolf we will be able to accelerate the ERAP2 program quickly through optimization, building on our leading position in ERAP disease-related biology.”
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The clinical diagnostics, company Beckman Coulter has implemented DxH 900 haematology analysers and the Early Sepsis Indicator across the South West London Pathology (SWLP) network. SWLP is an award-winning NHS pathology partnership set up by St. George’s University Hospitals NHS Foundation Trust, Croydon Health Services NHS Trust and Kingston Hospital NHS Foundation Trust. The installation enables SWLP laboratories to provide a single, integrated pathology service to more than 3.5 million people across South West London via three hospitals, 200 GP practices and 30 community healthcare sites.
Beckman Coulter’s DxH 900 haematology analysers enable clinical laboratories like SWLP to perform complete blood count and white blood cell differential tests. Demonstrating an industry-leading 93% first-pass yield, the DxH 900 reduces the number of manual slide reviews, helping to generate reportable results as quickly as possible. In addition, the DxH 900 features the Early Sepsis Indicator, the only CE marked and FDA-cleared haematologic biomarker that aids the diagnosis of sepsis in adult patients.
Commenting on the implementation, Simon Brewer, Managing Director at South West London Pathology, said: “Emergency departments across our network see 370,000 patients a year. And, with conditions like sepsis becoming more and more prevalent, it is mission critical to have the tools and technology to identify, diagnose, and begin treatment as early as possible.”
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Scientists develop test for uncommon brain diseases
, /in E-News /by 3wmediaNational Institutes of Health (NIH) scientists have developed an ultrasensitive new test to detect abnormal forms of the protein tau associated with uncommon types of neurodegenerative diseases called tauopathies. This advance gives them hope of using cerebrospinal fluid, or CSF – an accessible patient sample – to diagnose these and perhaps other, more common neurological diseases, such as Alzheimer’s disease.
Scientists have linked the abnormal deposition of tau in the brain to at least 25 different neurodegenerative diseases. However, to accurately diagnose these diseases, brain tissue often must be analysed after the patient has died. For their study, the researchers used the same test concept they developed when using postmortem brain tissue samples to detect the abnormal tau types associated with Pick disease, Alzheimer’s disease and chronic traumatic encephalopathy (CTE). They adapted the test to use CSF for the detection of abnormal tau of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other less common tauopathies.
They detected abnormal tau in CSF from both living and deceased patients. In one case, the test led to a corrected diagnosis in a patient who had died from CBD, but who was initially diagnosed with PSP. The new test is called 4R RT-QuIC – which stands for 4-repeat tau protein amplified in a real-time, quaking-induced conversion process.
The researchers plan to continue evaluating the clinical performance of 4R RT-QuIC by analysing larger sets of CSF samples. One focus will be to compare test results from tauopathy patients who agree to provide CSF samples both before and after death. The scientists hope this type of evaluation will help them better understand how abnormal tau in CSF evolves during brain disease.
NIHwww.niaid.nih.gov/news-events/nih-scientists-develop-test-uncommon-brain-diseases
Researchers develop method for identifying aggressive breast cancer drivers
, /in E-News /by 3wmediaPrecision cancer medicine requires personalized biomarkers to identify patients who will benefit from specific cancer therapies. In an effort to improve the accuracy of predictions about prognosis for patients with breast cancer and the efficacy of personalized therapy, University of North Carolina Lineberger Comprehensive Cancer Center researchers have developed a method to precisely identify individual patients who have aggressive breast cancer. The new approach involves sorting and characterizing invasive breast cancer cells by epigenetic characteristics – a method that involves analysing how particular regulatory proteins interact with DNA to control their expression – as well as by how the genes are amplified or abnormally expressed. The researchers reported that they used this technique to identify potential new prognostic markers to predict distinct clinical outcomes for two major subtypes of breast cancer.
“This paper describes a ground-breaking multi-omics technology to discover drivers of proliferative and invasive breast tumours,” said Xian Chen, PhD, professor in the UNC School of Medicine Department of Biochemistry & Biophysics. “We think that eventually, these tools could help doctors better predict which particular patients have a good response, or acquire resistance to treatment.” Doctors often rely on information about tumour size, whether the cancer has spread and the tumour subtype to make treatment decisions. In addition to clinical subtypes of breast cancer, researchers have discovered molecular subtypes that have been used to help make treatment decisions. However, Chen argues that existing markers do not adequately distinguish breast cancer patient sub-populations with different clinical outcomes.
“Single ‘omics’ approaches, which rely on either genomics, transcriptomics, or proteomics alone, fail to dissect the heterogeneity that contributes to individual patients’ variability in terms of their rates of tumour growth, metastasis, or susceptibility to anti-cancer therapies,” he said. “Because biomarkers are not available to distinguish distinct patient sub-populations that are either responsive or resistant to particular drugs, doctors do not have all the tools they need to predict patient response to treatment and outcomes.”
In their study, the researchers wanted to see if they could stratify patients beyond existing molecular subtypes. Their goal was to develop a method to determine which patients within a single subtype would develop resistance or invasive cancer. There are five major molecular subtypes of breast cancer, which are classified based on how genes are expressed in a tumour.
Chen and his colleagues analysed luminal breast cancer and basal-like breast cancer, which is more commonly known as triple negative breast cancer, using breast cancer samples from two large international studies, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium.
To move beyond subtype for identifying exactly which patients might develop resistance, they first sorted the most invasive tumour cells in frozen tissue using a molecular probe that was able to distinguish tumour from adjacent non-malignant cells or tissue by binding to an epigenetic regulator, or a histone methylase, called G9a. This enzyme has been reported by other scientists to be abnormally upregulated in many cancer types, including breast cancer.
They then identified select proteins that were working with G9a as partners-in-crime, and worked backwards from there to identify the genetic abnormalities linked to those partner proteins in the cancer cell. They found in many instances the genes for these interactor proteins were amplified in multiple copies, or abnormally overexpressed, rather than mutated.
“Nowadays, people think somatic mutations of select genes are the primary drivers of tumorigenesis,” Chen said. “We didn’t see many mutations on our identified driver genes. We actually found the genes encoding those interactors have a high frequency amplification in breast cancer patients with poor prognosis.”
They then used this information to generate sets of genes that encoded these “interactor proteins,” and identified those linked to poor prognosis in patients. Looking ahead, Chen and his colleagues plan to determine the specificity and sensitivity of multi-omic aberrations of particular interactor gene sets as new systems biomarkers to predict cancer patient prognosis.
University of Northern Carolina
www.med.unc.edu/biochem/news/New findings could improve diagnosis, treatment of depression
, /in E-News /by 3wmediaResearchers at the University of California, Berkeley, have identified biomarkers – genes and specific brain circuits in mice – associated with a common symptom of depression: lack of motivation.
The finding could guide research to find new ways to diagnose and potentially treat individuals suffering from lack of motivation and bring closer the day of precision medicine for psychiatric disorders like depression.
Depression is the most prevalent mental health disorder in the world, affecting around 9% of the American population each year, and is among the top causes of disability in the workplace. Depression symptoms can differ significantly between patients who have the same depression diagnosis, and the lack of a connection between symptoms and treatments is a main reason that about half of all people with depression fail to respond to medication or other therapies, and that side effects of these medications are common.
“If we had a biomarker for specific symptoms of depression, we simply could do a blood test or image the brain and then identify the appropriate medication for that patient,” said Stephan Lammel, a UC Berkeley assistant professor of molecular and cell biology. “That would be the ideal case, but we are far away from that situation right now.”
Now, for the first time, Lammel and his team have identified genes in a brain region – the lateral habenula – that are strongly turned on, or upregulated, in mice that show reduced motivation as a result of chronic stress. This brain region in mice is not associated with other depression symptoms, including anxiety and anhedonia, the inability to feel pleasure.
“We think that our study not only has the potential to transform how basic scientists study depression in animals, but the combination of anatomical, physiological and molecular biomarkers described could lay the foundation for guiding the development of the next generation of antidepressants that are tailored to specific depression symptoms,” Lammel said.
Lammel is senior author of a paper describing the discovery that appears this week in the journal Neuron. The study was led by first author Ignas Cerniauskas, who is a UC Berkeley graduate student.
Lammel and Cerniauskas work on mouse models of depression that have been a mainstay of basic research on this disorder for the past 60 years. Putting mice under constant stress produces at least three common symptoms of human depression – anxiety, lack of motivation and loss of pleasure – that scientists study to try to understand the disorder in humans.
Until now, however, researchers have sought answers by disregarding the variability of symptoms and instead categorizing all mice as either stressed (“depressed”) or non-stressed (“not depressed”). Cerniauskas and Lammel wanted to try to find changes in the brain that were associated with each specific symptom.
“Unfortunately, depression treatment is currently often based on guesswork. No one treatment works for everyone, and no one has objective data on how to differentiate the enormous variability of depression symptoms and subtypes,” Lammel said. “If we understand specifically how the brain changes in those animals with one certain type of symptom, there may be a way we can specifically reverse these symptoms.”
In response to a recent small clinical study in which doctors electrically stimulated the lateral habenula and found symptom improvement in depressed patients who were resistant to other therapies, Lammel and Cerniauskas decided to investigate that area of the brain. The lateral habenula has received increasing attention in the last few years, in part because it is connected to the dopamine and serotonin systems in the brain, both of which are known to be involved in depression. The most common drugs currently used to treat depression are serotonin reuptake inhibitors (SRIs) such as Zoloft and Prozac.
“After chronic stress, there is an increase in the neural activity of the lateral habenula cells – they fire more, they become overactive – and we found that this overactivity was present only in mice that showed very strong deficits in motivated behaviour, but not in animals that showed anxiety or animals that showed anhedonia,” Lammel said.
His team subsequently identified the specific synapses, cells and circuits in the lateral habenula that are altered by chronic stress in these particular mice, and in collaboration with Csaba Földy and colleagues at the University of Zürich, they found genes that are overexpressed as well.
University of California – Berkley news.berkeley.edu/2019/10/28/new-findings-could-improve-diagnosis-treatment-of-depression/
Scientists discover the implication of a new protein involved in liver cancer
, /in E-News /by 3wmediaResearchers at the Bellvitge Biomedical Research Institute (IDIBELL) have just described for the first time the crucial involvement of a cell membrane protein in the development and progression of liver cancer. This protein, called clathrin, is known for its key role in the process of internalization of molecules from the extracellular space into the cell, called endocytosis. In this process, the cell membrane folds creating vesicles with a cladded structure. Thanks to the new results, analysing the levels of clathrin expression in biopsies of hepatocellular carcinoma patients will help select those patients who will benefit from a much more targeted and personalized therapy.
The research team, led by Dr Isabel Fabregat, who is a professor at the Faculty of Medicine and Health Sciences of the University of Barcelona and a researcher at the CIBER of Hepatic and Digestive Diseases, has shown that liver cells with invasive features have high levels of clathrin, a protein whose involvement in liver cancer was unknown until now. Specifically, researchers showed that high expression levels of clathrin correlate with the activation of the pro-tumorigenic pathway of a known hepatic carcinogenesis actor: TGF-β. In this sense, the work provides completely new and clinically valuable knowledge when it comes to understanding the complex and controversial role of TGF-β in this type of cancer.
TGF-β, which belongs to a large group of proteins called cytokines, has a dual role:
in normal conditions, or in early stages of carcinogenesis, it plays a tumour suppressive role, promoting cell death and reducing tumour growth. But in advanced stages of liver cancer, where this signalling pathway is highly activated, tumour cells have acquired capabilities to escape its suppressor functions and respond to TGF-β by inducing cell migration and invasion, and thus contributing to tumour spreading.
Previous work by the Fabregat group had shown that for this change in cellular behaviour to take place, TGF-β activates the EGF receptor pathway (EGFR) in tumour cells, whose overexpression and hyperactivity has been associated with a large number of cancers. The new results have shown that clathrin is essential in the endocytosis of EGFR, a decisive step for the activation of this pathway by TGF-β. In vitro experiments of this recent work have allowed the IDIBELL researchers to demonstrate that clathrin cell levels determine, via EGFR, the function of TGF-β. If the expression of clathrin is eliminated, the cells die. On the contrary, high levels of clathrin promote the pro-invasive and tumorigenic character of the cells. The reason for this effect must be found in the functionality of the EGFR pathway: the elimination of clathrin results in an inhibition of this signalling pathway. Researchers have also shown that TGF-β is capable of inducing clathrin synthesis, ultimately encouraging a self-stimulation loop.
It is interesting to mention that the study also demonstrates that clathrin expression increases during hepatic tumorigenesis both in humans and mice, and its expression changes the response to TGF-β in favour of anti-apoptotic / pro-tumorigenic signals. There is a positive correlation between the expression of TGF-β and clathrin in samples of hepatocellular carcinoma patients. Patients expressing high levels of TGF-β and clathrin showed a worse prognosis and reduced survival. According to Dr. Fabregat, "determining the levels of clathrin expression in samples of hepato-cellular carcinoma patients can be of great help in selecting those who can be given a therapy based on inhibitors of the TGF-β pathway”.
IDIBELL
www.idibell.cat/en/whats-on/noticies/scientists-discover-implication-new-protein-involved-liver-cancerProtein misfolding as a risk marker for Alzheimer’s disease
, /in E-News /by 3wmediaIn symptom-free individuals, the detection of misfolded amyloid-β protein in the blood indicated a considerably higher risk of Alzheimer’s disease – up to 14 years before a clinical diagnosis was made. Amyloid-β folding proved to be superior to other risk markers evaluated, as shown by scientists from the German Cancer Research Center (DKFZ), Ruhr University Bochum (RUB), the Saarland Cancer Registry, and the Network Aging Research at Heidelberg University.
There is currently still no effective treatment for Alzheimer’s disease. For many experts, this is largely due to the fact that the disease cannot be clinically diagnosed until long after the biological onset of disease when characteristic symptoms such as forgetfulness appear. However, the underlying brain damage may already be advanced and irreversible by this stage.
"Everyone is now pinning their hopes on using new treatment approaches during this symptom-free early stage of disease to take preventive steps. In order to conduct studies to test these approaches, we need to identify people who have a particularly high risk of developing Alzheimer’s disease," explained Hermann Brenner from DKFZ. In patients with Alzheimer’s disease, misfolding of the amyloid-β protein may occur 15–20 years before the first clinical symptoms are observed. The misfolded proteins accumulate and form amyloid plaques in the brain. A technique devised by Klaus Gerwert from RUB can determine whether amyloid proteins are misfolded in blood plasma.
In a previous study, Gerwert and Brenner showed that the amyloid-β changes in the blood can be demonstrated many years before the clinical onset of disease. They also showed that demonstration of misfolded amyloid-β in the blood correlates with plaque formation in the brain. The researchers now wanted to investigate whether analysis of amyloid-β can be used to predict the risk of developing Alzheimer’s disease and how the risk marker performs in comparison to other known and suspected risk factors. To do so, they re-examined blood samples collected as part of ESTHER, a cohort study led by Hermann Brenner and conducted in collaboration with the Saarland Cancer Registry. The cohort study was initiated back in the year 2000.
In the current study, the researchers looked at the initial blood samples of 150 ESTHER participants in whom dementia was subsequently diagnosed during the 14-year follow-up period. These samples were compared with those of 620 randomly selected control participants not known to have been diagnosed with dementia who correlated with the dementia participants in terms of age, sex, and level of education.
Participants with Aβ misfolding had a 23-fold increased odds of Alzheimer’s disease diagnosis within 14 years. In patients with other types of dementia, such as those caused by reduced blood supply to the brain, the study did not demonstrate an increased risk, supporting Alzheimer’s disease specificity.
The researchers also included a number of other possible risk predictors in their analysis, including a particular variant of the gene for apolipoprotein E (APOE Ɛ4) and pre-existing diseases (diabetes, high blood pressure, de-pression) or lifestyle factors (bodyweight, level of education). With the exception of the APOE4 status, which showed a 2.4 times higher risk in those people who later went on to develop Alzheimer’s disease, none of the factors studied correlated with the risk of disease.
In predicting the risk of disease, it was largely irrelevant whether 0–8 or 8–14 years had passed between the time the blood sample was obtained and the clinical onset of dementia.
"This work was not about the use of amyloid-β folding as a diagnostic marker. Instead, we wanted to examine whether this marker could be used for risk stratification in the Alzheimer’s disease therapeutic development setting. Amyloid-β misfolding proved to be a far superior risk marker compared to the other potential risk factors," explained lead author Hannah Stocker from DKFZ and the University of Heidelberg’s Network Aging Research.
The German Cancer Research Center (DKFZ) www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-46-Protein-misfolding-as-a-risk-marker-for-Alzheimers-disease-up-to-14-years-before-the-diagnosis.php
Biomarker for schizophrenia can be detected in human hair
, /in E-News /by 3wmediaWorking with model mice, post-mortem human brains, and people with schizophrenia, researchers at the RIKEN Center for Brain Science in Japan have discovered that a subtype of schizophrenia is related to abnormally high levels hydrogen sulfide in the brain.
Experiments showed that this abnormality likely results from a DNA-modifying reaction during development that lasts throughout life. In addition to providing a new direction for research into drug therapies, higher than normal levels of the hydrogen sulfide-producing enzyme can act as biomarker for this type of schizophrenia.
Diagnosing disorders of thought is easier when a reliable and objective marker can be found. In the case of schizophrenia, we have known for more than 30 years that it is associated with an abnormal startle response. Normally, we are not startled as much by a burst of noise if a smaller burst – called a prepulse – comes a little bit earlier. This phenomenon is called prepulse inhibition (PPI) because the early pulse inhibits the startle response. In people with schizophrenia, PPI is lowed, meaning that their startle response is not dampened as much as it should be after the prepulse.
The PPI test is a good behavioural marker, and although it cannot directly help us understand the biology behind schizophrenia, it was the starting point that led to current discoveries.
The researchers at RIKEN CBS began first looked for differences in protein expression between strains of mice that exhibit extremely low or extremely high PPI.
Ultimately, they found that the enzyme Mpst was expressed much more in the brains of the mouse strain with low PPI than in the strain with high PPI. Knowing that this enzyme helps produce hydrogen sulfide, the team then measured hydrogen sulfide levels and found that they were higher in the low-PPI mice.
"Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia," says team leader Takeo Toshikawa. "Once we discovered this, we had to figure out how it happens and if these findings in mice would hold true for people with schizophrenia."
First, to be sure that Mpst was the culprit, the researchers created an Mpst knockout version of the low-PPI mice and showed that their PPI was higher than that in regular low-PPI mice. Thus, reducing the amount of Mpst helped the mice become more normal. Next, they found that MPST gene expression was indeed higher in postmortem brains from people with schizophrenia than in those from unaffected people. MPST protein levels in these brains also correlated well with the severity of premortem symptoms.
Now the team had enough information to look at MPST expression as a biomarker for schizophrenia. They examined hair follicles from more than 150 people with schizophrenia and found that expression of MPST mRNA was much higher than people without schizophrenia. Even though the results were not perfect-indicating that sulfide stress does not account for all cases of schizophrenia-MPST levels in hair could be a good biomarker for schizophrenia before other symptoms appear.
Whether a person develops schizophrenia is related to both their genetics and the environment. Testing in mice and postmortem brains indicated that high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. So, the next step was for the team to search for environmental factors that could result in permanently increased MPST production.
Because hydrogen sulfide can actually protect against inflammatory stress, the group hypothesized that inflammatory stress during early development might be the root cause. "We found that anti-oxidative markers – including the production of hydrogen sulfide – that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia," says Yoshikawa.
He proposes that once excess hydrogen sulfide production is primed, it persists throughout life due to permanent epigenetic changes to DNA, leading to "sulfide stress" induced schizophrenia.
EurekAlert
www.eurekalert.org/pub_releases/2019-10/r-bfs102519.phpCracking the colon code – new light shed on gut function
, /in E-News /by 3wmediaNew insights into how the colon functions and actually expels its contents have been revealed for the first time following decades of study by Flinders University researchers.
It promises new diagnostics tools and treatments for gastrointestinal disorders to address problems with bowel movements leading to constipation, diarrhoea and pain, affecting hundreds of millions of people worldwide.
Propulsion of intestinal contents is controlled by millions of neurons within the wall of the gut, known as the enteric nervous system. Capable of operating independently of the brain, a functioning enteric nervous system is essential for life – but exactly how it functions has been a mystery.
By unravelling the neural circuits of the enteric nervous system in guinea pigs and humans Professor Marcello Costa and colleagues are able to understand how the enteric nervous system ensures that food is slowly mixed and propelled along the digestive tube, allowing for absorption of nutrients and excretion of waste.
“For the first time we have combined video recording intestinal movements with a pressure-measuring manometric probe, enabling movements, pressures and electrical activities to be recorded all at the same time within the colon.
“This powerful combination of techniques applied to a guinea pig colon identified several distinct neural mechanisms involved in the propulsion of colonic contents.
“This answers the deceptively simple question of how neural mechanisms within the colon manage the propulsion of bowel contents” Professor Costa says.
“The findings also show how studies in human and animals can be complementary, identifying fundamental mechanisms that are shared across species – in this case guinea pigs and humans.
“Currently we treat intestinal disorders by addressing the symptoms, such a stopping-up diarrhoea or softening stools to ease constipation, but as a result of this new understanding of the neural networks of the enteric system, clinicians may be able to develop treatments that treat the cause of the problems” Professor Costa says.
Scimex www.scimex.org/newsfeed/cracking-the-colon-code-new-light-shed-on-gut-function
Using whole-genome sequencing for early identification and containment of AMR pathogens
, /in E-News /by 3wmediaA recently published study examines the evolutionary and epidemiologic history of an epidemic strain of extensively drug-resistant tuberculosis (XDR-TB) – called LAM4/KZN – in KwaZulu-Natal, South Africa. This strain was first reported in a 2005 outbreak in Tugela Ferry, KwaZulu-Natal, where it was associated with 90 % mortality among predominantly HIV infected individuals, and has since become widespread throughout the province. A new study identifies key host, pathogen and environmental factors that facilitated the success of this XDR-TB strain and steps that can be taken for early identification and containment of future epidemics.
The study, led by Columbia University, involved a multi-institutional team of researchers from South Africa, the United States, and Norway, used genomic, spatial and protein modelling to answer when and where this strain emerged, and how and why it became widespread. The study utilized data and TB strains collected in the prospective XDR-TB transmission study (TRAX) from 2011 to 2014 led by Emory University, the University of KwaZulu-Natal, and the U.S. Centers for Disease Control and Prevention.
Researchers localized the geographic origin of the strain to a rural district, bordering Mozambique and eSwatini, with high pre-existing rates of drug-resistant TB located 400 hundred kilometres away from where the first outbreak of LAM4/KZN was reported. Results also indicate that the strain emerged in the early 1990s, acquiring key advantageous mutations prior to undergoing marked expansion concurrent with the onset of the generalized HIV epidemic. In addition, the study suggests cyclical rural-urban migration in the rapid and widespread dissemination of this strain.
"Our results indicate that this strain of XDR-TB emerged approximately 12 years before it was identified by public health activities," said lead researcher Barun Mathema, PhD, assistant professor of epidemiology at Columbia University Mailman School of Public Health. "Our research highlights multiple environmental and pathogen-specific factors must align in order for these pathogens to establish sustained transmission and disperse into geographically separated populations. These processes take place in the so-called ‘pre-detection’ period, years before the pathogens are first noticed as public health threats," said Mathema.
"From our findings, we learned the importance of HIV coinfection, high pre-existing rates of drug-resistant TB, human migration, and adaptive evolution in the emergence and dispersal of this critical public health threat," noted first author Tyler S. Brown, MD, research fellow in the Infectious Diseases Division at Massachusetts General Hosptial.
"Routine integration of whole-genome sequencing into public health surveillance can address any knowledge gaps and enable us to better understand the pre-detection period and inform strategies for early identification and local containment of AMR pathogens," observed Mathema. "Surveillance, enabled by the rapidly decreasing cost of pathogen sequencing, can provide a powerful strategy for public health practitioners."
ScienceDaily
www.sciencedaily.com/releases/2019/10/191028175153.htmGrey Wolf Therapeutics completes £2.5 million financing to accelerate development of therapies targeting ERAP2
, /in E-News /by 3wmediaGrey Wolf Therapeutics, a drug discovery biotechnology company focused on developing first-in-class therapies for immuno- oncology (IO), has completed a £2.5 million ($3.3 million) Series A2 financing round with existing healthcare investors Andera Partners and Canaan.
The new funding will allow the company to accelerate development of therapies targeting endoplasmic reticulum aminopeptidase 2 (ERAP2), following many positive signals of its potential. Funds will also be used to continue to drive the lead endoplasmic reticulum aminopeptidase 1 (ERAP1) modulator program.
Both of Grey Wolf’s novel ERAP approaches are aimed at directly altering tumour cells, illuminating them for attack and destruction by the immune system. The goal is to exploit this increased tumour visibility in monotherapy and to extend the therapeutic benefit of already approved immunotherapies to many more cancers. The company is developing small molecule modulators of ERAP1 and ERAP2, two key proteins in the antigen presentation pathway, to change the antigen repertoire of tumours and thereby increase the number and range of cancer-related antigens, including neoantigens, presented on tumour cells available to engage an immune response. Grey Wolf is expanding efforts around ERAP2 for two reasons. First, clinical data continues to demonstrate that tumours which are more visible to the immune system show improved responses to checkpoint inhibitors. Second, the company has developed unique insight into the targeting of the ERAP enzymes through the lead program ERAP1 and validated the role for ERAP inhibition in modulating the cancer-related antigen repertoire.
“We have continued to generate data showing that modulation of both ERAP pathways drives change to the cancer-related antigen repertoire,” said Tom McCarthy, Executive Chairman and Co-Founder of Grey Wolf Therapeutics. “Data clearly demonstrates that modulation of ERAP2 drives an altogether different change to the antigen repertoire, when compared with ERAP1 modulation, due to ERAP2’s clearly differentiated peptide substrate specificities. With this investment and the prior knowledge base within Grey Wolf we will be able to accelerate the ERAP2 program quickly through optimization, building on our leading position in ERAP disease-related biology.”
Beckman Coulter partners with South West London Pathology to reduce the impact of sepsis
, /in E-News /by 3wmediaThe clinical diagnostics, company Beckman Coulter has implemented DxH 900 haematology analysers and the Early Sepsis Indicator across the South West London Pathology (SWLP) network. SWLP is an award-winning NHS pathology partnership set up by St. George’s University Hospitals NHS Foundation Trust, Croydon Health Services NHS Trust and Kingston Hospital NHS Foundation Trust. The installation enables SWLP laboratories to provide a single, integrated pathology service to more than 3.5 million people across South West London via three hospitals, 200 GP practices and 30 community healthcare sites.
Beckman Coulter’s DxH 900 haematology analysers enable clinical laboratories like SWLP to perform complete blood count and white blood cell differential tests. Demonstrating an industry-leading 93% first-pass yield, the DxH 900 reduces the number of manual slide reviews, helping to generate reportable results as quickly as possible. In addition, the DxH 900 features the Early Sepsis Indicator, the only CE marked and FDA-cleared haematologic biomarker that aids the diagnosis of sepsis in adult patients.
Commenting on the implementation, Simon Brewer, Managing Director at South West London Pathology, said: “Emergency departments across our network see 370,000 patients a year. And, with conditions like sepsis becoming more and more prevalent, it is mission critical to have the tools and technology to identify, diagnose, and begin treatment as early as possible.”