Braunschweig Municipal Hospital has put new technology in place for molecular diagnostics that will recognize genetic changes in cancer cells. Pathologists can thus accurately identify patients eligible for targeted treatment based on the genetic make-up of their tumours. The method was developed by Neo New Oncology, a subsidiary of Siemens Healthineers. Braunschweig Municipal Hospital, with 38 clinics making it one of the largest hospitals in northern Germany, will thus boost its position as a top oncology provider in the region. This concept serves as a model for regional clinics in Germany. The technology from Neo enables hospital pathologists to demonstrate many genetic changes relevant to a treatment decision with just a single diagnostic test. Conversely, standard diagnostic procedures usually involve a combination of many different diagnostic procedures to obtain all information about a tumour’s genetic make-up. The analysis can be time-consuming as a result, which prevents the treating oncologists from beginning treatment directly. In addition, with the standard procedure the tumour sample often is not enough to enable a full, end-to-end analysis. This creates the risk that patients who could benefit from targeted treatment will fail to be identified. Cancer patients are now living longer and also living better with their disease. One reason is the constant refinement of individual treatment options that modern medicine now makes available. This also includes “targeted medications”: In contrast to chemotherapy, which non-selectively targets all dividing cells, these substances act specifically on particular changes in a tumour’s genetic information. This not only makes them highly efficient, but also substantially reduces the risk of adverse drug reactions compared to chemotherapy. If tumours lack the relevant genetic changes, however, these targeted medications are virtually ineffective. Targeted treatment must therefore be coordinated with the specific characteristics of the cancer cells in a given patient. For lung cancer, for example, more than a dozen genetic changes are known, which can have different consequences for treatment. Patient treatment is therefore increasingly tailored to the individual tumour, which makes it more effective. For physicians to make the best possible treatment decision, therefore, it is essential that they understand the individual patient’s cancer down to molecular level. The Neo procedure is based on the method of “next generation sequencing.” This selects and analyses relevant parts of the tumour DNA at high resolution. The resulting large volumes of data are processed by software developed by Neo New Oncology using a quality-assured system. Hospital pathologists then evaluate the data. They analyse the changes in the patient’s tumour, the medications that can be used against it, and establish whether there are appropriate clinical studies for which the inclusion criteria are met, enabling the patient to benefit from innovative new treatment options. The results of this evaluation are then discussed by the hospital’s Tumour Board. This is where all the relevant medical disciplines at the hospital review all the radiological and molecular diagnostic results and discuss which treatment option would be the best for the patient in question. This ensures that every individual patient benefits from the all of the hospital’s medical expertise.
www.siemens-healthineers.com
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:31:582021-01-08 11:08:19Innovative cancer diagnostics at Braunschweig Municipal Hospital
Researchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage – mutational fingerprints that represent the origins of cancer – were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious. The resource will enable scientists to study what causes mutations that lead to the development of cancer, directly in human cancer cells. Further understanding into these mutational processes could help researchers find novel avenues for research towards cancer prevention and treatment. All cancers are caused by DNA mutations, and these mutations form molecular fingerprints in the DNA called mutational signatures. More than 50 different signatures have been found, many of which are caused by external factors, for example ultraviolet light exposure or tobacco smoking. Others are due to factors inside the cell such as the failure of DNA repair mechanisms. However, the causes of many mutational signatures are unknown and they are extremely challenging to study experimentally. The researchers studied the genome sequences of 1,001 human cancer cell lines and 577 grafts of human cancers, including the most widely used models in cancer research and therapeutics testing. They used all the known mutational signatures and catalogued which signature is present in each cancer model. This resource then allowed the scientists to choose specific cell lines and study how each mutational pattern changed over time in cancer cells. They found that mutational signatures from known external factors like smoking or UV light stopped being created in cell lines, whereas most signatures associated with factors inside the cell continued to be generated, and at a steady rate. Surprisingly however, they discovered that two common mutational signatures associated with a DNA editing protein known as APOBEC, actually switched on and off over time in cell lines, a phenomenon they called “episodic mutagenesis”. APOBEC DNA editing enzymes are part of the innate immune system, protecting us from infections by causing mutations in viruses such as HIV, leaving APOBEC mutational signatures in the viral genomes. APOBEC-like signatures are a major mutation pattern in cancers, found in more than 70 per cent of cancer types. A theory for this is that viruses or inflammation could activate the enzymes to mutate the human genome instead of the virus. However, cell lines are not subject to inflammation and no viruses were found, suggesting other factors are involved. Importantly, cell lines found to generate these and other signatures over time can now be used by researchers to investigate the underlying causes of mutations in cancer.
Wellcome Sanger Institute
https://tinyurl.com/y2fga87n
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Proteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood. Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1). Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests. “With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society
https://tinyurl.com/yynccngq
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:31:582021-01-08 11:08:18A highly sensitive new blood test can detect rare cancer proteins
Proteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood. Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1). Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests. “With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society
https://tinyurl.com/yynccngq
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:31:582021-01-08 11:08:18Scientists discover predictors that determine toxic fats in the liver
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
Researchers at the University of Exeter Medical School have developed simple and inexpensive ways to measure C-peptide and have demonstrated that this test can show what treatment will be most effective for people with diabetes. Clinicians at the Western General Hospital in Edinburgh have used the new test on every person thought to have type 1 diabetes for over three years in their clinic and shown that some actually have other types of diabetes and can stop insulin treatment.
C-peptide is produced at the same time and in the same quantities as the insulin that regulates our blood sugar. By measuring C-peptide levels, doctors can now tell how much insulin a person is producing themselves, even if they are taking insulin injections as treatment.
The Exeter team has developed a new urine test for C-peptide, and shown that a simple blood test when a person is seen in clinic can also accurately measure C-peptide, replacing previous methods which were expensive and time-consuming. These tests are now available in nearly every hospital in the UK, and cost as little as £10.
The team demonstrated how urine and blood C-peptide can be used to robustly identify what type of diabetes a person has, and help identify what treatment will work for them. This is crucial to getting the right treatment, education and follow-up care. By offering this test to people thought to have Type 1 diabetes in their clinic, the Edinburgh researchers have shown that many have high C-peptide, raising the possibility of other types of diabetes. Some of these patients have been able to stop insulin and switch to tablet treatment. This testing also revealed that in some of these patients, the diabetes had a genetic cause, which is important both for treatment and for other people in their families.
Professor Mark Strachan, from Western General Hospital, Edinburgh, said: “We have now measured C-peptide in over 750 people with a clinician-diagnosis of Type 1 diabetes, attending our clinic at the Westen General Hospital. So far, we have made a new diagnosis of genetic diabetes in eight people, and changed the diagnosis to Type 2 diabetes in 28 other people. This has allowed us to make changes to treatment in many of these individuals and in 12 people we have actually been able to stop insulin therapy.”
The team’s research also shows that C peptide testing is practical in clinics. They identified optimal storage conditions for the samples, which were previously thought to be unstable, so sample collection is now much easier. They showed that using a specific preservative means that blood C-peptide is stable for more than 24 hours. For the first time, this means it is viable to conduct a test to be measured in primary care and outpatient clinics. This evidence together removed crucial barriers to implementation that had previously blocked widespread adoption of this test in routine clinical care.
University of Exeter
www.exeter.ac.uk/news/research/title_707155_en.html
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Thermo Fisher and NX Prenatal Inc. have entered into a collaboration to develop clinical mass spectrometry-based proteomics assays to monitor fetal health in utero and assess the risk of adverse outcomes, including preterm birth and preeclampsia.
This new collaboration recognizes the challenges faced by medical professionals who have few tools available for noninvasive risk stratification for adverse pregnancy outcomes. By combining NX Prenatal’s NeXosome platform with Thermo Fisher’s leading liquid chromatography-mass spectrometry (LC-MS) instrumentation, the workflows can address the reliability, accuracy and precision of the analytical solutions currently available to clinical scientists.
"Our collaboration with NX Prenatal is aiming to enable us to better evaluate maternal and fetal biomarkers during pregnancy that correlate with adverse outcomes, such as preterm birth," said Brad Hart, senior director, clinical research, chromatography and mass spectrometry, Thermo Fisher Scientific. "The co-development of a commercially available clinical mass spectrometry-based proteomics assay has the potential to provide a diagnostic solution to both clinical scientists and medical professionals offering more confidence in the evaluation of novel biomarkers that can support a safe delivery and healthy future for mother and baby."
"At NX Prenatal, we are developing novel assays and noninvasive early warning systems to detect subtle molecular changes in the maternal-fetal environment, all with the goal of improving the rate of healthy pregnancy outcomes," said Brian D. Brohman, CEO of NX Prenatal. "Our collaboration with Thermo Fisher Scientific brings together our novel NeXosome platform with their leading analytical technology with the goal of optimizing clinical mass spectrometry-based workflows, in an effort to provide the precision necessary for personalized diagnostic solutions to improve health outcomes for both mother and child."
The unique NeXosome technology is used to enrich maternal blood samples for microparticles, such as exosomes, which play key roles in maintaining certain balances between the mother and fetus during pregnancy. Aberrations in these balances have been shown to correlate with the likelihood of adverse pregnancy outcomes. Merging the NeXosome platform with Thermo Fisher LC-MS technology has the potential to generate fast, efficient and accurate data for the analysis of exosome-derived proteomic biomarkers, which may lead to increased information about maternal and fetal health during pregnancy. Ultimately, the analysis has the potential to support obstetrical care decisions in conjunction with traditional clinical assessments.
https://www.thermofisher.com
https://www.nxprenatal.com
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New research on the X chromosome from the School of Veterinary Medicine points to an abnormality in the immune system’s T cells as a possible contributing factor in lupus and other autoimmune diseases.
The autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, strikes females far more often than males. Eight-five percent of people with lupus are female, and their second X chromosome seems partly to blame. According to a new study by Penn researchers, females with lupus don’t fully “silence” their second X chromosome in the immune system’s T cells, leading to abnormal expression of genes linked to that chromosome.
The work, led by Montserrat Anguera of the School of Veterinary Medicine is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus—the first time that nuclear organization has been noted as a feature of this disease.
“In normal circumstances, the inactive X should be silenced, and what we show is, in lupus, it’s not,” says Anguera, a biologist at Penn Vet. “And it’s ultimately affecting gene expression.”
Anguera’s lab has paid close attention to the link between X chromosome inactivation, an epigenetic process that balances gene expression between males and females, and autoimmune disease. In earlier studies, the team found that, in females, both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule that is necessary for X inactivation.
In the new work, Anguera and colleagues wanted to more closely examine this process in T cells and specifically in the context of an autoimmune disease, in this case, lupus.
They first tracked the process of X inactivation in T cells from healthy mice. Their observations revealed that, as T cells develop, Xist temporarily diffuses away from the inactive X chromosome. But when a T cell is activated, as it would be upon encountering a potential pathogen, for example, then Xist RNA returns to this chromosome.
To see what happens in autoimmune disease, the researchers used a mouse model that spontaneously develops lupus in a female-biased manner, similar to the human disease. All female mice of this strain develop the disease, while only 40 percent of males do. Examining the animals’ T cells, the researchers discovered that those at early stages of disease resembled healthy controls in their patterns of Xist localization. But those in the later stages of disease had a dramatically different pattern.
The only differences we detected happened at late stages of disease,” Anguera says. “What this means is that abnormal X inactivation is a consequence of the disease; it’s not predisposing the animal to develop the disease.”
Interestingly, when the researchers looked at T cells from paediatric lupus patients, provided by study co-author Edward M. Behrens of the Perelman School of Medicine and Children’s Hospital of Philadelphia, they found the same mislocalization of Xist that they had seen in the mice with lupus, even though the children were in remission from their disease.
Even stimulating those patients’ cells in vitro wasn’t enough to coax Xist into the normal pattern. “Even though they don’t have active disease, there’s something missing that’s preventing the RNA from staying targeted at that inactive X chromosome,” Anguera says.
University of Pennsylvania
https://tinyurl.com/y3nsrssw
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Researchers have discovered a way to better predict progression of Alzheimer’s disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published.
According to the Alzheimer’s Association, an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer’s disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain.
“The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain,” said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. “In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model.”
In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the travelled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density.
Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses.
“This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels,” noted Brendel. “Keeping the limitations of mouse models in mind, it could be crucial to modify an individual’s microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment.”
Society of Nuclear Medicine and Molecular Imaging
https://tinyurl.com/y6jyl4mw
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Patients with colorectal cancer have the same consistent changes in the gut bacteria across continents, cultures, and diets — a team of international researchers, from University of Copenhagen among others, find in a new study. The hope is the results in the future can be used to develop a new method of diagnosing colorectal cancer.
Cancers have long been known to arise due to environmental exposures such as unhealthy diet or smoking. Lately, the microbes living in and on our body have entered the stage as key players. But the role that gut microbes play in the development of colorectal cancer – the third most common cancer worldwide – is unclear. To determine their influence, association studies have aimed to map how the microbes colonizing the gut of colorectal cancer patients are different from those that inhabit healthy subjects.
Now, researchers from University of Copenhagen, EMBL, the University of Trento, and their international collaborators have analysed multiple existing microbiome association studies of colorectal cancer together with newly generated data. Their meta-analyses establish disease-specific microbiome changes, which are globally robust – consistent across seven countries on three continents – despite differences in environment, diet and life style.
“During disease our microbiome may change. If these changes are consistent in each person getting the same disease then it is a signature of disease. What we show in our study is that the gut microbiome signatures in colorectal cancer seem to be universal. This is despite geography, culture and life style. In the future we hope we can use these signatures as biomarkers and as a diagnostic tool for colorectal cancer,” says Manimozhiyan Arumugam, Associate Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research.
It is the first time a meta-analyses for colorectal cancer has been done on this scale. In the study, the researchers have analyzed and used data from seven cohorts from the countries China, Austria, France, Germany, the US, Italy and Japan.
“We used a rigorous machine learning analysis to identify microbial signatures for colorectal cancer. We validated these signatures in early cancer stages and in multiple studies, so they can serve as the basis for future non-invasive cancer screening,” explains Georg Zeller from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany.
University of Copenhagen
https://tinyurl.com/y4mx25au
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Innovative cancer diagnostics at Braunschweig Municipal Hospital
, /in E-News /by 3wmediaBraunschweig Municipal Hospital has put new technology in place for molecular diagnostics that will recognize genetic changes in cancer cells. Pathologists can thus accurately identify patients eligible for targeted treatment based on the genetic make-up of their tumours. The method was developed by Neo New Oncology, a subsidiary of Siemens Healthineers. Braunschweig Municipal Hospital, with 38 clinics making it one of the largest hospitals in northern Germany, will thus boost its position as a top oncology provider in the region. This concept serves as a model for regional clinics in Germany.
The technology from Neo enables hospital pathologists to demonstrate many genetic changes relevant to a treatment decision with just a single diagnostic test. Conversely, standard diagnostic procedures usually involve a combination of many different diagnostic procedures to obtain all information about a tumour’s genetic make-up. The analysis can be time-consuming as a result, which prevents the treating oncologists from beginning treatment directly. In addition, with the standard procedure the tumour sample often is not enough to enable a full, end-to-end analysis. This creates the risk that patients who could benefit from targeted treatment will fail to be identified.
Cancer patients are now living longer and also living better with their disease. One reason is the constant refinement of individual treatment options that modern medicine now makes available. This also includes “targeted medications”: In contrast to chemotherapy, which non-selectively targets all dividing cells, these substances act specifically on particular changes in a tumour’s genetic information. This not only makes them highly efficient, but also substantially reduces the risk of adverse drug reactions compared to chemotherapy. If tumours lack the relevant genetic changes, however, these targeted medications are virtually ineffective. Targeted treatment must therefore be coordinated with the specific characteristics of the cancer cells in a given patient. For lung cancer, for example, more than a dozen genetic changes are known, which can have different consequences for treatment. Patient treatment is therefore increasingly tailored to the individual tumour, which makes it more effective. For physicians to make the best possible treatment decision, therefore, it is essential that they understand the individual patient’s cancer down to molecular level.
The Neo procedure is based on the method of “next generation sequencing.” This selects and analyses relevant parts of the tumour DNA at high resolution. The resulting large volumes of data are processed by software developed by Neo New Oncology using a quality-assured system. Hospital pathologists then evaluate the data. They analyse the changes in the patient’s tumour, the medications that can be used against it, and establish whether there are appropriate clinical studies for which the inclusion criteria are met, enabling the patient to benefit from innovative new treatment options.
The results of this evaluation are then discussed by the hospital’s Tumour Board. This is where all the relevant medical disciplines at the hospital review all the radiological and molecular diagnostic results and discuss which treatment option would be the best for the patient in question. This ensures that every individual patient benefits from the all of the hospital’s medical expertise. www.siemens-healthineers.com
Major mutation pattern in cancer occurs in bursts
, /in E-News /by 3wmediaResearchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage – mutational fingerprints that represent the origins of cancer – were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious.
The resource will enable scientists to study what causes mutations that lead to the development of cancer, directly in human cancer cells. Further understanding into these mutational processes could help researchers find novel avenues for research towards cancer prevention and treatment.
All cancers are caused by DNA mutations, and these mutations form molecular fingerprints in the DNA called mutational signatures. More than 50 different signatures have been found, many of which are caused by external factors, for example ultraviolet light exposure or tobacco smoking. Others are due to factors inside the cell such as the failure of DNA repair mechanisms. However, the causes of many mutational signatures are unknown and they are extremely challenging to study experimentally.
The researchers studied the genome sequences of 1,001 human cancer cell lines and 577 grafts of human cancers, including the most widely used models in cancer research and therapeutics testing. They used all the known mutational signatures and catalogued which signature is present in each cancer model. This resource then allowed the scientists to choose specific cell lines and study how each mutational pattern changed over time in cancer cells.
They found that mutational signatures from known external factors like smoking or UV light stopped being created in cell lines, whereas most signatures associated with factors inside the cell continued to be generated, and at a steady rate. Surprisingly however, they discovered that two common mutational signatures associated with a DNA editing protein known as APOBEC, actually switched on and off over time in cell lines, a phenomenon they called “episodic mutagenesis”.
APOBEC DNA editing enzymes are part of the innate immune system, protecting us from infections by causing mutations in viruses such as HIV, leaving APOBEC mutational signatures in the viral genomes. APOBEC-like signatures are a major mutation pattern in cancers, found in more than 70 per cent of cancer types. A theory for this is that viruses or inflammation could activate the enzymes to mutate the human genome instead of the virus. However, cell lines are not subject to inflammation and no viruses were found, suggesting other factors are involved. Importantly, cell lines found to generate these and other signatures over time can now be used by researchers to investigate the underlying causes of mutations in cancer.
Wellcome Sanger Institute https://tinyurl.com/y2fga87n
A highly sensitive new blood test can detect rare cancer proteins
, /in E-News /by 3wmediaProteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood.
Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1).
Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests.
“With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society https://tinyurl.com/yynccngq
Scientists discover predictors that determine toxic fats in the liver
, /in E-News /by 3wmediaProteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood.
Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1).
Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests.
“With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society https://tinyurl.com/yynccngq
Detecting cyanide exposure
, /in E-News /by 3wmediaCyanide 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
Simple, cheap C-Peptide helps patients get the right diabetes diagnosis and treatment
, /in E-News /by 3wmediaResearchers at the University of Exeter Medical School have developed simple and inexpensive ways to measure C-peptide and have demonstrated that this test can show what treatment will be most effective for people with diabetes. Clinicians at the Western General Hospital in Edinburgh have used the new test on every person thought to have type 1 diabetes for over three years in their clinic and shown that some actually have other types of diabetes and can stop insulin treatment.
C-peptide is produced at the same time and in the same quantities as the insulin that regulates our blood sugar. By measuring C-peptide levels, doctors can now tell how much insulin a person is producing themselves, even if they are taking insulin injections as treatment.
The Exeter team has developed a new urine test for C-peptide, and shown that a simple blood test when a person is seen in clinic can also accurately measure C-peptide, replacing previous methods which were expensive and time-consuming. These tests are now available in nearly every hospital in the UK, and cost as little as £10.
The team demonstrated how urine and blood C-peptide can be used to robustly identify what type of diabetes a person has, and help identify what treatment will work for them. This is crucial to getting the right treatment, education and follow-up care. By offering this test to people thought to have Type 1 diabetes in their clinic, the Edinburgh researchers have shown that many have high C-peptide, raising the possibility of other types of diabetes. Some of these patients have been able to stop insulin and switch to tablet treatment. This testing also revealed that in some of these patients, the diabetes had a genetic cause, which is important both for treatment and for other people in their families.
Professor Mark Strachan, from Western General Hospital, Edinburgh, said: “We have now measured C-peptide in over 750 people with a clinician-diagnosis of Type 1 diabetes, attending our clinic at the Westen General Hospital. So far, we have made a new diagnosis of genetic diabetes in eight people, and changed the diagnosis to Type 2 diabetes in 28 other people. This has allowed us to make changes to treatment in many of these individuals and in 12 people we have actually been able to stop insulin therapy.”
The team’s research also shows that C peptide testing is practical in clinics. They identified optimal storage conditions for the samples, which were previously thought to be unstable, so sample collection is now much easier. They showed that using a specific preservative means that blood C-peptide is stable for more than 24 hours. For the first time, this means it is viable to conduct a test to be measured in primary care and outpatient clinics. This evidence together removed crucial barriers to implementation that had previously blocked widespread adoption of this test in routine clinical care.
University of Exeter www.exeter.ac.uk/news/research/title_707155_en.html
Thermo Fisher Scientific has announced collaboration to advance noninvasive risk assessments of pregnancy outcomes
, /in E-News /by 3wmediaThermo Fisher and NX Prenatal Inc. have entered into a collaboration to develop clinical mass spectrometry-based proteomics assays to monitor fetal health in utero and assess the risk of adverse outcomes, including preterm birth and preeclampsia.
This new collaboration recognizes the challenges faced by medical professionals who have few tools available for noninvasive risk stratification for adverse pregnancy outcomes. By combining NX Prenatal’s NeXosome platform with Thermo Fisher’s leading liquid chromatography-mass spectrometry (LC-MS) instrumentation, the workflows can address the reliability, accuracy and precision of the analytical solutions currently available to clinical scientists.
"Our collaboration with NX Prenatal is aiming to enable us to better evaluate maternal and fetal biomarkers during pregnancy that correlate with adverse outcomes, such as preterm birth," said Brad Hart, senior director, clinical research, chromatography and mass spectrometry, Thermo Fisher Scientific. "The co-development of a commercially available clinical mass spectrometry-based proteomics assay has the potential to provide a diagnostic solution to both clinical scientists and medical professionals offering more confidence in the evaluation of novel biomarkers that can support a safe delivery and healthy future for mother and baby."
"At NX Prenatal, we are developing novel assays and noninvasive early warning systems to detect subtle molecular changes in the maternal-fetal environment, all with the goal of improving the rate of healthy pregnancy outcomes," said Brian D. Brohman, CEO of NX Prenatal. "Our collaboration with Thermo Fisher Scientific brings together our novel NeXosome platform with their leading analytical technology with the goal of optimizing clinical mass spectrometry-based workflows, in an effort to provide the precision necessary for personalized diagnostic solutions to improve health outcomes for both mother and child."
The unique NeXosome technology is used to enrich maternal blood samples for microparticles, such as exosomes, which play key roles in maintaining certain balances between the mother and fetus during pregnancy. Aberrations in these balances have been shown to correlate with the likelihood of adverse pregnancy outcomes. Merging the NeXosome platform with Thermo Fisher LC-MS technology has the potential to generate fast, efficient and accurate data for the analysis of exosome-derived proteomic biomarkers, which may lead to increased information about maternal and fetal health during pregnancy. Ultimately, the analysis has the potential to support obstetrical care decisions in conjunction with traditional clinical assessments. https://www.thermofisher.com https://www.nxprenatal.com
Unlocking the female bias in lupus
, /in E-News /by 3wmediaNew research on the X chromosome from the School of Veterinary Medicine points to an abnormality in the immune system’s T cells as a possible contributing factor in lupus and other autoimmune diseases.
The autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, strikes females far more often than males. Eight-five percent of people with lupus are female, and their second X chromosome seems partly to blame. According to a new study by Penn researchers, females with lupus don’t fully “silence” their second X chromosome in the immune system’s T cells, leading to abnormal expression of genes linked to that chromosome.
The work, led by Montserrat Anguera of the School of Veterinary Medicine is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus—the first time that nuclear organization has been noted as a feature of this disease.
“In normal circumstances, the inactive X should be silenced, and what we show is, in lupus, it’s not,” says Anguera, a biologist at Penn Vet. “And it’s ultimately affecting gene expression.”
Anguera’s lab has paid close attention to the link between X chromosome inactivation, an epigenetic process that balances gene expression between males and females, and autoimmune disease. In earlier studies, the team found that, in females, both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule that is necessary for X inactivation.
In the new work, Anguera and colleagues wanted to more closely examine this process in T cells and specifically in the context of an autoimmune disease, in this case, lupus.
They first tracked the process of X inactivation in T cells from healthy mice. Their observations revealed that, as T cells develop, Xist temporarily diffuses away from the inactive X chromosome. But when a T cell is activated, as it would be upon encountering a potential pathogen, for example, then Xist RNA returns to this chromosome.
To see what happens in autoimmune disease, the researchers used a mouse model that spontaneously develops lupus in a female-biased manner, similar to the human disease. All female mice of this strain develop the disease, while only 40 percent of males do. Examining the animals’ T cells, the researchers discovered that those at early stages of disease resembled healthy controls in their patterns of Xist localization. But those in the later stages of disease had a dramatically different pattern.
The only differences we detected happened at late stages of disease,” Anguera says. “What this means is that abnormal X inactivation is a consequence of the disease; it’s not predisposing the animal to develop the disease.”
Interestingly, when the researchers looked at T cells from paediatric lupus patients, provided by study co-author Edward M. Behrens of the Perelman School of Medicine and Children’s Hospital of Philadelphia, they found the same mislocalization of Xist that they had seen in the mice with lupus, even though the children were in remission from their disease.
Even stimulating those patients’ cells in vitro wasn’t enough to coax Xist into the normal pattern. “Even though they don’t have active disease, there’s something missing that’s preventing the RNA from staying targeted at that inactive X chromosome,” Anguera says.
University of Pennsylvania https://tinyurl.com/y3nsrssw
New PET imaging biomarker could better predict progression of Alzheimer’s Disease
, /in E-News /by 3wmediaResearchers have discovered a way to better predict progression of Alzheimer’s disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published.
According to the Alzheimer’s Association, an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer’s disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain.
“The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain,” said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. “In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model.”
In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the travelled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density.
Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses.
“This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels,” noted Brendel. “Keeping the limitations of mouse models in mind, it could be crucial to modify an individual’s microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment.”
Society of Nuclear Medicine and Molecular Imaging https://tinyurl.com/y6jyl4mw
Researchers establish global microbial signatures for colorectal cancer
, /in E-News /by 3wmediaPatients with colorectal cancer have the same consistent changes in the gut bacteria across continents, cultures, and diets — a team of international researchers, from University of Copenhagen among others, find in a new study. The hope is the results in the future can be used to develop a new method of diagnosing colorectal cancer.
Cancers have long been known to arise due to environmental exposures such as unhealthy diet or smoking. Lately, the microbes living in and on our body have entered the stage as key players. But the role that gut microbes play in the development of colorectal cancer – the third most common cancer worldwide – is unclear. To determine their influence, association studies have aimed to map how the microbes colonizing the gut of colorectal cancer patients are different from those that inhabit healthy subjects.
Now, researchers from University of Copenhagen, EMBL, the University of Trento, and their international collaborators have analysed multiple existing microbiome association studies of colorectal cancer together with newly generated data. Their meta-analyses establish disease-specific microbiome changes, which are globally robust – consistent across seven countries on three continents – despite differences in environment, diet and life style.
“During disease our microbiome may change. If these changes are consistent in each person getting the same disease then it is a signature of disease. What we show in our study is that the gut microbiome signatures in colorectal cancer seem to be universal. This is despite geography, culture and life style. In the future we hope we can use these signatures as biomarkers and as a diagnostic tool for colorectal cancer,” says Manimozhiyan Arumugam, Associate Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research.
It is the first time a meta-analyses for colorectal cancer has been done on this scale. In the study, the researchers have analyzed and used data from seven cohorts from the countries China, Austria, France, Germany, the US, Italy and Japan.
“We used a rigorous machine learning analysis to identify microbial signatures for colorectal cancer. We validated these signatures in early cancer stages and in multiple studies, so they can serve as the basis for future non-invasive cancer screening,” explains Georg Zeller from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany.
University of Copenhagen https://tinyurl.com/y4mx25au