About 10 percent of kids born with kidney defects have large alterations in their genomes known to be linked with neuro-developmental delay and mental illness, a new study by Columbia University Medical Center (CUMC) researchers has shown.
Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the US and are present in about 1 in every 200 births. Eventually, an evaluation for genomic alterations will be part of the standard clinical workup. Patients with congenital kidney disease—who are currently lumped into one category—will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis.
‘This changes the way we should handle these kids,’ said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital.’
‘If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neuro-developmental delay or mental illness later in life,’ he said. ‘This is a major opportunity for personalising medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.’
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC’s Department of Medicine.
Until now, no studies have linked congenital kidney disease with neuro-developmental disorders.
‘If you talk to clinicians, they tell you that some of these kids behave differently,’ Dr. Sanna-Cherchi said. ‘There has been a general assumption, though, that behavioural or cognitive issues in children with chronic illnesses such as kidney disease stem from the child’s difficulty in coping with the illness. Our study suggests that in some cases, neuro-developmental issues may be attributable to an underlying genomic disorder, not the kidney disease.’
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the ‘dose’ of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
Until the mid-2000s, when effective techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders—including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centres in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said.
University of Columbia
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Unfortunately, newspaper articles about young athletes dying suddenly on the field are not unheard of. Such reports fuel discussions about compulsory screening, for example of young footballers, for heart failure. Research by scientists from Ghent (VIB/UGent) and Italy will benefit these screening methods. They have discovered a link between mutations in a certain gene and the heart condition Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).
ARVC is a hereditary heart condition in which the heart muscle (particularly the right ventricle) is partly replaced by fatty tissue and connective tissue. Cardiac arrhythmias can occur as a result of the changes in the heart muscle. Severe arrhythmias can cause dizziness or even lead to fainting or an acute cardiac arrest (= sudden death). ARVC is a progressive disease that usually presents during the teenage years.
Mutations in various genes have already been linked to ARVC. These are primarily genes that are responsible for the production of proteins in the desmosomes. Desmosomes are structures in the heart that ensure that the heart muscle cells remain connected to each other. Therefore, it was assumed that defects in the desmosomes were the most important factors in developing ARVC.
Together with Italian scientists, Jolanda van Hengel, studied patients with ARVC who did not exhibit mutations in the desmosomal genes. The scientists identified mutations in the CTNNA3 gene in these patients, which codes for the protein αT-catenin – a component of the area composita. The area composita is a structure specifically modified to the heart, where extra strong connections between cardiac muscle cells occur.
The scientists’ findings indicate that there is a link between mutations in the CTNNA3 gene and ARVC. It was demonstrated for the first time that – in addition to desmosomal genes – an area composita gene also plays a role in the development of ARVC. Future genetic screening tests for ARVC should include the CTNNA3 gene as a standard part of the test. This would increase the value of the screening.
VIB
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Hot flushes are not ‘in the head,’ but new research suggests they may start there. A UA research team has identified a region in the brain that may trigger the uncomfortable surges of heat most women experience in the first few years of menopause.
Hot flushes – also called hot flashes – affect millions of people, and not just women. Yet, it is still unclear what causes the episodes of temperature discomfort, often accompanied by profuse sweating.
Now a team of researchers around Dr. Naomi Rance, a professor in the department of pathology at the UA College of Medicine, has come closer to understanding the mechanism of hot flushes, a necessary step for potential treatment options down the road.
The team identified a group of brain cells known as KNDy neurons as a likely control switch of hot flushes. KNDy neurons (pronounced ‘candy’) are located in the hypothalamus, a portion of the brain controlling vital functions that also serves as the switchboard between the central nervous system and hormone signals.
‘Although the KNDy neurons are a very small population of cells, our research reveals that they play extremely important roles in how the body controls its energy resources, reproduction and temperature,’ said Melinda Mittelman-Smith, who led the study as part of her doctoral thesis. ‘They are true multitaskers.’
By studying KNDy neurons in rats, the research team created an animal model of menopause to elucidate the biological mechanisms of temperature control in response to withdrawal of the hormone oestrogen, the main trigger of the changes that go along with menopause.
They discovered that tail skin temperature was consistently lower in rats whose KNDy neurons were inactivated, suggesting the neurons control a process known as vasodilation, or widening of the blood vessels to increase blood flow through the skin.
‘The hallmark of hot flushes is vasodilation,’ explained Rance, who also is a neuropathologist at The University of Arizona Medical Center. ‘When you flush, your skin gets hot and you can see the redness of the skin. It is an attempt of the body to get rid of heat, just like sweating. Except that if you were to measure core temperature at that point, you would find it is not even elevated.’
Although the results are not yet directly applicable in helping individuals affected by hot flushes, they mark a necessary first step, Rance said.
‘Obviously we can’t do these studies in women, and only if we understand the mechanism is there a chance of developing therapies. All that is known so far is that dwindling estrogen levels have something to do with it but anything after that is a black box.’
University of Arizona
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A research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper. The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as ‘astrocyte activation.’ The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial.
University of Kentucky
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New research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection.
George Washington University
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A review in the December issue of the journal Archives of Pathology & Laboratory Medicine by Paul Bunn Jr, MD, University of Colorado Cancer Center investigator and past president of ASCO, IASLC and AACI describes the current state of lung cancer care.
‘We’re in a new paradigm in which we realize this top cause of cancer deaths is actually a number of related diseases, each potentially with its own cause and cure,’ Bunn says.
The review describes the shift from blanketing lung cancer with radiation and chemotherapy, to targeting the specific genetic mutations that cause lung cancer’s many varieties. The first of these oncogenic lung cancer mutations to be exploited by a drug was the epidermal growth factor receptor (EGFR), described in 2004 and targeted by the drugs erlotinib and gefitinib. Then in 2007 the oncogenic ALK/EML4 fusion protein was described, and is now targeted by the drug crizotinib, which earned FDA approval in 2011. Drugs in the development pipeline target a handful of additional lung-cancer-causing mutations including KRAS, HER2/neu, BRAF, NRAF, and ROS.
‘Pathologists used to define lung cancer as one of four types, based on its appearance,’ Bunn says, ‘but it’s much more heterogenous than that. Some of these driver mutations may only be present in 1 or 2 percent of the lung cancer population, and mutations in combination may make for hundreds of species of the disease, each with its own response characteristics to targeted drugs and drug combinations.’
‘Whole exome sequencing shows there are about 300 mutations in the average lung cancer,’ Bunn says. ‘You may have an EGFR mutation driving the cancer, but then the other 299 mutations may help define who will do well on an EGFR inhibitor.’
Bunn points out that in the lung cancer varieties whose driver oncogenes can be matched with targeted therapy, we tend to see 70-80 percent patient response as opposed to 20-30 percent response to traditional chemotherapies, and with much reduced side effects.
But with this great promise of picking off cancer varieties one-by-one according to their oncogenes comes the challenge of testing drugs that are effective in perhaps only one of every 100 lung cancer patients. The challenge is twofold: enrolling enough patients on a clinical trial to make the results meaningful, and securing funding for a trial in which the drug will only be marketable to a small slice of the lung cancer population.
‘How do you get drug approvals for what we’d normally call orphan diseases?’ Bunn asks.
Then, Bunn points to the major challenge of staying ahead of lung cancer as it mutates in response to these targeted first-line drugs. ‘Targeted therapies don’t cure patients yet,’ Bunn says. Instead, lung cancer eventually mutates around the drug’s effectiveness. ‘And so we have to discover the most rational combinations and see if these combinations allow complete response,’ Bunn says.
In addition to therapies targeting oncogenes, Bunn describes completely new approaches to treating the disease, including Phase III clinical trials of lung cancer vaccines that aid the body’s immune response against the cancer, and the search for ways to promote the function of tumour-suppressor genes that are commonly turned off in cancers.
What is clear is that after many years of chemotherapy and radiation, we’re in the midst of an explosion in novel lung cancer treatment options.
University of Colorado Cancer Center
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Oxidative stress is believed to cause a number of diseases. Up to now, it has been common practice to measure oxidative stress levels by determining the oxidation state of a small molecule called glutathione in cell extracts. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have been the first to discover that cells under stress deposit their oxidised glutathione in a cellular waste repository. This protects cells from oxidative stress – and questions the validity of the conventional measuring method.
Cancer, Alzheimer’s, arteriosclerosis– the list of diseases which have been linked to oxidative stress is long and even includes the very process of ageing. Oxidative stress is caused by so-called reactive oxygen compounds, which include the notorious ‘free radicals’. If a cell is exposed to more reactive oxygen compounds than it can instantly degrade, it is under oxidative stress. As a result, important components such as proteins, DNA and lipids are oxidised and thus get damaged.
To determine whether a cell is under oxidative stress, scientists often analyse the oxidation state of glutathione. Glutathione is a small molecule which gets oxidised to protect the cell from reactive oxygen compounds. In theory, the amount of oxidised glutathione should therefore indicate whether a cell is healthy or under oxidative stress. However, researchers in the team of Associate Professor (PD) Dr. Tobias Dick have demonstrated that this hypothesis, which is the basis of a large number of scientific studies, is deceptive.
‘Up to now, it was necessary to destroy the cells in order to measure the amount of oxidised glutathione,’ Tobias Dick explains. ‘However, this means that any spatial resolution is lost.’ Therefore, virtually nothing was known about where exactly oxidised glutathione is found in the cells. Scientists have presumed that it remains in the cytoplasm, where it is formed.
To find out more about the whereabouts of glutathione in the cell, Tobias Dick and co-workers developed biosensors which indicate the oxidation state of glutathione in intact cells by releasing light signals. In yeast cells, the researchers were able, for the first time, to follow the path of oxidised glutathione through the living cell in real time. They were surprised to find that, rather than remaining in the cytoplasm, it promptly gets locked up in a safe depot, the vacuole.
The cytoplasm, where all important cellular metabolic processes happen, is thus reliably protected from oxidative damage. Cells that would have been considered to be under oxidative stress using the conventional method appeared entirely healthy in their cytoplasm. Tobias Dick and his team could subsequently show that this is not only true for yeast cells but also for various mammalian cells and also for cancer cells.
These results mean that – contrary to previously held beliefs – the level of oxidative glutathione does not indicate whether or not a cell is under oxidative stress. ‘Therefore, it is important to re-evaluate prior studies that have established a link between oxidative stress and various diseases based on the conventional method.’
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
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There’s a reason emergency personnel train for the aftermath of a dirty bomb or an explosion at a nuclear power plant. They’ll be faced with a deluge of urgent tasks, such as identifying who’s been irradiated, who has an injury-induced infection, and who’s suffering from both.
Unfortunately, there isn’t a quick way to screen for people exposed to dangerous levels of radiation. There also isn’t a quick way to distinguish between people suffering from radiation exposure versus an infection due to an injury or chemical exposure.
The most common way to measure exposure is a blood assay that tracks chromosomal changes. Another approach is to watch for the onset of physical symptoms. But these methods can take several days to provide results, which is far too late to identify people who’d benefit from immediate treatment.
A much faster way could be coming. Research conducted by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) could lead to a blood test that detects if a person has been exposed to radiation, measures their dose, and separates people suffering from inflammation injuries—all in a matter of hours.
The scientists identified eight DNA-repair genes in human blood whose expression responses change more than twofold soon after blood is exposed to radiation. They also learned how these genes respond when blood is exposed to inflammation stress, which can occur because of an injury or infection. Inflammation can mimic the effects of radiation and lead to false diagnoses.
The result is a panel of biochemical markers that can discriminate between blood samples exposed to radiation, inflammation, or both. The scientists believe these markers could be incorporated into a blood test that quickly triages people involved in radiation-related incidents.
‘In an emergency involving radiation exposure, it’s likely that only a small fraction of all possibly exposed people will be exposed to high doses that require immediate medical attention,’ says Andy Wyrobek of Berkeley Lab’s Life Sciences Division. ‘The goal is to quickly screen for these people so they can get treatment, and avoid overwhelming medical facilities with the larger number of people exposed to low levels of radiation with no immediate medical needs. Our research could lead to a blood test that enables this.’
Wyrobek conducted the research with fellow Berkeley Lab scientists Helen Budworth and Antoine Snijders, as well as several other scientists from Berkeley Lab and other institutions.
Because DNA is one of the major targets of radiation, the Berkeley Lab scientists began their research by focusing on 40 genes that regulate the expression of proteins that carry out DNA-repair tasks. They studied these genes in blood samples taken from healthy people before and after exposing the samples to 2 Gray of X-rays per year, which is about the radiation dose received by radiotherapy patients. They found twelve genes that underwent more than a twofold change in response after exposure. From these, they isolated eight genes that had no overlap between unirradiated and irradiated samples.
The scientists also treated the blood samples with a compound that mimics inflammatory stress. This enabled them to account for gene-expression responses that could be mistaken for signs of radiation exposure, but which are actually caused by injury or infection. In addition, they irradiated a portion of these samples to learn how the genes respond to both inflammation and radiation.
To validate their findings, the scientists analysed a separate dataset of blood samples that had also been irradiated. They found a close match between their own data and the independent dataset in how the eight genes respond after radiation exposure.
They also compared their findings to a large group of bone marrow transplant patients who received total-body radiation. Again, they found a close match between their data and the gene-expression responses of the patients after they received treatment.
More work is needed, but Wyrobek envisions a blood test using their biochemical markers could be administered via a handheld device similar to what diabetes patients use to check their blood sugar. The test could help emergency personnel quickly identify people exposed to high radiation doses who need immediate care, and people exposed to lower doses who only need long-term monitoring.
Lawrence Berkeley National Laboratory
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Scientists from the RIKEN Advanced Science Institute in Japan and University of California Los Angeles report a new nanoscale Velcro-like device that captures and releases tumour cells that have broken away from primary tumours and are circulating in the bloodstream. This new nanotechnology could be used for cancer diagnosis and give insight into the mechanisms of how cancer spreads throughout the body. The device provides a convenient and non-invasive alternative to biopsy, the current method for diagnosis of metastatic cancer. It could enable doctors to detect tumour cells that circulate in cancer patients’ blood well before they subsequently colonise as tumours in other organs. The device also enables researchers to keep the tumour cells alive and subsequently study them.
Similar cell-capture devices have been reported but this technology is unique in that it is capable of catching the tumour cells with great efficiency and releasing them with great cell viability. Blood is passed through the device like a filter that contains a molecule capable of adhering to tumour cells like Velcro and separating them with efficiency ranging from 40% to 70%. The cancer cells are retained by tiny temperature-responsive polymer brushes inside the device. At 37 degrees Celsius, these polymer brushes stick to the tumour cells, but when cooled to 4 degrees Celsius, they release them, allowing scientists to examine the cells.
‘Until now, most devices have demonstrated the ability to capture circulating tumor cells with high efficiency. However, it is equally important to release these captured cells, to preserve and study them in order to obtain insightful information about them. This is the big difference with our device.’ Explains Hsiao-hua Yu, who led the team that developed the technique to coat the device with polymer brushes.
RIKEN
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In a study, researchers from Monash University tracked the movements of white blood cells, or leukocytes, leading to a new understanding of their behaviour in both healthy and diseased kidneys.
Leukocytes play important protective roles in the body’s immune system, but in some cases they cause damaging inflammation. Glomerulonephritis is an inflammatory disease of the kidney that can lead to the need for transplantation or regular dialysis. More than 20 per cent of end-stage renal failure cases result from glomerulonephritis.
Lead researcher, Associate Professor Michael Hickey of the University’s Centre for Inflammatory Diseases in the Department of Medicine said the team used advanced microscopy techniques to visualise the movements of leukocytes through the kidney.
‘In order to manipulate a system, you must understand it. Now, we have a really clear understanding of the disease process and the molecules involved in the key steps,’ Associate Professor Hickey said.
‘Contrary to conventional medical and scientific opinion, we found that leukocytes are constantly circulating through and patrolling the blood vessels within healthy kidneys. It was previously believed that they only arrived in the kidney during the development of disease. That’s not the case. However, during disease they linger in the kidney during the course of their normal journey, become agitated and cause inflammation and kidney damage.’
End-stage renal failure leads to significant health and personal impacts, including ongoing visits to a dialysis unit several times a week, or a significant wait for a donor.
Renal Physician and co-investigator Professor Richard Kitching said therapies to effectively target glomerulonephritis were needed before end-stage was reached.
‘The treatments we have can be fairly effective, but they are non-specific and they often have unacceptable side effects,’ Professor Kitching said.
‘Currently, we have to suppress the immune system to combat the inflammation and this immunosuppression leaves the body more prone to infections. Additionally, some of the drugs have metabolic side effects, such as weight gain and bone thinning.
‘Now we have a better understanding of how the disease develops, we can identify targets for more specific drugs, with fewer side-effects.’
Monash University
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Surprising link between kidney defects and neuro-developmental disorders in kids
, /in E-News /by 3wmediaAbout 10 percent of kids born with kidney defects have large alterations in their genomes known to be linked with neuro-developmental delay and mental illness, a new study by Columbia University Medical Center (CUMC) researchers has shown.
Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the US and are present in about 1 in every 200 births. Eventually, an evaluation for genomic alterations will be part of the standard clinical workup. Patients with congenital kidney disease—who are currently lumped into one category—will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis.
‘This changes the way we should handle these kids,’ said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital.’
‘If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neuro-developmental delay or mental illness later in life,’ he said. ‘This is a major opportunity for personalising medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.’
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC’s Department of Medicine.
Until now, no studies have linked congenital kidney disease with neuro-developmental disorders.
‘If you talk to clinicians, they tell you that some of these kids behave differently,’ Dr. Sanna-Cherchi said. ‘There has been a general assumption, though, that behavioural or cognitive issues in children with chronic illnesses such as kidney disease stem from the child’s difficulty in coping with the illness. Our study suggests that in some cases, neuro-developmental issues may be attributable to an underlying genomic disorder, not the kidney disease.’
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the ‘dose’ of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
Until the mid-2000s, when effective techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders—including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centres in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said. University of Columbia
Discovery in Ghent could improve screening for sudden cardiac death
, /in E-News /by 3wmediaUnfortunately, newspaper articles about young athletes dying suddenly on the field are not unheard of. Such reports fuel discussions about compulsory screening, for example of young footballers, for heart failure. Research by scientists from Ghent (VIB/UGent) and Italy will benefit these screening methods. They have discovered a link between mutations in a certain gene and the heart condition Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).
ARVC is a hereditary heart condition in which the heart muscle (particularly the right ventricle) is partly replaced by fatty tissue and connective tissue. Cardiac arrhythmias can occur as a result of the changes in the heart muscle. Severe arrhythmias can cause dizziness or even lead to fainting or an acute cardiac arrest (= sudden death). ARVC is a progressive disease that usually presents during the teenage years.
Mutations in various genes have already been linked to ARVC. These are primarily genes that are responsible for the production of proteins in the desmosomes. Desmosomes are structures in the heart that ensure that the heart muscle cells remain connected to each other. Therefore, it was assumed that defects in the desmosomes were the most important factors in developing ARVC.
Together with Italian scientists, Jolanda van Hengel, studied patients with ARVC who did not exhibit mutations in the desmosomal genes. The scientists identified mutations in the CTNNA3 gene in these patients, which codes for the protein αT-catenin – a component of the area composita. The area composita is a structure specifically modified to the heart, where extra strong connections between cardiac muscle cells occur.
The scientists’ findings indicate that there is a link between mutations in the CTNNA3 gene and ARVC. It was demonstrated for the first time that – in addition to desmosomal genes – an area composita gene also plays a role in the development of ARVC. Future genetic screening tests for ARVC should include the CTNNA3 gene as a standard part of the test. This would increase the value of the screening. VIB
What causes hot flushes during menopause?
, /in E-News /by 3wmediaHot flushes are not ‘in the head,’ but new research suggests they may start there. A UA research team has identified a region in the brain that may trigger the uncomfortable surges of heat most women experience in the first few years of menopause.
Hot flushes – also called hot flashes – affect millions of people, and not just women. Yet, it is still unclear what causes the episodes of temperature discomfort, often accompanied by profuse sweating.
Now a team of researchers around Dr. Naomi Rance, a professor in the department of pathology at the UA College of Medicine, has come closer to understanding the mechanism of hot flushes, a necessary step for potential treatment options down the road.
The team identified a group of brain cells known as KNDy neurons as a likely control switch of hot flushes. KNDy neurons (pronounced ‘candy’) are located in the hypothalamus, a portion of the brain controlling vital functions that also serves as the switchboard between the central nervous system and hormone signals.
‘Although the KNDy neurons are a very small population of cells, our research reveals that they play extremely important roles in how the body controls its energy resources, reproduction and temperature,’ said Melinda Mittelman-Smith, who led the study as part of her doctoral thesis. ‘They are true multitaskers.’
By studying KNDy neurons in rats, the research team created an animal model of menopause to elucidate the biological mechanisms of temperature control in response to withdrawal of the hormone oestrogen, the main trigger of the changes that go along with menopause.
They discovered that tail skin temperature was consistently lower in rats whose KNDy neurons were inactivated, suggesting the neurons control a process known as vasodilation, or widening of the blood vessels to increase blood flow through the skin.
‘The hallmark of hot flushes is vasodilation,’ explained Rance, who also is a neuropathologist at The University of Arizona Medical Center. ‘When you flush, your skin gets hot and you can see the redness of the skin. It is an attempt of the body to get rid of heat, just like sweating. Except that if you were to measure core temperature at that point, you would find it is not even elevated.’
Although the results are not yet directly applicable in helping individuals affected by hot flushes, they mark a necessary first step, Rance said.
‘Obviously we can’t do these studies in women, and only if we understand the mechanism is there a chance of developing therapies. All that is known so far is that dwindling estrogen levels have something to do with it but anything after that is a black box.’
University of ArizonaUK team inhibits Alzheimer’s biomarkers in animal model by targeting astrocytes
, /in E-News /by 3wmediaA research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper. The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as ‘astrocyte activation.’ The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial. University of Kentucky
New research helps predict susceptibility to Burkitt Lymphoma
, /in E-News /by 3wmediaNew research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection. George Washington University
The current state of lung cancer treatment
, /in E-News /by 3wmediaA review in the December issue of the journal Archives of Pathology & Laboratory Medicine by Paul Bunn Jr, MD, University of Colorado Cancer Center investigator and past president of ASCO, IASLC and AACI describes the current state of lung cancer care.
‘We’re in a new paradigm in which we realize this top cause of cancer deaths is actually a number of related diseases, each potentially with its own cause and cure,’ Bunn says.
The review describes the shift from blanketing lung cancer with radiation and chemotherapy, to targeting the specific genetic mutations that cause lung cancer’s many varieties. The first of these oncogenic lung cancer mutations to be exploited by a drug was the epidermal growth factor receptor (EGFR), described in 2004 and targeted by the drugs erlotinib and gefitinib. Then in 2007 the oncogenic ALK/EML4 fusion protein was described, and is now targeted by the drug crizotinib, which earned FDA approval in 2011. Drugs in the development pipeline target a handful of additional lung-cancer-causing mutations including KRAS, HER2/neu, BRAF, NRAF, and ROS.
‘Pathologists used to define lung cancer as one of four types, based on its appearance,’ Bunn says, ‘but it’s much more heterogenous than that. Some of these driver mutations may only be present in 1 or 2 percent of the lung cancer population, and mutations in combination may make for hundreds of species of the disease, each with its own response characteristics to targeted drugs and drug combinations.’
‘Whole exome sequencing shows there are about 300 mutations in the average lung cancer,’ Bunn says. ‘You may have an EGFR mutation driving the cancer, but then the other 299 mutations may help define who will do well on an EGFR inhibitor.’
Bunn points out that in the lung cancer varieties whose driver oncogenes can be matched with targeted therapy, we tend to see 70-80 percent patient response as opposed to 20-30 percent response to traditional chemotherapies, and with much reduced side effects.
But with this great promise of picking off cancer varieties one-by-one according to their oncogenes comes the challenge of testing drugs that are effective in perhaps only one of every 100 lung cancer patients. The challenge is twofold: enrolling enough patients on a clinical trial to make the results meaningful, and securing funding for a trial in which the drug will only be marketable to a small slice of the lung cancer population.
‘How do you get drug approvals for what we’d normally call orphan diseases?’ Bunn asks.
Then, Bunn points to the major challenge of staying ahead of lung cancer as it mutates in response to these targeted first-line drugs. ‘Targeted therapies don’t cure patients yet,’ Bunn says. Instead, lung cancer eventually mutates around the drug’s effectiveness. ‘And so we have to discover the most rational combinations and see if these combinations allow complete response,’ Bunn says.
In addition to therapies targeting oncogenes, Bunn describes completely new approaches to treating the disease, including Phase III clinical trials of lung cancer vaccines that aid the body’s immune response against the cancer, and the search for ways to promote the function of tumour-suppressor genes that are commonly turned off in cancers.
What is clear is that after many years of chemotherapy and radiation, we’re in the midst of an explosion in novel lung cancer treatment options. University of Colorado Cancer Center
Preventive detention for oxidising agents
, /in E-News /by 3wmediaOxidative stress is believed to cause a number of diseases. Up to now, it has been common practice to measure oxidative stress levels by determining the oxidation state of a small molecule called glutathione in cell extracts. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have been the first to discover that cells under stress deposit their oxidised glutathione in a cellular waste repository. This protects cells from oxidative stress – and questions the validity of the conventional measuring method.
Cancer, Alzheimer’s, arteriosclerosis– the list of diseases which have been linked to oxidative stress is long and even includes the very process of ageing. Oxidative stress is caused by so-called reactive oxygen compounds, which include the notorious ‘free radicals’. If a cell is exposed to more reactive oxygen compounds than it can instantly degrade, it is under oxidative stress. As a result, important components such as proteins, DNA and lipids are oxidised and thus get damaged.
To determine whether a cell is under oxidative stress, scientists often analyse the oxidation state of glutathione. Glutathione is a small molecule which gets oxidised to protect the cell from reactive oxygen compounds. In theory, the amount of oxidised glutathione should therefore indicate whether a cell is healthy or under oxidative stress. However, researchers in the team of Associate Professor (PD) Dr. Tobias Dick have demonstrated that this hypothesis, which is the basis of a large number of scientific studies, is deceptive.
‘Up to now, it was necessary to destroy the cells in order to measure the amount of oxidised glutathione,’ Tobias Dick explains. ‘However, this means that any spatial resolution is lost.’ Therefore, virtually nothing was known about where exactly oxidised glutathione is found in the cells. Scientists have presumed that it remains in the cytoplasm, where it is formed.
To find out more about the whereabouts of glutathione in the cell, Tobias Dick and co-workers developed biosensors which indicate the oxidation state of glutathione in intact cells by releasing light signals. In yeast cells, the researchers were able, for the first time, to follow the path of oxidised glutathione through the living cell in real time. They were surprised to find that, rather than remaining in the cytoplasm, it promptly gets locked up in a safe depot, the vacuole.
The cytoplasm, where all important cellular metabolic processes happen, is thus reliably protected from oxidative damage. Cells that would have been considered to be under oxidative stress using the conventional method appeared entirely healthy in their cytoplasm. Tobias Dick and his team could subsequently show that this is not only true for yeast cells but also for various mammalian cells and also for cancer cells.
These results mean that – contrary to previously held beliefs – the level of oxidative glutathione does not indicate whether or not a cell is under oxidative stress. ‘Therefore, it is important to re-evaluate prior studies that have established a link between oxidative stress and various diseases based on the conventional method.’ The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Scientists developing quick way to ID people exposed to ionising radiation
, /in E-News /by 3wmediaThere’s a reason emergency personnel train for the aftermath of a dirty bomb or an explosion at a nuclear power plant. They’ll be faced with a deluge of urgent tasks, such as identifying who’s been irradiated, who has an injury-induced infection, and who’s suffering from both.
Unfortunately, there isn’t a quick way to screen for people exposed to dangerous levels of radiation. There also isn’t a quick way to distinguish between people suffering from radiation exposure versus an infection due to an injury or chemical exposure.
The most common way to measure exposure is a blood assay that tracks chromosomal changes. Another approach is to watch for the onset of physical symptoms. But these methods can take several days to provide results, which is far too late to identify people who’d benefit from immediate treatment.
A much faster way could be coming. Research conducted by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) could lead to a blood test that detects if a person has been exposed to radiation, measures their dose, and separates people suffering from inflammation injuries—all in a matter of hours.
The scientists identified eight DNA-repair genes in human blood whose expression responses change more than twofold soon after blood is exposed to radiation. They also learned how these genes respond when blood is exposed to inflammation stress, which can occur because of an injury or infection. Inflammation can mimic the effects of radiation and lead to false diagnoses.
The result is a panel of biochemical markers that can discriminate between blood samples exposed to radiation, inflammation, or both. The scientists believe these markers could be incorporated into a blood test that quickly triages people involved in radiation-related incidents.
‘In an emergency involving radiation exposure, it’s likely that only a small fraction of all possibly exposed people will be exposed to high doses that require immediate medical attention,’ says Andy Wyrobek of Berkeley Lab’s Life Sciences Division. ‘The goal is to quickly screen for these people so they can get treatment, and avoid overwhelming medical facilities with the larger number of people exposed to low levels of radiation with no immediate medical needs. Our research could lead to a blood test that enables this.’
Wyrobek conducted the research with fellow Berkeley Lab scientists Helen Budworth and Antoine Snijders, as well as several other scientists from Berkeley Lab and other institutions.
Because DNA is one of the major targets of radiation, the Berkeley Lab scientists began their research by focusing on 40 genes that regulate the expression of proteins that carry out DNA-repair tasks. They studied these genes in blood samples taken from healthy people before and after exposing the samples to 2 Gray of X-rays per year, which is about the radiation dose received by radiotherapy patients. They found twelve genes that underwent more than a twofold change in response after exposure. From these, they isolated eight genes that had no overlap between unirradiated and irradiated samples.
The scientists also treated the blood samples with a compound that mimics inflammatory stress. This enabled them to account for gene-expression responses that could be mistaken for signs of radiation exposure, but which are actually caused by injury or infection. In addition, they irradiated a portion of these samples to learn how the genes respond to both inflammation and radiation.
To validate their findings, the scientists analysed a separate dataset of blood samples that had also been irradiated. They found a close match between their own data and the independent dataset in how the eight genes respond after radiation exposure.
They also compared their findings to a large group of bone marrow transplant patients who received total-body radiation. Again, they found a close match between their data and the gene-expression responses of the patients after they received treatment.
More work is needed, but Wyrobek envisions a blood test using their biochemical markers could be administered via a handheld device similar to what diabetes patients use to check their blood sugar. The test could help emergency personnel quickly identify people exposed to high radiation doses who need immediate care, and people exposed to lower doses who only need long-term monitoring. Lawrence Berkeley National Laboratory
New technology allows scientists to capture and preserve cancer cells circulating in the bloodstream
, /in E-News /by 3wmediaScientists from the RIKEN Advanced Science Institute in Japan and University of California Los Angeles report a new nanoscale Velcro-like device that captures and releases tumour cells that have broken away from primary tumours and are circulating in the bloodstream. This new nanotechnology could be used for cancer diagnosis and give insight into the mechanisms of how cancer spreads throughout the body. The device provides a convenient and non-invasive alternative to biopsy, the current method for diagnosis of metastatic cancer. It could enable doctors to detect tumour cells that circulate in cancer patients’ blood well before they subsequently colonise as tumours in other organs. The device also enables researchers to keep the tumour cells alive and subsequently study them.
Similar cell-capture devices have been reported but this technology is unique in that it is capable of catching the tumour cells with great efficiency and releasing them with great cell viability. Blood is passed through the device like a filter that contains a molecule capable of adhering to tumour cells like Velcro and separating them with efficiency ranging from 40% to 70%. The cancer cells are retained by tiny temperature-responsive polymer brushes inside the device. At 37 degrees Celsius, these polymer brushes stick to the tumour cells, but when cooled to 4 degrees Celsius, they release them, allowing scientists to examine the cells.
‘Until now, most devices have demonstrated the ability to capture circulating tumor cells with high efficiency. However, it is equally important to release these captured cells, to preserve and study them in order to obtain insightful information about them. This is the big difference with our device.’ Explains Hsiao-hua Yu, who led the team that developed the technique to coat the device with polymer brushes. RIKEN
Kidney failure under the microscope
, /in E-News /by 3wmediaIn a study, researchers from Monash University tracked the movements of white blood cells, or leukocytes, leading to a new understanding of their behaviour in both healthy and diseased kidneys.
Leukocytes play important protective roles in the body’s immune system, but in some cases they cause damaging inflammation. Glomerulonephritis is an inflammatory disease of the kidney that can lead to the need for transplantation or regular dialysis. More than 20 per cent of end-stage renal failure cases result from glomerulonephritis.
Lead researcher, Associate Professor Michael Hickey of the University’s Centre for Inflammatory Diseases in the Department of Medicine said the team used advanced microscopy techniques to visualise the movements of leukocytes through the kidney.
‘In order to manipulate a system, you must understand it. Now, we have a really clear understanding of the disease process and the molecules involved in the key steps,’ Associate Professor Hickey said.
‘Contrary to conventional medical and scientific opinion, we found that leukocytes are constantly circulating through and patrolling the blood vessels within healthy kidneys. It was previously believed that they only arrived in the kidney during the development of disease. That’s not the case. However, during disease they linger in the kidney during the course of their normal journey, become agitated and cause inflammation and kidney damage.’
End-stage renal failure leads to significant health and personal impacts, including ongoing visits to a dialysis unit several times a week, or a significant wait for a donor.
Renal Physician and co-investigator Professor Richard Kitching said therapies to effectively target glomerulonephritis were needed before end-stage was reached.
‘The treatments we have can be fairly effective, but they are non-specific and they often have unacceptable side effects,’ Professor Kitching said.
‘Currently, we have to suppress the immune system to combat the inflammation and this immunosuppression leaves the body more prone to infections. Additionally, some of the drugs have metabolic side effects, such as weight gain and bone thinning.
‘Now we have a better understanding of how the disease develops, we can identify targets for more specific drugs, with fewer side-effects.’ Monash University