Scientists from the University of Iowa and Brigham Young University (BYU) have identified a gene that may be a target for overcoming drug resistance in cancer. The finding could not only improve prognostic and diagnostic tools for evaluating cancer and monitoring patients’ response to treatment but also could lead to new therapies directed at eradicating drug-resistant cancer cells.
Drug resistance is a common problem in many metastatic cancers. It leads to failure of chemotherapy treatments and is associated with poor patient outcomes, including rapid relapse and death.
Fenghuang Zhan, Ph.D.The research team, including Fenghuang (Frank) Zhan, M.D., Ph.D., and Guido Tricot, M.D., Ph.D., from the UI, and David Bearss, Ph.D., from BYU, initially focused on identifying genes linked to the development of drug resistance in multiple myeloma, a bone marrow cancer that affects more than 20,000 Americans and causes almost 11,000 deaths annually.
Working with serial biopsied cells from 19 myeloma patients, the researchers analysed genetic changes in the cells that occurred over the course of treatment with very intensive chemotherapy drugs. This approach identified a gene called NEK2 that is strongly associated with increased drug-resistance, faster cancer growth, and poorer survival for patients.
Guido Tricot, M.D., Ph.D.Having established the relationship between high expression of the NEK2 gene and poor patient outcome in myeloma, the team then examined the relationship in other common cancers—including breast, lung, and bladder cancer—by analysing gene expression profiles from 2,500 patients’ cells with eight different cancers in Zhan’s lab.
Taking the findings back to the lab, the team then examined the effect on cancer cells of either enhancing or blocking the expression of the NEK2 gene. "In all cases, an increase in the NEK2 gene was associated with rapid death of the patient," says Tricot, who is director of Holden Comprehensive Cancer Center’s Bone Marrow Transplant and Myeloma Program at UI Hospitals and Clinics. "So this finding was not unique to myeloma; this is basically seen in every single cancer we looked at."
The research team is now developing compounds to inhibit NEK2 by collaborating with David Bearss, Ph.D., associate professor of physiology and developmental biology at BYU, in the hope that these compounds may overcome drug resistance in cancer cells. "Our studies show that over-expression of NEK2 in cancer cells significantly enhances the activity of drug efflux proteins to pump chemotherapy drugs out of cells, resulting in drug resistance. Furthermore, silencing NEK2 in cancer cells potently decreased drug resistance, induced cell-cycle arrest, cell death, and inhibited cancer cell growth in vitro and in vivo," says Zhan, UI professor of internal medicine.
“We were able to show that if we inhibit NEK2, then we can actually restore sensitivity to drugs that we use right now,” Bearss says.
Although development and clinical testing of such drugs for use in patients is not imminent, Tricot notes that the findings may have clinical use within the next several years.
"NEK2 expression may be a diagnostic or prognostic marker for drug-resistant cancer," he says. "If NEK2 is high, that would suggest that the prognosis is poorer and the patient might benefit from more aggressive treatment. The other potential use is for monitoring the cancer’s response to therapy. If NEK2 levels increase, that would suggest development of increased drug resistance and might indicate that a change of treatment would be helpful."University of Iowa Health Care
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Breast cancer is the second leading cause of cancer deaths among women in the United States. Many of these deaths occur when there is an initial diagnosis of invasive or metastatic disease. A protein called NEDD9—which regulates cell migration, division and survival—has been linked to tumour invasion and metastasis in a variety of cancers. Researchers at Fox Chase Cancer Center have now shown that NEDD9 plays a surprising role in the early stages of breast tumour development by controlling the growth of progenitor cells that give rise to tumours. The findings could lead to personalised treatment strategies for women with breast cancer based on the levels of NEDD9 in their tumours.
"For several years, NEDD9 has been linked to tumour metastasis and invasion at later stages. This is the first study that really shows how important NEDD9 can be for the initiation of tumours in breast cancer, and to link this initiation process to progenitor cells," says lead study author Joy Little, PhD, a postdoctoral fellow at Fox Chase who works in the laboratory of senior study investigator Erica A. Golemis, PhD, Deputy Chief Scientific Officer and Vice President at Fox Chase.
In the study, Little, Golemis and their collaborators mated mice without the NEDD9 gene to mice engineered to develop HER2+ mammary tumours and unexpectedly found that these mice were largely resistant to tumour formation. Only 18% of the mice developed mammary tumours, compared with 80% of mice that had a functional NEDD9 gene. In contrast to previous research findings showing that an increase in NEDD9 levels promotes tumour aggressiveness, the researchers found that loss of NEDD9 had little effect on tumour metastasis, indicating that it is not required for this process in this specific context. Once formed, the tumours in mice lacking NEDD9 grew rapidly, suggesting that it either plays a less important role at later stages of tumour growth or tumours undergo compensatory changes that allow them to bypass the need for NEDD9.
Importantly, mice lacking NEDD9 showed a significant reduction in progenitor cell populations in the mammary gland compared with mice that had a functional NEDD9 gene. Progenitor cells from NEDD9-null mice were less likely to form three-dimensional mammospheres in culture, but proliferated at the same rate as cells from control mice. The loss of Nedd9 also made progenitor cells more sensitive to lower doses of two tumour-inhibiting drugs—a Food and Drug Administration-approved Src inhibitor called dasatinib, and a focal adhesion kinase inhibitor from a class of drugs currently being tested in clinical trials for the treatment of cancer. These findings suggest that these types of drugs would more effectively control breast cancer tumours with low levels of NEDD9.
"Eventually, with a biopsy, you may be able to get a read-out of all the mutations that a tumour has, and each one would potentially dictate whether or not a certain line of therapy would work for a specific tumour," Little says. "If NEDD9 levels are higher in a particular tumour, we could potentially determine whether or not it would be more sensitive to specific inhibitors."Fox Chase Cancer Center
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Research led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukaemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukaemia, which is known as hypodiploid acute lymphoblastic leukaemia (ALL). Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterised by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumour has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbour. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbour inherited mutations in the TP53 tumour suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognised as a common manifestation of Li-Fraumeni syndrome.
Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterised by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
‘This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukaemia subtypes that we would otherwise have missed,’ said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organisation devoted exclusively to childhood and adolescent cancer research.
‘The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,’ said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. ‘This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukaemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.’
Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.
The whole genome sequencing was done in conjunction with the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.
Near haploid ALL was characterised by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.
Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumour suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumour suppressor gene.
About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.
Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brain tumour associated with Li-Fraumeni syndrome. His son later developed low hypodiploid ALL.
‘Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,’ said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. ‘Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,’ Holmfeldt said.
St. Jude Children’s Research Hospital
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A simple, inexpensive blood test performed on trauma patients upon admission can help doctors easily identify patients at greatest risk of death, according to a new study by researchers at Intermountain Medical Center.
The Intermountain Medical Center research study of more than 9,500 patients discovered that some trauma patients are up to 58 times more likely to die than others, regardless of the severity of their original injury.
Researchers say the study findings provide important insight into the long-term prognosis of trauma patients, something not previously well understood.
‘The results were very surprising,’ said Sarah Majercik, MD, an Intermountain Medical Center surgeon and trauma researcher, whose team discovered that a tool developed at Intermountain Medical Center, called the Intermountain Risk Score, can predict mortality among trauma patients.
The Intermountain Risk Score is a computerised tool available to physicians that combines factors like age, gender, and common blood tests known as the complete blood count (CBC) and the basic metabolic profile (BMP) to determine an individual’s mortality risk.
All of the components of the tool have been helpful in evaluating individuals with medical problems like heart failure or chronic pulmonary disease. But until now, the benefit of the tool had not been tested for trauma patients hospitalised due to an accident or traumatic injury, rather than an underlying condition.
‘As surgeons, we don’t often use all of the CBC results in evaluating a patient who needs surgery for a bleeding spleen or after a motor vehicle accident, said Dr. Majercik. ‘There are certain values, such as haemoglobin, hematocrit, and platelets that we scrutinise closely as part of good clinical care, but then other parts, such as the red blood cell distribution width (RDW) that we pay no attention to at all in the acute setting. These factors are generally overlooked, even though they are part of the CBC that every trauma patient gets when he or she arrives in the emergency room.’
Data from the Intermountain Risk Score tool will allow physicians to take additional precautions with patients who are at greatest risk, and also give doctors important information to consider when talking about prognosis with patients and families.
Dr. Majercik and her colleague Benjamin Horne, PhD, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute, reviewed the cases of 9,538 patients who had been admitted to the hospital with trauma during a six-year period.
Using the tool, the Intermountain Medical Center categorised patients according to high, moderate, and low risk levels. Some surprising findings:
High-risk men were nearly 58 times more likely to die within a year than low-risk men. Men with a moderate risk were nearly 13 times more likely to die than those with low risk.
High-risk women were 19 times more likely to die within a year than low-risk women. And women with moderate risk were five times more likely to die than those with low risk.
‘Some risk factors will be already apparent for physicians, but others aren’t intuitive,’ said Dr. Horne. For example, a trauma patient may look completely healthy apart from his or her injury. But if the Intermountain Risk Score tool uncovers an irregular red blood cell distribution width — a common sign of anaemia — that will increase his risk of dying.
‘It’s a standard part of the CBC test, but it’s not usually taken into consideration when treating a patient with injuries,’ said Dr. Horne. ‘Based on the findings of our research, it’s something that should be looked at as part of the care plan model.’
Dr. Majercik and Dr. Horne believe their research will give physicians a simple, fast way to better understand their patients’ condition, and may lead to new treatment approaches that could reduce the risk of death.
Intermountain Medical Center
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The risk of kidney failure is greater for people with chronic kidney disease who also have atrial fibrillation, one of the most common forms of irregular heart rhythm in adults, according to a new study by researchers at UCSF and the Kaiser Permanente Northern California Division of Research.
The finding opens the way for further studies into the relationship between the two factors, which could lead to new treatment approaches that would improve outcomes for people with chronic kidney disease.
Many people who suffer from chronic kidney disease progressively lose their kidney function over time and eventually develop a condition called end-stage renal disease – the complete failure of the kidneys – placing them in need of lifelong dialysis or a kidney transplant.
Doctors have known that patients with chronic kidney disease or end-stage renal disease commonly have atrial fibrillation and as a result are more likely to have a stroke or to die. However, the long-term impact of atrial fibrillation on kidney function among patients with known chronic kidney disease has been unknown.
The new study involved 206,229 adults with chronic kidney disease who were drawn from members of Kaiser Permanente Northern California, a large integrated health care delivery system.. Over the course of about five years, approximately 16,400 patients developed atrial fibrillation, and those who did were 67 percent more likely to progress to end-stage renal disease compared with patients who had chronic kidney disease but did not develop atrial fibrillation.
‘These novel findings expand on previous knowledge by highlighting that atrial fibrillation is linked to a worse kidney prognosis in patients with underlying kidney dysfunction,’ said kidney specialist Nisha Bansal, MD, an assistant professor in the Division of Nephrology at UCSF.
‘There is a knowledge gap about the long-term impact of atrial fibrillation on the risk of adverse kidney-related outcomes in patients with chronic kidney disease,’ said senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research. ‘This study addresses that gap and may have important implications for clinical management by providing better prognostic information and leading to future work determining how to improve outcomes in this high-risk group of patients.’
UCSF is one of the world’s leading centres for kidney disease treatment, research and education. Its Division of Nephrology is ranked among the best programs in the nation by U.S. News & World Report.
People who have chronic kidney disease fall into a spectrum in terms of how severe their disease is.
At one end are those who have very minor loss of kidney function. They may not have any symptoms at all, and only by applying a simple blood test can doctors properly diagnose their disease.
At the other end of the spectrum are the people who have progressed to end-stage renal disease, which is basically complete kidney failure. They require lifelong dialysis or a kidney transplant. Some people progress rapidly to end-stage renal disease while others may live for decades without ever progressing.
Doctors are interested in understanding the factors that place patients at greater risk for end-stage renal disease, Bansal said, because it may be possible to address those factors through medications or lifestyle changes like diet or exercise.
Bansal added, however, that while the two conditions are intertwined, scientists do not know exactly which specific genes, pathways and biological mechanisms connect irregular heartbeat to declines in kidney function. Neither do they yet know the extent to which treating atrial fibrillation will improve outcomes for people with chronic kidney disease.
University of California – San Francisco
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In a study researchers from the University of North Carolina Lineberger Comprehensive Cancer Center have developed a new method to visualise ageing and tumour growth in mice using a gene closely linked to these processes.
Researchers have long known that the gene, p16INK4a (p16), plays a role in ageing and cancer suppression by activating an important tumour defence mechanism called ‘cellular senescence’. The UNC team led by Norman Sharpless, MD, Wellcome Distinguished Professor of Cancer Research and Deputy Cancer Center Director, has developed a strain of mice that turns on a gene from fireflies when the normal p16 gene is activated. In cells undergoing senescence, the p16 gene is switched on, activating the firefly gene and causing the affected tissue to glow.
Throughout the entire lifespan of these mice, the researchers followed p16 activation by simply tracking the brightness of each animal. They found that old mice are brighter than young mice, and that sites of cancer formation become extremely bright, allowing for the early identification of developing cancers.
‘With these mice, we can visualise in real-time the activation of cellular senescence, which prevents cancer but causes ageing. We can literally see the earliest molecular stages of cancer and ageing in living mice.’ said Sharpless.
The researchers envision immediate practical uses for these mice. By providing a visual indication of the activation cellular senescence, the mice will allow researchers to test substances and exposures that promote cellular ageing (‘gerontogen testing’) in the same way that other mouse models currently allow toxicologists to identify cancer-causing substances (‘carcinogen testing’). Moreover, these mice are already being used by scientists at UNC and other institutions to identify early cancer development and the response of tumours to anti-cancer treatments.
‘This work builds on previous work by the same group, as well as others, showing intriguing relationships among aging, cancer and cell senescence. It provides a valuable new tool to probe these relationships,’ said Felipe Sierra, Ph.D., director of the Division of Aging Biology, National Institute on Aging, NIH.
The researchers used these mice to make several unexpected discoveries. First, the group was able to track the accumulation of senescent cells in ageing mice by assessing how brightly each mouse glowed. Surprisingly, the brightest animals were no more likely to die from spontaneous cancer than dimmer animals of the same age. That is, the number of senescent cells in the mouse did not predict its risk of dying.
‘The result we, and I think others, predicted is that the animals with the highest number of senescent cells would get more cancers and die sooner, but this was not the case’ said Sharpless.
Another surprise came from the disparities in p16 levels among the mice. The authors studied a large group of genetically identical animals that were all housed in the same way and fed the same diet. However, despite identical genetic and environmental conditions, the brightness of individual mice at any given age was highly variable, suggesting that factors beyond genetics and diet influence ageing.
The glowing mice also provide a window into the formation of cancers. Expression of p16 is activated in the earliest stages of cancer formation to suppress cancer. Usually activation of p16 prevents cancer, but rarely this tumour suppressor mechanism fails and tumours develop, while still activating the p16 gene. As such, all tumours forming in these mice strongly glowed, allowing researchers to monitor early tumour formation in a wide variety of cancer types. In contrast to expectations, the researchers also found that p16 was activated not only in the tumour cells themselves, but also in normal, neighbouring cells.
‘This finding suggests that activation of senescence results from an abnormal milieu within a developing cancer. Somehow, many or all the cells in a would-be tumour know they are in a bad place, and activate this tumour suppressor gene as a defence mechanism, even if they are not the would-be cancer cells themselves. This occurs really early in the cancer; we’re talking about the earliest events of neoplasia that have ever been measured in living animals,’ said Sharpless.
The Sharpless group believes similar approaches to monitoring senescence can be developed in order to study ageing and tumour development in humans. The group is particularly interested in how cancer therapies influence human ageing and patient outcome. Working with UNC oncologists, the Sharpless group has already measured p16 expression in several hundred patients undergoing cancer therapy. These studies, along with efforts employing the glowing mouse, aims to develop more effective and tolerable patient treatment schemes based upon ‘molecular’, as opposed to ‘chronologic’, age.
EurekAlert
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A certain enzyme, the CaM kinase II, keeps the cardiac muscle flexible. By transferring phosphate groups to the giant protein titin, it relaxes the muscle cells. This is reported by researchers led by Prof. Dr. Wolfgang Linke of the Institute of Physiology at the. In failing hearts, which don’t pump enough blood around the body, the scientists found an overly active CaM kinase II. ‘The phosphorylation of titin could be a new starting point for the treatment of heart failure’ Prof. Linke speculates.
Titin phosphorylation determines the mechanical tension of the muscle cell
Titin is the largest protein in the human body, and it acts like a spring which tenses or relaxes the muscle cell. The attachment of phosphate groups to specific titin sites – known as phosphorylation – relaxes the cell. It was already known that the calcium/calmodulin-dependent kinase II, CaM kinase II for short, phosphorylates several proteins in heart cells. Whether it also targets the spring protein titin, has now been examined by the researchers in Bochum.
For the study, the researchers used heart cells of ‘normal’ mice, mice that have no CaM kinase II, and mice that produce more CaM kinase II than usual. In cells without the enzyme, titin phosphorylation was reduced by more than 50 percent compared to the normal state. In cells with excess enzyme, however, titin phosphorylation was twice as strong as in normal cells. The CaM kinase II is therefore crucial for the attachment of phosphate groups to the giant protein titin. Linke’s team identified two regions within the flexible segment of the titin molecule which are phosphorylated by the enzyme, namely the PEVK and N2Bus region. These sites contain several amino acids of the type serine and threonine, which have changed little in the course of evolution.
In further analyses, the research team also showed that a lack or an excess of CaM kinase II affected the stiffness of the muscle cells. Cells without the enzyme were stiffer, cells with the enzyme more flexible. If they added CaM kinase II to cells that were not able to produce the enzyme themselves, these relaxed. In failing human hearts, the team found increased activity of CaM kinase II in comparison with healthy hearts, and thus excessive phosphorylation in the PEVK and N2Bus titin regions. ‘This seems to alter the mechanical properties of the human heart muscle’, says Wolfgang Linke.
Ruhr University Bochum
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Cannabis use may double the stroke risk in young adults, according to a recent study by researchers in the Centre for Brain Research at The University of Auckland.
The study showed that ischemic stroke and transient ischemic attack (TIA) patients were 2.3 times more likely to have cannabis detected in urine tests as other age and sex matched patients.
‘This is the first case-controlled study to show a possible link to the increased risk of stroke from cannabis,’ said Professor Alan Barber, lead investigator for the study and Neurological Foundation professor of clinical neurology at the University. ‘Cannabis has been thought by the public to be a relatively safe, although illegal substance. This study shows this might not be the case; it may lead to stroke.’
The study included 160 ischemic stroke/TIA patients aged 18-55 years who had urine screens upon admission to the hospital.
Among the patients, 150 had ischemic stroke and 10 had TIAs. Sixteen percent of patients tested positive for cannabis, and were mostly male who also smoked tobacco, while only 8.1 percent of controls tested positive for cannabis in urine samples. Researchers found no differences in age, stroke mechanism or most vascular risk factors between cannabis users and non-users.
In previous case reports, ischemic stroke and TIAs developed hours after cannabis use, says Professor Barber. ‘These patients usually had no other vascular risk factors apart from tobacco, alcohol and other drug usage. It’s challenging to perform prospective studies involving illegal substances such as cannabis because ‘questioning stroke and control patients about cannabis use is likely to obtain unreliable responses,’ he says.
The study provides the strongest evidence to date of an association between cannabis and stroke, says Professor Barber. But the association is confounded because all but one of the stroke patients who were cannabis users also used tobacco regularly.
‘We believe it is the cannabis use and not tobacco,’ says Professor Barber, who hopes to conduct another study to determine whether there’s an association between cannabis and stroke independent of tobacco use.
‘This may prove difficult given the risks of bias and ethical strictures of studying the use of an illegal substance,’ he says. ‘However, the high prevalence of cannabis use in this cohort of younger stroke patients makes this research imperative.’
Physicians should test young people who come in with stroke for cannabis use, says Professor Barber. ‘People need to think twice about using cannabis, because it can affect brain development and result in emphysema, heart attack and now stroke.’
University of Auckland
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Researchers at the Perelman School of Medicine at the University of Pennsylvania and the University of Massachusetts Amherst report utilising a novel statistical tool to analyse existing large databases of genetic information to mine new information about genes that modulate low density lipoprotein (LDL) cholesterol and its downstream consequences, heart attack, stroke and death. This new approach to analysing existing data suggested a dozen new LDL cholesterol genes for analysis and provides opportunities for developing new treatments and advancing approaches to identifying those at greatest risk for heart disease.
The new analytical approach, called ‘mixed modelling of meta-analysis P-values’ or MixMAP, offers new and complementary information as compared to single nucleotide polymorphism-based analysis approaches that have been used in past studies to identify novel genes linked to heart disease. The researchers say the tool is straightforward to implement and can be used with freely available computer software. The approach may also be applied broadly to advance genetic knowledge of many other diseases.
‘The MixMAP approach provides a significant advance by unlocking more information regarding the genetic basis of disease using existing large data and at little additional cost to the research community and funding agencies,’ said Muredach P. Reilly, MBBCH, MSC, associate professor of Medicine at Penn and senior study author. ‘For complex diseases such as heart attack and diabetes, this provides a real opportunity to generate substantial new knowledge and advance treatment and diagnostic opportunities.’
Perelman School of Medicine
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Miniaturised laboratory-on-chip systems promise rapid, sensitive, and multiplexed detection of biological samples for medical diagnostics, drug discovery, and high-throughput screening. Using micro-fabrication techniques and incorporating a unique design of transistor-based heating, researchers at the University of Illinois at Urbana-Champaign are further advancing the use of silicon transistor and electronics into chemistry and biology for point-of-care diagnostics.
Lab-on-a-chip technologies are attractive as they require fewer reagents, have lower detection limits, allow for parallel analyses, and can have a smaller footprint.
‘Integration of various laboratory functions onto microchips has been intensely studied for many years,’ explained Rashid Bashir, an Abel Bliss Professor of electrical and computer engineering and of bioengineering at Illinois. ‘Further advances of these technologies require the ability to integrate additional elements, such as the miniaturised heating element, and the ability to integrate heating elements in a massively parallel format compatible with silicon technology.
‘In this work, we demonstrated that we can heat nanoliter volume droplets, individually and in an array, using VLSI silicon based devices, up to temperatures that make it interesting to do various biochemical reactions within these droplets.’
‘Our method positions droplets on an array of individual silicon microwave heaters on chip to precisely control the temperature of droplets-in-air, allowing us to perform biochemical reactions, including DNA melting and detection of single base mismatches,’ said Eric Salm, first author of the paper.
According to Salm, approaches to perform localised heating of these individual subnanoliter droplets can allow for new applications that require parallel, time-, and space multiplex reactions on a single integrated circuit. Within miniaturised laboratory-on-chips, static and dynamic droplets of fluids in different immiscible media have been used as individual vessels to perform biochemical reactions and confine the products.
‘This technology makes it possible to do cell lysing and nucleic acid amplification reactions within these individual droplets – the droplets are the reaction vessels or cuvettes that can be individually heated,’ Salm added.
‘We also demonstrate that ssDNA probe molecules can be placed on heaters in solution, dried, and then rehydrated by ssDNA target molecules in droplets for hybridisation and detection,’ said Bashir, who is director of the Micro and Nanotechnology Laboratory at Illinois. ‘This platform enables many applications in droplets including hybridisation of low copy number DNA molecules, lysing of single cells, interrogation of ligand–receptor interactions, and rapid temperature cycling for amplification of DNA molecules.
‘Notably,’ Bashir added, ‘our miniaturised heater could also function as dual heater/sensor elements, as these silicon-on-insulator nanowire or nanoribbon structures have been used to detect DNA, proteins, pH, and pyrophosphates.
By using microfabrication techniques and incorporating the unique design of transistor-based heating with individual reaction volumes, ‘laboratory-on-a-chip’ technologies can be scaled down to ‘laboratory-on-a-transistor’ technologies as sensor/heater hybrids that could be used for point-of-care diagnostics.’
University of Illinois at Urbana-Champaign
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 09:35:432021-01-08 11:13:13Building a biochemistry lab on a chip
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Team finds gene that promotes drug resistance in cancer
, /in E-News /by 3wmediaScientists from the University of Iowa and Brigham Young University (BYU) have identified a gene that may be a target for overcoming drug resistance in cancer. The finding could not only improve prognostic and diagnostic tools for evaluating cancer and monitoring patients’ response to treatment but also could lead to new therapies directed at eradicating drug-resistant cancer cells.
Drug resistance is a common problem in many metastatic cancers. It leads to failure of chemotherapy treatments and is associated with poor patient outcomes, including rapid relapse and death.
Fenghuang Zhan, Ph.D.The research team, including Fenghuang (Frank) Zhan, M.D., Ph.D., and Guido Tricot, M.D., Ph.D., from the UI, and David Bearss, Ph.D., from BYU, initially focused on identifying genes linked to the development of drug resistance in multiple myeloma, a bone marrow cancer that affects more than 20,000 Americans and causes almost 11,000 deaths annually.
Working with serial biopsied cells from 19 myeloma patients, the researchers analysed genetic changes in the cells that occurred over the course of treatment with very intensive chemotherapy drugs. This approach identified a gene called NEK2 that is strongly associated with increased drug-resistance, faster cancer growth, and poorer survival for patients.
Guido Tricot, M.D., Ph.D.Having established the relationship between high expression of the NEK2 gene and poor patient outcome in myeloma, the team then examined the relationship in other common cancers—including breast, lung, and bladder cancer—by analysing gene expression profiles from 2,500 patients’ cells with eight different cancers in Zhan’s lab.
Taking the findings back to the lab, the team then examined the effect on cancer cells of either enhancing or blocking the expression of the NEK2 gene. "In all cases, an increase in the NEK2 gene was associated with rapid death of the patient," says Tricot, who is director of Holden Comprehensive Cancer Center’s Bone Marrow Transplant and Myeloma Program at UI Hospitals and Clinics. "So this finding was not unique to myeloma; this is basically seen in every single cancer we looked at."
The research team is now developing compounds to inhibit NEK2 by collaborating with David Bearss, Ph.D., associate professor of physiology and developmental biology at BYU, in the hope that these compounds may overcome drug resistance in cancer cells. "Our studies show that over-expression of NEK2 in cancer cells significantly enhances the activity of drug efflux proteins to pump chemotherapy drugs out of cells, resulting in drug resistance. Furthermore, silencing NEK2 in cancer cells potently decreased drug resistance, induced cell-cycle arrest, cell death, and inhibited cancer cell growth in vitro and in vivo," says Zhan, UI professor of internal medicine.
“We were able to show that if we inhibit NEK2, then we can actually restore sensitivity to drugs that we use right now,” Bearss says.
Although development and clinical testing of such drugs for use in patients is not imminent, Tricot notes that the findings may have clinical use within the next several years.
"NEK2 expression may be a diagnostic or prognostic marker for drug-resistant cancer," he says. "If NEK2 is high, that would suggest that the prognosis is poorer and the patient might benefit from more aggressive treatment. The other potential use is for monitoring the cancer’s response to therapy. If NEK2 levels increase, that would suggest development of increased drug resistance and might indicate that a change of treatment would be helpful."University of Iowa Health Care
Researchers discover novel role of the NEDD9 gene in early stages of breast cancer
, /in E-News /by 3wmediaBreast cancer is the second leading cause of cancer deaths among women in the United States. Many of these deaths occur when there is an initial diagnosis of invasive or metastatic disease. A protein called NEDD9—which regulates cell migration, division and survival—has been linked to tumour invasion and metastasis in a variety of cancers. Researchers at Fox Chase Cancer Center have now shown that NEDD9 plays a surprising role in the early stages of breast tumour development by controlling the growth of progenitor cells that give rise to tumours. The findings could lead to personalised treatment strategies for women with breast cancer based on the levels of NEDD9 in their tumours.
"For several years, NEDD9 has been linked to tumour metastasis and invasion at later stages. This is the first study that really shows how important NEDD9 can be for the initiation of tumours in breast cancer, and to link this initiation process to progenitor cells," says lead study author Joy Little, PhD, a postdoctoral fellow at Fox Chase who works in the laboratory of senior study investigator Erica A. Golemis, PhD, Deputy Chief Scientific Officer and Vice President at Fox Chase.
In the study, Little, Golemis and their collaborators mated mice without the NEDD9 gene to mice engineered to develop HER2+ mammary tumours and unexpectedly found that these mice were largely resistant to tumour formation. Only 18% of the mice developed mammary tumours, compared with 80% of mice that had a functional NEDD9 gene. In contrast to previous research findings showing that an increase in NEDD9 levels promotes tumour aggressiveness, the researchers found that loss of NEDD9 had little effect on tumour metastasis, indicating that it is not required for this process in this specific context. Once formed, the tumours in mice lacking NEDD9 grew rapidly, suggesting that it either plays a less important role at later stages of tumour growth or tumours undergo compensatory changes that allow them to bypass the need for NEDD9.
Importantly, mice lacking NEDD9 showed a significant reduction in progenitor cell populations in the mammary gland compared with mice that had a functional NEDD9 gene. Progenitor cells from NEDD9-null mice were less likely to form three-dimensional mammospheres in culture, but proliferated at the same rate as cells from control mice. The loss of Nedd9 also made progenitor cells more sensitive to lower doses of two tumour-inhibiting drugs—a Food and Drug Administration-approved Src inhibitor called dasatinib, and a focal adhesion kinase inhibitor from a class of drugs currently being tested in clinical trials for the treatment of cancer. These findings suggest that these types of drugs would more effectively control breast cancer tumours with low levels of NEDD9.
"Eventually, with a biopsy, you may be able to get a read-out of all the mutations that a tumour has, and each one would potentially dictate whether or not a certain line of therapy would work for a specific tumour," Little says. "If NEDD9 levels are higher in a particular tumour, we could potentially determine whether or not it would be more sensitive to specific inhibitors."Fox Chase Cancer Center
Genetic basis of high-risk childhood cancer points to possible new drug treatment strategy
, /in E-News /by 3wmediaResearch led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukaemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukaemia, which is known as hypodiploid acute lymphoblastic leukaemia (ALL). Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterised by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumour has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbour. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbour inherited mutations in the TP53 tumour suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognised as a common manifestation of Li-Fraumeni syndrome.
Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterised by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
‘This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukaemia subtypes that we would otherwise have missed,’ said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organisation devoted exclusively to childhood and adolescent cancer research.
‘The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,’ said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. ‘This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukaemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.’
Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.
The whole genome sequencing was done in conjunction with the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.
Near haploid ALL was characterised by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.
Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumour suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumour suppressor gene.
About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.
Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brain tumour associated with Li-Fraumeni syndrome. His son later developed low hypodiploid ALL.
‘Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,’ said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. ‘Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,’ Holmfeldt said. St. Jude Children’s Research Hospital
Intermountain Medical Center study may help save lives of trauma patients
, /in E-News /by 3wmediaA simple, inexpensive blood test performed on trauma patients upon admission can help doctors easily identify patients at greatest risk of death, according to a new study by researchers at Intermountain Medical Center.
The Intermountain Medical Center research study of more than 9,500 patients discovered that some trauma patients are up to 58 times more likely to die than others, regardless of the severity of their original injury.
Researchers say the study findings provide important insight into the long-term prognosis of trauma patients, something not previously well understood.
‘The results were very surprising,’ said Sarah Majercik, MD, an Intermountain Medical Center surgeon and trauma researcher, whose team discovered that a tool developed at Intermountain Medical Center, called the Intermountain Risk Score, can predict mortality among trauma patients.
The Intermountain Risk Score is a computerised tool available to physicians that combines factors like age, gender, and common blood tests known as the complete blood count (CBC) and the basic metabolic profile (BMP) to determine an individual’s mortality risk.
All of the components of the tool have been helpful in evaluating individuals with medical problems like heart failure or chronic pulmonary disease. But until now, the benefit of the tool had not been tested for trauma patients hospitalised due to an accident or traumatic injury, rather than an underlying condition.
‘As surgeons, we don’t often use all of the CBC results in evaluating a patient who needs surgery for a bleeding spleen or after a motor vehicle accident, said Dr. Majercik. ‘There are certain values, such as haemoglobin, hematocrit, and platelets that we scrutinise closely as part of good clinical care, but then other parts, such as the red blood cell distribution width (RDW) that we pay no attention to at all in the acute setting. These factors are generally overlooked, even though they are part of the CBC that every trauma patient gets when he or she arrives in the emergency room.’
Data from the Intermountain Risk Score tool will allow physicians to take additional precautions with patients who are at greatest risk, and also give doctors important information to consider when talking about prognosis with patients and families.
Dr. Majercik and her colleague Benjamin Horne, PhD, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute, reviewed the cases of 9,538 patients who had been admitted to the hospital with trauma during a six-year period.
Using the tool, the Intermountain Medical Center categorised patients according to high, moderate, and low risk levels. Some surprising findings:
High-risk men were nearly 58 times more likely to die within a year than low-risk men. Men with a moderate risk were nearly 13 times more likely to die than those with low risk.
High-risk women were 19 times more likely to die within a year than low-risk women. And women with moderate risk were five times more likely to die than those with low risk.
‘Some risk factors will be already apparent for physicians, but others aren’t intuitive,’ said Dr. Horne. For example, a trauma patient may look completely healthy apart from his or her injury. But if the Intermountain Risk Score tool uncovers an irregular red blood cell distribution width — a common sign of anaemia — that will increase his risk of dying.
‘It’s a standard part of the CBC test, but it’s not usually taken into consideration when treating a patient with injuries,’ said Dr. Horne. ‘Based on the findings of our research, it’s something that should be looked at as part of the care plan model.’
Dr. Majercik and Dr. Horne believe their research will give physicians a simple, fast way to better understand their patients’ condition, and may lead to new treatment approaches that could reduce the risk of death. Intermountain Medical Center
Irregular heartbeat elevates risk of kidney failure
, /in E-News /by 3wmediaThe risk of kidney failure is greater for people with chronic kidney disease who also have atrial fibrillation, one of the most common forms of irregular heart rhythm in adults, according to a new study by researchers at UCSF and the Kaiser Permanente Northern California Division of Research.
The finding opens the way for further studies into the relationship between the two factors, which could lead to new treatment approaches that would improve outcomes for people with chronic kidney disease.
Many people who suffer from chronic kidney disease progressively lose their kidney function over time and eventually develop a condition called end-stage renal disease – the complete failure of the kidneys – placing them in need of lifelong dialysis or a kidney transplant.
Doctors have known that patients with chronic kidney disease or end-stage renal disease commonly have atrial fibrillation and as a result are more likely to have a stroke or to die. However, the long-term impact of atrial fibrillation on kidney function among patients with known chronic kidney disease has been unknown.
The new study involved 206,229 adults with chronic kidney disease who were drawn from members of Kaiser Permanente Northern California, a large integrated health care delivery system.. Over the course of about five years, approximately 16,400 patients developed atrial fibrillation, and those who did were 67 percent more likely to progress to end-stage renal disease compared with patients who had chronic kidney disease but did not develop atrial fibrillation.
‘These novel findings expand on previous knowledge by highlighting that atrial fibrillation is linked to a worse kidney prognosis in patients with underlying kidney dysfunction,’ said kidney specialist Nisha Bansal, MD, an assistant professor in the Division of Nephrology at UCSF.
‘There is a knowledge gap about the long-term impact of atrial fibrillation on the risk of adverse kidney-related outcomes in patients with chronic kidney disease,’ said senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research. ‘This study addresses that gap and may have important implications for clinical management by providing better prognostic information and leading to future work determining how to improve outcomes in this high-risk group of patients.’
UCSF is one of the world’s leading centres for kidney disease treatment, research and education. Its Division of Nephrology is ranked among the best programs in the nation by U.S. News & World Report.
People who have chronic kidney disease fall into a spectrum in terms of how severe their disease is.
At one end are those who have very minor loss of kidney function. They may not have any symptoms at all, and only by applying a simple blood test can doctors properly diagnose their disease.
At the other end of the spectrum are the people who have progressed to end-stage renal disease, which is basically complete kidney failure. They require lifelong dialysis or a kidney transplant. Some people progress rapidly to end-stage renal disease while others may live for decades without ever progressing.
Doctors are interested in understanding the factors that place patients at greater risk for end-stage renal disease, Bansal said, because it may be possible to address those factors through medications or lifestyle changes like diet or exercise.
Bansal added, however, that while the two conditions are intertwined, scientists do not know exactly which specific genes, pathways and biological mechanisms connect irregular heartbeat to declines in kidney function. Neither do they yet know the extent to which treating atrial fibrillation will improve outcomes for people with chronic kidney disease. University of California – San Francisco
UNC researchers use luminescent mice to track cancer and ageing in real-time
, /in E-News /by 3wmediaIn a study researchers from the University of North Carolina Lineberger Comprehensive Cancer Center have developed a new method to visualise ageing and tumour growth in mice using a gene closely linked to these processes.
Researchers have long known that the gene, p16INK4a (p16), plays a role in ageing and cancer suppression by activating an important tumour defence mechanism called ‘cellular senescence’. The UNC team led by Norman Sharpless, MD, Wellcome Distinguished Professor of Cancer Research and Deputy Cancer Center Director, has developed a strain of mice that turns on a gene from fireflies when the normal p16 gene is activated. In cells undergoing senescence, the p16 gene is switched on, activating the firefly gene and causing the affected tissue to glow.
Throughout the entire lifespan of these mice, the researchers followed p16 activation by simply tracking the brightness of each animal. They found that old mice are brighter than young mice, and that sites of cancer formation become extremely bright, allowing for the early identification of developing cancers.
‘With these mice, we can visualise in real-time the activation of cellular senescence, which prevents cancer but causes ageing. We can literally see the earliest molecular stages of cancer and ageing in living mice.’ said Sharpless.
The researchers envision immediate practical uses for these mice. By providing a visual indication of the activation cellular senescence, the mice will allow researchers to test substances and exposures that promote cellular ageing (‘gerontogen testing’) in the same way that other mouse models currently allow toxicologists to identify cancer-causing substances (‘carcinogen testing’). Moreover, these mice are already being used by scientists at UNC and other institutions to identify early cancer development and the response of tumours to anti-cancer treatments.
‘This work builds on previous work by the same group, as well as others, showing intriguing relationships among aging, cancer and cell senescence. It provides a valuable new tool to probe these relationships,’ said Felipe Sierra, Ph.D., director of the Division of Aging Biology, National Institute on Aging, NIH.
The researchers used these mice to make several unexpected discoveries. First, the group was able to track the accumulation of senescent cells in ageing mice by assessing how brightly each mouse glowed. Surprisingly, the brightest animals were no more likely to die from spontaneous cancer than dimmer animals of the same age. That is, the number of senescent cells in the mouse did not predict its risk of dying.
‘The result we, and I think others, predicted is that the animals with the highest number of senescent cells would get more cancers and die sooner, but this was not the case’ said Sharpless.
Another surprise came from the disparities in p16 levels among the mice. The authors studied a large group of genetically identical animals that were all housed in the same way and fed the same diet. However, despite identical genetic and environmental conditions, the brightness of individual mice at any given age was highly variable, suggesting that factors beyond genetics and diet influence ageing.
The glowing mice also provide a window into the formation of cancers. Expression of p16 is activated in the earliest stages of cancer formation to suppress cancer. Usually activation of p16 prevents cancer, but rarely this tumour suppressor mechanism fails and tumours develop, while still activating the p16 gene. As such, all tumours forming in these mice strongly glowed, allowing researchers to monitor early tumour formation in a wide variety of cancer types. In contrast to expectations, the researchers also found that p16 was activated not only in the tumour cells themselves, but also in normal, neighbouring cells.
‘This finding suggests that activation of senescence results from an abnormal milieu within a developing cancer. Somehow, many or all the cells in a would-be tumour know they are in a bad place, and activate this tumour suppressor gene as a defence mechanism, even if they are not the would-be cancer cells themselves. This occurs really early in the cancer; we’re talking about the earliest events of neoplasia that have ever been measured in living animals,’ said Sharpless.
The Sharpless group believes similar approaches to monitoring senescence can be developed in order to study ageing and tumour development in humans. The group is particularly interested in how cancer therapies influence human ageing and patient outcome. Working with UNC oncologists, the Sharpless group has already measured p16 expression in several hundred patients undergoing cancer therapy. These studies, along with efforts employing the glowing mouse, aims to develop more effective and tolerable patient treatment schemes based upon ‘molecular’, as opposed to ‘chronologic’, age. EurekAlert
The enzyme CaM kinase II relaxes the muscle cells
, /in E-News /by 3wmediaA certain enzyme, the CaM kinase II, keeps the cardiac muscle flexible. By transferring phosphate groups to the giant protein titin, it relaxes the muscle cells. This is reported by researchers led by Prof. Dr. Wolfgang Linke of the Institute of Physiology at the. In failing hearts, which don’t pump enough blood around the body, the scientists found an overly active CaM kinase II. ‘The phosphorylation of titin could be a new starting point for the treatment of heart failure’ Prof. Linke speculates.
Titin phosphorylation determines the mechanical tension of the muscle cell
Titin is the largest protein in the human body, and it acts like a spring which tenses or relaxes the muscle cell. The attachment of phosphate groups to specific titin sites – known as phosphorylation – relaxes the cell. It was already known that the calcium/calmodulin-dependent kinase II, CaM kinase II for short, phosphorylates several proteins in heart cells. Whether it also targets the spring protein titin, has now been examined by the researchers in Bochum.
For the study, the researchers used heart cells of ‘normal’ mice, mice that have no CaM kinase II, and mice that produce more CaM kinase II than usual. In cells without the enzyme, titin phosphorylation was reduced by more than 50 percent compared to the normal state. In cells with excess enzyme, however, titin phosphorylation was twice as strong as in normal cells. The CaM kinase II is therefore crucial for the attachment of phosphate groups to the giant protein titin. Linke’s team identified two regions within the flexible segment of the titin molecule which are phosphorylated by the enzyme, namely the PEVK and N2Bus region. These sites contain several amino acids of the type serine and threonine, which have changed little in the course of evolution.
In further analyses, the research team also showed that a lack or an excess of CaM kinase II affected the stiffness of the muscle cells. Cells without the enzyme were stiffer, cells with the enzyme more flexible. If they added CaM kinase II to cells that were not able to produce the enzyme themselves, these relaxed. In failing human hearts, the team found increased activity of CaM kinase II in comparison with healthy hearts, and thus excessive phosphorylation in the PEVK and N2Bus titin regions. ‘This seems to alter the mechanical properties of the human heart muscle’, says Wolfgang Linke. Ruhr University Bochum
Smoking cannabis linked to higher stroke risk in young adults
, /in E-News /by 3wmediaCannabis use may double the stroke risk in young adults, according to a recent study by researchers in the Centre for Brain Research at The University of Auckland.
The study showed that ischemic stroke and transient ischemic attack (TIA) patients were 2.3 times more likely to have cannabis detected in urine tests as other age and sex matched patients.
‘This is the first case-controlled study to show a possible link to the increased risk of stroke from cannabis,’ said Professor Alan Barber, lead investigator for the study and Neurological Foundation professor of clinical neurology at the University. ‘Cannabis has been thought by the public to be a relatively safe, although illegal substance. This study shows this might not be the case; it may lead to stroke.’
The study included 160 ischemic stroke/TIA patients aged 18-55 years who had urine screens upon admission to the hospital.
Among the patients, 150 had ischemic stroke and 10 had TIAs. Sixteen percent of patients tested positive for cannabis, and were mostly male who also smoked tobacco, while only 8.1 percent of controls tested positive for cannabis in urine samples. Researchers found no differences in age, stroke mechanism or most vascular risk factors between cannabis users and non-users.
In previous case reports, ischemic stroke and TIAs developed hours after cannabis use, says Professor Barber. ‘These patients usually had no other vascular risk factors apart from tobacco, alcohol and other drug usage. It’s challenging to perform prospective studies involving illegal substances such as cannabis because ‘questioning stroke and control patients about cannabis use is likely to obtain unreliable responses,’ he says.
The study provides the strongest evidence to date of an association between cannabis and stroke, says Professor Barber. But the association is confounded because all but one of the stroke patients who were cannabis users also used tobacco regularly.
‘We believe it is the cannabis use and not tobacco,’ says Professor Barber, who hopes to conduct another study to determine whether there’s an association between cannabis and stroke independent of tobacco use.
‘This may prove difficult given the risks of bias and ethical strictures of studying the use of an illegal substance,’ he says. ‘However, the high prevalence of cannabis use in this cohort of younger stroke patients makes this research imperative.’
Physicians should test young people who come in with stroke for cannabis use, says Professor Barber. ‘People need to think twice about using cannabis, because it can affect brain development and result in emphysema, heart attack and now stroke.’ University of Auckland
New statistical tool may help detect novel genes linked to heart disease
, /in E-News /by 3wmediaResearchers at the Perelman School of Medicine at the University of Pennsylvania and the University of Massachusetts Amherst report utilising a novel statistical tool to analyse existing large databases of genetic information to mine new information about genes that modulate low density lipoprotein (LDL) cholesterol and its downstream consequences, heart attack, stroke and death. This new approach to analysing existing data suggested a dozen new LDL cholesterol genes for analysis and provides opportunities for developing new treatments and advancing approaches to identifying those at greatest risk for heart disease.
The new analytical approach, called ‘mixed modelling of meta-analysis P-values’ or MixMAP, offers new and complementary information as compared to single nucleotide polymorphism-based analysis approaches that have been used in past studies to identify novel genes linked to heart disease. The researchers say the tool is straightforward to implement and can be used with freely available computer software. The approach may also be applied broadly to advance genetic knowledge of many other diseases.
‘The MixMAP approach provides a significant advance by unlocking more information regarding the genetic basis of disease using existing large data and at little additional cost to the research community and funding agencies,’ said Muredach P. Reilly, MBBCH, MSC, associate professor of Medicine at Penn and senior study author. ‘For complex diseases such as heart attack and diabetes, this provides a real opportunity to generate substantial new knowledge and advance treatment and diagnostic opportunities.’ Perelman School of Medicine
Building a biochemistry lab on a chip
, /in E-News /by 3wmediaMiniaturised laboratory-on-chip systems promise rapid, sensitive, and multiplexed detection of biological samples for medical diagnostics, drug discovery, and high-throughput screening. Using micro-fabrication techniques and incorporating a unique design of transistor-based heating, researchers at the University of Illinois at Urbana-Champaign are further advancing the use of silicon transistor and electronics into chemistry and biology for point-of-care diagnostics.
Lab-on-a-chip technologies are attractive as they require fewer reagents, have lower detection limits, allow for parallel analyses, and can have a smaller footprint.
‘Integration of various laboratory functions onto microchips has been intensely studied for many years,’ explained Rashid Bashir, an Abel Bliss Professor of electrical and computer engineering and of bioengineering at Illinois. ‘Further advances of these technologies require the ability to integrate additional elements, such as the miniaturised heating element, and the ability to integrate heating elements in a massively parallel format compatible with silicon technology.
‘In this work, we demonstrated that we can heat nanoliter volume droplets, individually and in an array, using VLSI silicon based devices, up to temperatures that make it interesting to do various biochemical reactions within these droplets.’
‘Our method positions droplets on an array of individual silicon microwave heaters on chip to precisely control the temperature of droplets-in-air, allowing us to perform biochemical reactions, including DNA melting and detection of single base mismatches,’ said Eric Salm, first author of the paper.
According to Salm, approaches to perform localised heating of these individual subnanoliter droplets can allow for new applications that require parallel, time-, and space multiplex reactions on a single integrated circuit. Within miniaturised laboratory-on-chips, static and dynamic droplets of fluids in different immiscible media have been used as individual vessels to perform biochemical reactions and confine the products.
‘This technology makes it possible to do cell lysing and nucleic acid amplification reactions within these individual droplets – the droplets are the reaction vessels or cuvettes that can be individually heated,’ Salm added.
‘We also demonstrate that ssDNA probe molecules can be placed on heaters in solution, dried, and then rehydrated by ssDNA target molecules in droplets for hybridisation and detection,’ said Bashir, who is director of the Micro and Nanotechnology Laboratory at Illinois. ‘This platform enables many applications in droplets including hybridisation of low copy number DNA molecules, lysing of single cells, interrogation of ligand–receptor interactions, and rapid temperature cycling for amplification of DNA molecules.
‘Notably,’ Bashir added, ‘our miniaturised heater could also function as dual heater/sensor elements, as these silicon-on-insulator nanowire or nanoribbon structures have been used to detect DNA, proteins, pH, and pyrophosphates.
By using microfabrication techniques and incorporating the unique design of transistor-based heating with individual reaction volumes, ‘laboratory-on-a-chip’ technologies can be scaled down to ‘laboratory-on-a-transistor’ technologies as sensor/heater hybrids that could be used for point-of-care diagnostics.’ University of Illinois at Urbana-Champaign