Researchers at the University of Alabama at Birmingham have found that the amount of proteins excreted in the urine of preterm infants with acute kidney injury, or AKI, is different from that excreted by infants with healthy kidneys.
The study was led by principal investigator David Askenazi, M.D.
“The findings in this study could help physicians better diagnose kidney health in newborns,” said Askenazi, associate professor in the UAB Department of Pediatrics and director of UAB’s Pediatric and Infant Center for Acute Nephrology. “Having better diagnostic tests to diagnose kidney injury will have an important impact on how we care for infants and how we prognosticate outcomes, and will enable us to design studies to prevent and/or mitigate kidney damage in these very vulnerable babies.”
Improving the ability to diagnose AKI, a sudden decline in kidney function, is critical, as approximately 25 percent of preterm infants develop AKI. Compared to those without AKI, preterm infants with this common problem have a lower chance for survival, increased hospital stays and increased hospital expenditures.
Importantly, premature infants are at high risk for chronic kidney disease, and AKI may be an important cause for this.
Investigators took a single drop of urine from 113 preterm infants and measured 14 urine proteins. The concentrations of many of these proteins, including cystatin c, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin and alpha glutathione S-transferase, were higher in preterm infants who later showed abnormal kidney function, compared to their counterparts with normal function.
“Additional studies to determine how AKI contributes to chronic kidney disease in these newborns are underway,” Askenazi said. “Improving our ability to diagnose AKI accurately is critical to improving our understanding of the natural course of disease and developing strategies to improve outcomes.”
University of Alabama at Birmingham
www.uab.edu/news/innovation/item/7485-acute-kidney-injury-identifiable-in-preterm-infants
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Not only is breast cancer more than one disease, but a single breast cancer tumour can vary within itself, a finding that University of Pittsburgh Cancer Institute (UPCI) researchers discovered has the potential to lead to very different patient treatment plans depending on the tumour sample and diagnostic testing used.
The results demonstrate that tumour sampling techniques used with newly developed “personalized medicine” gene expression profile tests may need to be refined to ensure that the most appropriate tumour sections are selected for testing.
“These tests are a good thing—they’ve done an incredible job identifying women with breast cancers that have a low risk of recurrence who don’t need chemotherapy, saving them from the toxicity and discomfort of unnecessary treatment,” said Adrian V. Lee, Ph.D., professor of pharmacology and chemical biology at UPCI, partner with UPMC CancerCenter. “However, as with any new technology, we need to understand how these tests work, and we’re finding that the sampling process, which involves liquefying tumours, loses information that could be important in determining the best treatment plan for patients with more aggressive tumours.”
Gene expression profiling is an increasingly popular type of test that tells doctors what certain genes are doing in a tissue sample, such as causing the cells to actively divide and multiply. Several tests have been developed in recent years to aid oncologists in developing breast cancer treatment plans. They involve taking a small bit of the tumour—or multiple small bits mixed together—and testing it.
The tests can tell oncologists if the cancer has a low, intermediate or high risk of recurring. The level of risk can help doctors and patients decide whether an aggressive treatment plan involving chemotherapy is beneficial or likely to do more harm than good.
Dr. Lee and his team examined 71 cases of a type of breast cancer called “estrogen-receptor-positive” that was caught early and hadn’t yet spread to other parts of the body. In all cases, the tumour had been removed and samples taken for gene expression profiling. A total of 181 samples were taken from various parts of the tumours, and the researchers measured the expression of 141 different genes from five different types of gene expression profile tests commonly used for breast cancer tumours.
For 25 percent of the patients, their tumours received a different risk of recurrence score depending on which sample was processed.
“This indicates that one part of the tumour is more aggressive than another part. If an oncologist were to know this, he or she would likely recommend a treatment plan tailored to destroy the most aggressive section of the tumour,” said Dr. Lee.
Because the patients in this study were all caught early, their risk of recurrence was low to begin with, and there weren’t enough recurrences to make a meaningful determination on whether they would have done better if more samples were tested from their tumours.
“It would be valuable to repeat this study with a much larger group of breast cancer patients and follow them over time so that we could definitively determine if the way sampling is done with these tests is, indeed, resulting in patients getting cancer recurrences that wouldn’t have happened if the sampling process was changed,” said Dr. Lee.
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Prostate cancer patients have been offered hope after scientists at Newcastle University have identified a new group of molecules that could be targeted to slow tumour growth.
Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
Experts used an advanced screening technique which found hundreds of genes were affected by the male hormone testosterone. It is believed this could lead to new diagnostic tests and treatments.
Among the 700 genes identified was an important set that add sugar groups – known as glycans – to the surface of prostate cancer cells. This group has never been investigated before.
Treatments targeting glycan sugar groups have been developed for other types of the illness, such as breast cancer. It is hoped these treatments could also be used for prostate cancer.
Results of the research suggest that testosterone changes glycans to make cancer cells more likely to survive, grow and spread to other parts of the body.
Scientists say there is the potential to target these glycans which could stop the growth and spread of tumours and save lives.
Dr Jennifer Munkley, Research Associate at the Institute of Genetic Medicine, Newcastle University, co-led the three-year research project with Professor David Elliott.
She said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.
Glycans have the potential to be used as part of a diagnostic test to help doctors decide which prostate cancers need treatment.
One in eight men will be diagnosed with the condition. It is the most common cancer in UK males, and there is a need to identify how the disease progresses and for treatment options to be established.
Researchers at Newcastle University used a technique, called RNA-sequencing, to identify the new set of genes that are important.
The genes identified may provide novel ways the disease can be monitored in patients to predict the most aggressive prostate cancers that need to be treated.
Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them.
“However, in order to develop new, effective treatments, we need to understand more about the genetic makeup of aggressive prostate cancers and identify what makes them tick.
“This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.
Newcastle University
www.ncl.ac.uk/press/news/2016/07/prostatecancerstudy/
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In contrast to the general belief that the airways of an infant are sterile until after birth, University of Alabama at Birmingham researchers and colleagues have found that the infant airway is already colonised with bacteria or bacterial DNA when a baby is born — and this is true for infants born as early as 24 weeks gestation.
How microbes get into the airways and the purpose of this pre-birth colonisation are still unclear, but the pattern of colonisation appears to have an important link to later severe neonatal lung disease.
An early microbial imbalance, or dysbiosis, is predictive for the development of bronchopulmonary dysplasia, or BPD, a chronic lung disease of prematurity. The extremely low birth-weight, or ELBW, infants in this study had an average birth weight of 1 pound, 8 ounces. Researchers found that the ELBW infants who went on to develop life-threatening BPD showed abnormal microbial colonisation patterns at birth, as compared to pre-term infants who did not get BPD.
“Right at birth, your respiratory microbiome can possibly predict your risk for BPD,” said Charitharth Vivek Lal, M.D., assistant professor in the UAB Pediatrics Division of Neonatology and the lead investigator of this study.
Extremely premature infants are at risk for BPD, which is the most common lung pathology of these tiny infants and a significant cause of morbidity, mortality and health care expenditures. Adults and children who had BPD as infants have lungs that failed to develop properly and are more prone to worse lung function, asthma, lung infections and pulmonary hypertension.
The researchers also looked at the airway microbiomes of 18 ELBW infants with established BPD and found that their microbiomes had a decreased diversity of types of microbes, and the pattern was very different from those of ELBW infants shortly after birth or full-term infants at birth.
As to specific groups of microbes, the phylum Proteobacteria, which includes bacteria like E. coli, appeared to be involved in BPD pathology, and the genus Lactobaccillus, part of the phylum Firmicutes, appeared to be involved in disease protection.
Lal and colleagues found decreased Lactobacillus abundance in the airway microbiomes of 10 infants born to mothers who had chorioamnionitis — an infection of the membranes of the placenta and an independent risk factor for BPD — as well as decreased Lactobacillus abundance at birth in the airways of the BPD-predisposed, ELBW infants, as compared to BPD-resistant infants. Research elsewhere has suggested a beneficial role for Lactobacillus against airway diseases and for lung development.
“I predict that researchers will study the use of respiratory probiotics, and the role of the gut-lung microbiome axis in the future,” Lal said.
For five ELBW infants who later developed BPD, the researchers collected periodic airway microbiome samples from birth through 9 weeks and saw extremely similar patterns of change in the microbiomes over time.
As for the source of the microbes, Lal and colleagues wrote, “As it is commonly believed that colonization of neonates originates in the birth canal, we were surprised to find that the airway microbiome of vaginally delivered and caesarean section-delivered neonates were similar, which suggests that the microbial DNA in the airways is probably transplacentally derived, consistent with reports that the placenta has a rich microbiome.”
The researchers speculate that this transmission of bacteria or bacterial DNA to the in-utero infant could be via blood or amniotic fluid.
University of Alabama at Birmingham
www.uab.edu/news/innovation/item/7505-discovery-of-infants-airway-microbiomes-may-help-predict-lung-disease
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Myeloid-derived suppressor cells (MDSCs) are a population of immune cells that have been implicated in tumour resistance to various types of cancer treatment, including targeted therapies, chemotherapy and immunotherapy. Polymorphonuclear (PMN) cells represent the largest population of MDSCs. However, fully understanding the biology and clinical importance of these cells has been hampered by a lack of markers that set them apart from normal neutrophils.
Now, scientists at The Wistar Institute have identified a marker that distinguishes PMN-MDSCs from neutrophils in the blood of patients with a variety of cancers. Study results showed that higher numbers of cells positive for the marker were associated with larger tumour size.
‘Before we started this work, the only way to isolate PMN-MDSCs was by density centrifugation of blood because they could not be properly identified in tumour tissue,’ said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and professor and program leader of the Translational Tumor Immunology program at Wistar, and senior author of the study. ‘Identifying a marker for PMN-MDSCs will allow us to study these cells in much more depth. In addition, if our clinical results are verified in larger studies, the marker could also be used to help physicians and patients make informed treatment decisions and, ultimately, it could be exploited to target PMN-MDSCs for therapeutic benefit.’
MDSCs are potent suppressors of immune responses. They naturally regulate immune responses in healthy individuals, but the population rapidly expands in patients with cancer, and the presence of these cells has been associated with poor patient outcomes. One of the few ways to know for sure that cells are MDSCs is by showing that they suppress immune responses in vitro.
Gabrilovich and colleagues used whole-genome analysis to compare the genes expressed by PMN-MDSCs and neutrophils from the blood of patients with non-small cell lung cancer and head and neck cancer. The researchers focused on the genes expressed at higher levels in PMN-MDSCs compared with neutrophils, in particular those genes that encoded proteins detectable on the surface of cells. This led them to the protein LOX-1, which was almost undetectable on the surface of neutrophils but detectable on the surface of about one-third of PMN-MDSCs.
When they tested the ability of LOX-1-positive and LOX-1-negative cells to suppress immune responses in vitro only the LOX-1-positive cells had this function. The results showed that LOX-1 was a marker of PMN-MDSCs.
Gabrilovich and colleagues speculated that the number of LOX-1-positive PMN-MDSCs in blood and tumour samples from patients with cancer might help predict disease severity and outcome. They had samples from only a few patients with non-small cell lung cancer to study, but found that patients with larger tumours had higher numbers of these cells in both blood and tumour samples.
‘Now that we have a specific marker for MDSCs, we can begin to ask new questions about the biology of these cells and their clinical significance,’ added Gabrilovich.
Ribonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.
A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.
The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.
In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.
It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.
Tohoku University
www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html
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In a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.
In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.
Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.
The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.
The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.
Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.
“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.
“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.
“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.
“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”
Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.
“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.
“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”
“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”
Garvan Institute
www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk
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A research team at the Krembil Research Institute has discovered a pair of tissue biomarkers that directly contribute to the harmful joint degeneration associated with spine osteoarthritis.
The study is the first to show that elevated levels of both of these biomarkers cause inflammation, cartilage destruction and collagen depletion.
‘These biomarkers are actively involved in increasing inflammation and destructive activities in spine cartilage and assist in its destruction,’ says principal investigator Dr. Mohit Kapoor, Senior Scientist at the Krembil Research Institute and Associate Professor in the Department of Surgery and the Department of Laboratory Medicine and Pathobiology at the University of Toronto. Dr. Kapoor specializes in arthritis research.
Osteoarthritis affects about three million Canadians and is characterized by a breakdown of the protective cartilage found in the body’s spine, hand, knee and hip joints. There is no known cure.
The study involved tissue biopsies from 55 patients undergoing decompression or discectomy at the Krembil Neuroscience Centre at Toronto Western Hospital. As part of the study, the research team – led by Dr. Kapoor and comprising Dr. Akihiro Nakamura, a post-doctoral fellow, and Dr. Y. Raja Rampersaud, a clinical expert and spine surgeon – explored the role, function and signaling mechanisms of two tissue biomarkers: microRNA-181a-5p and microRNA-4454.
The study screened 2,100 microRNAs and found that measuring the levels of these two specific biomarkers can help clinicians determine the stage to which the disease has progressed, and provide a tool for determining the degree of cartilage destruction.
‘These are biologically active molecules. By detecting them in the tissue biopsies, we have a tool for determining the stage of spine osteoarthritis,’ says Dr. Kapoor. ‘What is really significant, however, is we have discovered that these biomarkers are actively involved in destroying cartilage and increasing inflammation. Furthermore, they promote cartilage cells to die and deplete the most important component of your cartilage, which is your collagen.’
The discovery represents the end of the first stage of research. The team is now investigating whether these biomarkers can be detected in the blood – which would help clinicians more simply determine the stage of spine osteoarthritis – and whether further studying the biomarkers will allow researchers to halt and reverse spine degeneration.
‘The most critical aspect of this discovery is that we have found that they are active. Now that we know what they are, we are currently looking at blocking them and restoring the joint,’ says Dr. Kapoor.
Krembil Research Institute
www.uhn.ca/corporate/News/PressReleases/Pages/research_team_discovers_two_biomarkers_that_contribute_to_spine_osteoarthritis.aspx
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Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.
“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.
Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.
The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.
Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.
After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.
The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.
In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.
In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.
University of Pittsburgh School of Medicine
www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx
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Researchers from the National Institutes of Health and their colleagues identified the genetic cause and a possible therapeutic target for a rare form of paediatric progressive neuropathy. Neuropathy, damage or disease affecting the peripheral nervous system, can range from rare conditions linked to a patient’s exome to more common causes like diabetes and viral infections. Neuropathies can affect both motor and sensory neurons, producing muscle weakness, numbness, pain, and a wide range of symptoms.
These types of discoveries underscore the importance of the families who volunteer to participate in clinical research. “This case superbly illustrates how the intensive study of children with very rare neurological disorders can lead quickly to a deep knowledge of a specific genetic condition, as well as uncover mysteries of the nervous system relevant to a wide spectrum of disorders,” said Walter J. Koroshetz, M.D., director of NINDS.
In their report, researchers examined a 10-year-old child with early onset, progressive neuropathy primarily affecting his ability to walk, grasp, and perform fine motor skills. When the patient’s complete genetic makeup, or genome, was analysed, a mutation was found in the gene associated with the protein KCC3. This protein is important for the ability of cells to respond to swelling.
When a neuron swells, KCC3 is involved in the mechanism that drives fluid out, returning the cell to normal. In the absence of this protein (in what is called a loss-of-function mutation), extreme swelling of the neurons can occur, which in turn leads to nerve damage.
In the study, the patient’s mutation affected the ability of KCC3 to turn off once it was no longer needed, leading to the opposite effect—shrunken neurons that also fail to communicate properly. This is referred to as a gain-of-function mutation, causing the affected protein to behave in a new and damaging way.
“This protein, KCC3, has been connected to other forms of neuropathy in the past,” said Carsten G. Bonnemann, M.D., a senior investigator in the Neuromuscular and Neurogenetic Disorders of Childhood Section at NINDS and a senior author of the paper. “What’s unique here is that this is the first time that we have seen a gain-of-function mutation in the KCC3 protein that leads to neuropathy.”
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Acute kidney injury identifiable in preterm infants
, /in E-News /by 3wmediaResearchers at the University of Alabama at Birmingham have found that the amount of proteins excreted in the urine of preterm infants with acute kidney injury, or AKI, is different from that excreted by infants with healthy kidneys.
The study was led by principal investigator David Askenazi, M.D.
“The findings in this study could help physicians better diagnose kidney health in newborns,” said Askenazi, associate professor in the UAB Department of Pediatrics and director of UAB’s Pediatric and Infant Center for Acute Nephrology. “Having better diagnostic tests to diagnose kidney injury will have an important impact on how we care for infants and how we prognosticate outcomes, and will enable us to design studies to prevent and/or mitigate kidney damage in these very vulnerable babies.”
Improving the ability to diagnose AKI, a sudden decline in kidney function, is critical, as approximately 25 percent of preterm infants develop AKI. Compared to those without AKI, preterm infants with this common problem have a lower chance for survival, increased hospital stays and increased hospital expenditures.
Importantly, premature infants are at high risk for chronic kidney disease, and AKI may be an important cause for this.
Investigators took a single drop of urine from 113 preterm infants and measured 14 urine proteins. The concentrations of many of these proteins, including cystatin c, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin and alpha glutathione S-transferase, were higher in preterm infants who later showed abnormal kidney function, compared to their counterparts with normal function.
“Additional studies to determine how AKI contributes to chronic kidney disease in these newborns are underway,” Askenazi said. “Improving our ability to diagnose AKI accurately is critical to improving our understanding of the natural course of disease and developing strategies to improve outcomes.”
University of Alabama at Birmingham www.uab.edu/news/innovation/item/7485-acute-kidney-injury-identifiable-in-preterm-infants
Sampling method used for new breast cancer tests may lead to underestimate of risk
, /in E-News /by 3wmediaNot only is breast cancer more than one disease, but a single breast cancer tumour can vary within itself, a finding that University of Pittsburgh Cancer Institute (UPCI) researchers discovered has the potential to lead to very different patient treatment plans depending on the tumour sample and diagnostic testing used.
The results demonstrate that tumour sampling techniques used with newly developed “personalized medicine” gene expression profile tests may need to be refined to ensure that the most appropriate tumour sections are selected for testing.
“These tests are a good thing—they’ve done an incredible job identifying women with breast cancers that have a low risk of recurrence who don’t need chemotherapy, saving them from the toxicity and discomfort of unnecessary treatment,” said Adrian V. Lee, Ph.D., professor of pharmacology and chemical biology at UPCI, partner with UPMC CancerCenter. “However, as with any new technology, we need to understand how these tests work, and we’re finding that the sampling process, which involves liquefying tumours, loses information that could be important in determining the best treatment plan for patients with more aggressive tumours.”
Gene expression profiling is an increasingly popular type of test that tells doctors what certain genes are doing in a tissue sample, such as causing the cells to actively divide and multiply. Several tests have been developed in recent years to aid oncologists in developing breast cancer treatment plans. They involve taking a small bit of the tumour—or multiple small bits mixed together—and testing it.
The tests can tell oncologists if the cancer has a low, intermediate or high risk of recurring. The level of risk can help doctors and patients decide whether an aggressive treatment plan involving chemotherapy is beneficial or likely to do more harm than good.
Dr. Lee and his team examined 71 cases of a type of breast cancer called “estrogen-receptor-positive” that was caught early and hadn’t yet spread to other parts of the body. In all cases, the tumour had been removed and samples taken for gene expression profiling. A total of 181 samples were taken from various parts of the tumours, and the researchers measured the expression of 141 different genes from five different types of gene expression profile tests commonly used for breast cancer tumours.
For 25 percent of the patients, their tumours received a different risk of recurrence score depending on which sample was processed.
“This indicates that one part of the tumour is more aggressive than another part. If an oncologist were to know this, he or she would likely recommend a treatment plan tailored to destroy the most aggressive section of the tumour,” said Dr. Lee.
Because the patients in this study were all caught early, their risk of recurrence was low to begin with, and there weren’t enough recurrences to make a meaningful determination on whether they would have done better if more samples were tested from their tumours.
“It would be valuable to repeat this study with a much larger group of breast cancer patients and follow them over time so that we could definitively determine if the way sampling is done with these tests is, indeed, resulting in patients getting cancer recurrences that wouldn’t have happened if the sampling process was changed,” said Dr. Lee.
University of Pittsburgh Cancer Institute
www.upmc.com/media/NewsReleases/2016/Pages/lee-tumorhetero-gep-cancerresearch.aspxProstate cancer study may lead to new diagnostic tests and treatments
, /in E-News /by 3wmediaProstate cancer patients have been offered hope after scientists at Newcastle University have identified a new group of molecules that could be targeted to slow tumour growth.
Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
Experts used an advanced screening technique which found hundreds of genes were affected by the male hormone testosterone. It is believed this could lead to new diagnostic tests and treatments.
Among the 700 genes identified was an important set that add sugar groups – known as glycans – to the surface of prostate cancer cells. This group has never been investigated before.
Treatments targeting glycan sugar groups have been developed for other types of the illness, such as breast cancer. It is hoped these treatments could also be used for prostate cancer.
Results of the research suggest that testosterone changes glycans to make cancer cells more likely to survive, grow and spread to other parts of the body.
Scientists say there is the potential to target these glycans which could stop the growth and spread of tumours and save lives.
Dr Jennifer Munkley, Research Associate at the Institute of Genetic Medicine, Newcastle University, co-led the three-year research project with Professor David Elliott.
She said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.
“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.
Glycans have the potential to be used as part of a diagnostic test to help doctors decide which prostate cancers need treatment.
One in eight men will be diagnosed with the condition. It is the most common cancer in UK males, and there is a need to identify how the disease progresses and for treatment options to be established.
Researchers at Newcastle University used a technique, called RNA-sequencing, to identify the new set of genes that are important.
The genes identified may provide novel ways the disease can be monitored in patients to predict the most aggressive prostate cancers that need to be treated.
Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them.
“However, in order to develop new, effective treatments, we need to understand more about the genetic makeup of aggressive prostate cancers and identify what makes them tick.
“This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.
Newcastle University www.ncl.ac.uk/press/news/2016/07/prostatecancerstudy/
Discovery of infants’ airway microbiomes may help predict lung disease
, /in E-News /by 3wmediaIn contrast to the general belief that the airways of an infant are sterile until after birth, University of Alabama at Birmingham researchers and colleagues have found that the infant airway is already colonised with bacteria or bacterial DNA when a baby is born — and this is true for infants born as early as 24 weeks gestation.
How microbes get into the airways and the purpose of this pre-birth colonisation are still unclear, but the pattern of colonisation appears to have an important link to later severe neonatal lung disease.
An early microbial imbalance, or dysbiosis, is predictive for the development of bronchopulmonary dysplasia, or BPD, a chronic lung disease of prematurity. The extremely low birth-weight, or ELBW, infants in this study had an average birth weight of 1 pound, 8 ounces. Researchers found that the ELBW infants who went on to develop life-threatening BPD showed abnormal microbial colonisation patterns at birth, as compared to pre-term infants who did not get BPD.
“Right at birth, your respiratory microbiome can possibly predict your risk for BPD,” said Charitharth Vivek Lal, M.D., assistant professor in the UAB Pediatrics Division of Neonatology and the lead investigator of this study.
Extremely premature infants are at risk for BPD, which is the most common lung pathology of these tiny infants and a significant cause of morbidity, mortality and health care expenditures. Adults and children who had BPD as infants have lungs that failed to develop properly and are more prone to worse lung function, asthma, lung infections and pulmonary hypertension.
The researchers also looked at the airway microbiomes of 18 ELBW infants with established BPD and found that their microbiomes had a decreased diversity of types of microbes, and the pattern was very different from those of ELBW infants shortly after birth or full-term infants at birth.
As to specific groups of microbes, the phylum Proteobacteria, which includes bacteria like E. coli, appeared to be involved in BPD pathology, and the genus Lactobaccillus, part of the phylum Firmicutes, appeared to be involved in disease protection.
Lal and colleagues found decreased Lactobacillus abundance in the airway microbiomes of 10 infants born to mothers who had chorioamnionitis — an infection of the membranes of the placenta and an independent risk factor for BPD — as well as decreased Lactobacillus abundance at birth in the airways of the BPD-predisposed, ELBW infants, as compared to BPD-resistant infants. Research elsewhere has suggested a beneficial role for Lactobacillus against airway diseases and for lung development.
“I predict that researchers will study the use of respiratory probiotics, and the role of the gut-lung microbiome axis in the future,” Lal said.
For five ELBW infants who later developed BPD, the researchers collected periodic airway microbiome samples from birth through 9 weeks and saw extremely similar patterns of change in the microbiomes over time.
As for the source of the microbes, Lal and colleagues wrote, “As it is commonly believed that colonization of neonates originates in the birth canal, we were surprised to find that the airway microbiome of vaginally delivered and caesarean section-delivered neonates were similar, which suggests that the microbial DNA in the airways is probably transplacentally derived, consistent with reports that the placenta has a rich microbiome.”
The researchers speculate that this transmission of bacteria or bacterial DNA to the in-utero infant could be via blood or amniotic fluid.
University of Alabama at Birmingham www.uab.edu/news/innovation/item/7505-discovery-of-infants-airway-microbiomes-may-help-predict-lung-disease
Scientists identify marker for myeloid-derived suppressor cells
, /in E-News /by 3wmediaMyeloid-derived suppressor cells (MDSCs) are a population of immune cells that have been implicated in tumour resistance to various types of cancer treatment, including targeted therapies, chemotherapy and immunotherapy. Polymorphonuclear (PMN) cells represent the largest population of MDSCs. However, fully understanding the biology and clinical importance of these cells has been hampered by a lack of markers that set them apart from normal neutrophils.
Now, scientists at The Wistar Institute have identified a marker that distinguishes PMN-MDSCs from neutrophils in the blood of patients with a variety of cancers. Study results showed that higher numbers of cells positive for the marker were associated with larger tumour size.
‘Before we started this work, the only way to isolate PMN-MDSCs was by density centrifugation of blood because they could not be properly identified in tumour tissue,’ said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and professor and program leader of the Translational Tumor Immunology program at Wistar, and senior author of the study. ‘Identifying a marker for PMN-MDSCs will allow us to study these cells in much more depth. In addition, if our clinical results are verified in larger studies, the marker could also be used to help physicians and patients make informed treatment decisions and, ultimately, it could be exploited to target PMN-MDSCs for therapeutic benefit.’
MDSCs are potent suppressors of immune responses. They naturally regulate immune responses in healthy individuals, but the population rapidly expands in patients with cancer, and the presence of these cells has been associated with poor patient outcomes. One of the few ways to know for sure that cells are MDSCs is by showing that they suppress immune responses in vitro.
Gabrilovich and colleagues used whole-genome analysis to compare the genes expressed by PMN-MDSCs and neutrophils from the blood of patients with non-small cell lung cancer and head and neck cancer. The researchers focused on the genes expressed at higher levels in PMN-MDSCs compared with neutrophils, in particular those genes that encoded proteins detectable on the surface of cells. This led them to the protein LOX-1, which was almost undetectable on the surface of neutrophils but detectable on the surface of about one-third of PMN-MDSCs.
When they tested the ability of LOX-1-positive and LOX-1-negative cells to suppress immune responses in vitro only the LOX-1-positive cells had this function. The results showed that LOX-1 was a marker of PMN-MDSCs.
Gabrilovich and colleagues speculated that the number of LOX-1-positive PMN-MDSCs in blood and tumour samples from patients with cancer might help predict disease severity and outcome. They had samples from only a few patients with non-small cell lung cancer to study, but found that patients with larger tumours had higher numbers of these cells in both blood and tumour samples.
‘Now that we have a specific marker for MDSCs, we can begin to ask new questions about the biology of these cells and their clinical significance,’ added Gabrilovich.
EurekAlert www.eurekalert.org/pub_releases/2016-08/twi-wsi080316.php
New analytical tool for fluorescence detection of double-stranded RNA
, /in E-News /by 3wmediaRibonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.
A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.
The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.
In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.
It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.
Tohoku University www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html
Researchers uncover complex genetic secrets of cancer risk
, /in E-News /by 3wmediaIn a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.
In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.
Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.
The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.
The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.
Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.
“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.
“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.
“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.
“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”
Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.
“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.
“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”
“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”
Garvan Institute www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk
Two biomarkers that contribute to spine osteoarthritis
, /in E-News /by 3wmediaA research team at the Krembil Research Institute has discovered a pair of tissue biomarkers that directly contribute to the harmful joint degeneration associated with spine osteoarthritis.
The study is the first to show that elevated levels of both of these biomarkers cause inflammation, cartilage destruction and collagen depletion.
‘These biomarkers are actively involved in increasing inflammation and destructive activities in spine cartilage and assist in its destruction,’ says principal investigator Dr. Mohit Kapoor, Senior Scientist at the Krembil Research Institute and Associate Professor in the Department of Surgery and the Department of Laboratory Medicine and Pathobiology at the University of Toronto. Dr. Kapoor specializes in arthritis research.
Osteoarthritis affects about three million Canadians and is characterized by a breakdown of the protective cartilage found in the body’s spine, hand, knee and hip joints. There is no known cure.
The study involved tissue biopsies from 55 patients undergoing decompression or discectomy at the Krembil Neuroscience Centre at Toronto Western Hospital. As part of the study, the research team – led by Dr. Kapoor and comprising Dr. Akihiro Nakamura, a post-doctoral fellow, and Dr. Y. Raja Rampersaud, a clinical expert and spine surgeon – explored the role, function and signaling mechanisms of two tissue biomarkers: microRNA-181a-5p and microRNA-4454.
The study screened 2,100 microRNAs and found that measuring the levels of these two specific biomarkers can help clinicians determine the stage to which the disease has progressed, and provide a tool for determining the degree of cartilage destruction.
‘These are biologically active molecules. By detecting them in the tissue biopsies, we have a tool for determining the stage of spine osteoarthritis,’ says Dr. Kapoor. ‘What is really significant, however, is we have discovered that these biomarkers are actively involved in destroying cartilage and increasing inflammation. Furthermore, they promote cartilage cells to die and deplete the most important component of your cartilage, which is your collagen.’
The discovery represents the end of the first stage of research. The team is now investigating whether these biomarkers can be detected in the blood – which would help clinicians more simply determine the stage of spine osteoarthritis – and whether further studying the biomarkers will allow researchers to halt and reverse spine degeneration.
‘The most critical aspect of this discovery is that we have found that they are active. Now that we know what they are, we are currently looking at blocking them and restoring the joint,’ says Dr. Kapoor.
Krembil Research Institute www.uhn.ca/corporate/News/PressReleases/Pages/research_team_discovers_two_biomarkers_that_contribute_to_spine_osteoarthritis.aspx
Correcting metabolic deficiencies may improve depression symptoms
, /in E-News /by 3wmediaIdentifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.
“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.
Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.
The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.
Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.
After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.
The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.
In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.
In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.
University of Pittsburgh School of Medicine www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx
Novel genetic mutation may lead to the progressive loss of motor function
, /in E-News /by 3wmediaResearchers from the National Institutes of Health and their colleagues identified the genetic cause and a possible therapeutic target for a rare form of paediatric progressive neuropathy. Neuropathy, damage or disease affecting the peripheral nervous system, can range from rare conditions linked to a patient’s exome to more common causes like diabetes and viral infections. Neuropathies can affect both motor and sensory neurons, producing muscle weakness, numbness, pain, and a wide range of symptoms.
These types of discoveries underscore the importance of the families who volunteer to participate in clinical research. “This case superbly illustrates how the intensive study of children with very rare neurological disorders can lead quickly to a deep knowledge of a specific genetic condition, as well as uncover mysteries of the nervous system relevant to a wide spectrum of disorders,” said Walter J. Koroshetz, M.D., director of NINDS.
In their report, researchers examined a 10-year-old child with early onset, progressive neuropathy primarily affecting his ability to walk, grasp, and perform fine motor skills. When the patient’s complete genetic makeup, or genome, was analysed, a mutation was found in the gene associated with the protein KCC3. This protein is important for the ability of cells to respond to swelling.
When a neuron swells, KCC3 is involved in the mechanism that drives fluid out, returning the cell to normal. In the absence of this protein (in what is called a loss-of-function mutation), extreme swelling of the neurons can occur, which in turn leads to nerve damage.
In the study, the patient’s mutation affected the ability of KCC3 to turn off once it was no longer needed, leading to the opposite effect—shrunken neurons that also fail to communicate properly. This is referred to as a gain-of-function mutation, causing the affected protein to behave in a new and damaging way.
“This protein, KCC3, has been connected to other forms of neuropathy in the past,” said Carsten G. Bonnemann, M.D., a senior investigator in the Neuromuscular and Neurogenetic Disorders of Childhood Section at NINDS and a senior author of the paper. “What’s unique here is that this is the first time that we have seen a gain-of-function mutation in the KCC3 protein that leads to neuropathy.”
NIH www.nih.gov/news-events/news-releases/novel-genetic-mutation-may-lead-progressive-loss-motor-function