A study by researchers in Nottingham has identified seven distinct types of breast cancer, a discovery which could lead to new and improved prognostic tests for patients with the disease.
The findings could revolutionise the way in which breast cancer patients are treated by giving clinicians more detailed information about a patient’s breast cancer type and helping them create a more personalised treatment plan, avoiding over or under-treatment.
Dr Green said: ‘With an increasing number of treatment options available for breast cancer patients, decision making regarding the choice of the most appropriate treatment method is becoming increasingly complex. Improvements in care and outcome for patients with breast cancer will involve improved targeting of effective therapies to appropriate patients.
‘Equally important should be improvement in parallel strategies to avoid unnecessary or inappropriate treatment and side effects.’
Breast cancer is a biologically complex disease and each tumour can have very different properties, so the more information that doctors have about each patient’s cancer, the better they can plan treatments. Currently just two proteins are tested for as standard in breast cancer cells (known as biomarkers): the oestrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2), alongside information about the tumour size, spread and grade.
Dr Green and colleagues, who also included Professor Ian Ellis in the Division of Oncology and Jon Garibaldi and Daniele Soria in the University’s School of Computer Science, wanted to see if, by testing for more biomarkers, but keeping the number of biomarkers as low as possible to make an affordable test a realistic proposition, they could devise categories that better reflect the diversity of breast cancer and, importantly, better predict how a patient’s cancer is likely to progress.
Using tissue that now forms part of the Breast Cancer Campaign Tissue Bank, the team tested 1073 tumour samples and from these, 997 (93%) fitted perfectly into one of seven classes, whereas 76 (7%) had mixed characteristics and couldn’t be put into a distinct category. They then verified these classes in another 238 tumour samples.
The seven classes are defined by different combinations and levels of ten biomarkers found in breast cancer cells. These biomarkers include ER and HER2, the two biomarkers currently tested for in clinics, but also others that are not currently tested for, such as p53, cytokeratins, HER3 and HER4.
To test whether the new classes could give doctors more information about prognosis, Dr Green’s team compared the classes to survival outcomes from the patient samples. Each of the seven classes was found to have its own unique survival outcome. This indicates that the classes can tell us more about prognosis and help doctors to fine-tune treatment plans to improve survival.
Importantly, the technology required to measure protein biomarkers in tumour samples is already in place in most pathology laboratories across the UK, whereas newly developed genetic profiling tests such as Oncotype DX need to be sent to specialist laboratories, which brings additional costs.
University of Nottingham
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A research team from Weill Cornell Medical College and The Rockefeller University has identified a bacterium it believes may trigger multiple sclerosis (MS), a chronic, debilitating disorder that damages myelin forming cells in the brain and spinal cord.
Their study is the first to identify the bacterium, Clostridium (C.) perfringens type B, in humans.
The scientists say their study is small and must be expanded before a definitive connection between the pathogen and MS can be made, but they also say their findings are so intriguing that they have already begun to work on new treatments for the disease.
‘This bacterium produces a toxin that we normally think humans never encounter. That we identified this bacterium in a human is important enough, but the fact that it is present in MS patients is truly significant because the toxin targets the exact tissues damaged during the acute MS disease process,’ say the study’s first author, K. Rashid Rumah, an MD/PhD student at Weill Cornell Medical College, and the study’s senior investigator, Dr. Timothy Vartanian, professor of neurology and neuroscience at Weill Cornell Medical College and director of the Judith Jaffe Multiple Sclerosis Center at New York-Presbyterian Hospital/Weill Cornell Medical Center.
‘While it is clear that new MS disease activity requires an environmental trigger, the identity of this trigger has eluded the MS scientific community for decades,’ Dr. Vartanian says. ‘Work is underway to test our hypothesis that the environmental trigger for MS lays within the microbiome, the ecosystem of bacteria that populates the gastrointestinal tract and other body habitats of MS patients.’
The study describes discovery of C. perfringens type B in a 21-year-old woman who was experiencing a flare-up of her MS.
The woman was part of the Harboring the Initial Trigger for MS (HITMS) observational trial launched by Dr. Vartanian and K. Rashid Rumah, who works both with Dr. Vartanian and with co-author Dr. Vincent Fischetti at The Rockefeller University.
C. perfringens, found in soil, is one of the most common bacteria in the world. It is divided into five types. C. perfringens type A is commonly found in the human gastrointestinal tract and is believed to be largely harmless.
C. perfringens types B and D carry a gene (epsilon toxin) that emits a protoxin — a non-active precursor form of the toxin — which is turned into the potent ‘epsilon’ toxin within the intestines of grazing animals. The epsilon toxin travels through the blood to the brain, where it damages brain blood vessels and myelin, the insulation protecting neurons, resulting in MS-like symptoms in the animals. While the D subtype has only been found in two people, based on prior studies by other investigators, the B subtype had never been found in humans.
Nevertheless, Rumah and the research team set out to see if subtypes B or D exist in humans and if they are associated with MS. They tested banked blood and spinal fluid from both MS patients and healthy controls for antibody reactivity to the epsilon toxin. Investigators found that levels of epsilon toxin antibodies in MS patients were 10 times higher than in the healthy controls — the blood of only one out of 100 control participants showed an immune reaction to the toxin.
The team also examined stool samples from both MS patients and healthy controls enrolled in the HITMS clinical study, and found that 52 percent of healthy controls carried the A subtype compared to 23 percent of MS patients. ‘This is important because it is believed that the type A bacterium competes with the other subtypes for resources, so that makes it potentially protective against being colonised by epsilon toxin secreting subtypes and developing MS,’ say Rumah and Vartanian.
The search by investigators for evidence of C. perfringens type B paid off in the case of a young MS patient. Co-author Dr. Jennifer Linden, a microbiologist at Weill Cornell Medical College, isolated the actual bacterium from the patient’s stool.
The authors suspect that once a human is infected with C. perfringens type B or D, the pathogen usually lives in the gut as an endospore, a seed-like structure that allows some bacteria to remain dormant for long periods. ‘The human gastrointestinal tract is host to approximately 1,000 different bacterial species, but is not a hospitable environment for C. perfringens type B or D, so it does not grow well there. It hibernates in a protective spore. When it does grow, we anticipate it generates a small quantity of epsilon toxin, which travels through the blood into the brain,’ Dr. Vartanian says. ‘We believe the bacterium’s growth is episodic, meaning the environmental trigger is always present, and it rears its ugly head from time to time.’
He says researchers do not know how humans are infected with C. perfringens type B or D, but they are studying potential routes of exposure. The scientists are also in the first stages of investigating potential treatments against the pathogen.
Weill Cornell Medical College
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Recent research from University of Copenhagen sheds light on previously unknown facts about muscular dystrophy at molecular level. The breakthrough is hoped to improve future diagnosis and treatment of the disease. Researchers have developed a method that will make it easier to map the proteins that have an important kind of sugar monomer, mannose, attached. This is an important finding, as mannose deficiency can lead to diseases such as muscular dystrophy.
About 3,000 people in Denmark suffer from one of the serious muscle-related diseases that come under the heading of muscular dystrophy. Some patients diagnosed with muscular dystrophy die shortly after birth, others become severely retarded and develop eye problems, while certain groups are confined to life in a wheelchair. Common to all muscular dystrophy sufferers is the difficulty of their muscle cells to attach themselves to each other and to the surrounding tissue. However, little is actually known about the root causes of the disease.
New basic research from University of Copenhagen now offers insight into previously unknown facts about muscular dystrophy that may improve future diagnosis and treatment of the disease.
‘Our new research findings may shed light on some of the cellular processes that take place in connection with, for example, muscular dystrophy. This is important information because it is crucial for us to gain as detailed an understanding as possible about the individual cell components. Although the journey from the current basic research to any potential treatment options or diagnostic tools is a long one, our discoveries give grounds for optimism,’ says postdoc Malene Bech Vester-Christensen – who carried out the new experiments from her base at the Faculty of Health and Medical Sciences, University of Copenhagen, and has since taken up a research position at Novo Nordisk.
The new method developed by researchers makes it easier to map the proteins that The protein previously associated with muscular dystrophy is a so-called glycoprotein – a protein with chains of sugar molecules attached. The special kind of sugar attached to these glycoproteins is called mannose. A functional pathway for binding mannose to the proteins is key to the functioning of the human organism, and genetic defects in the process that attaches mannose to the proteins – known as O-mannosylation – can lead to diseases such as muscular dystrophy.
‘To date, only one single protein has been identified and characterised where the mannose deficiency on the protein leads to muscular dystrophy, but our method enables us to faster identify many new proteins that have mannose attached and therefore potentially play a key role for the disease,’ says Adnan Halim, who is associated with the research project and a postdoc with the Danish National Research Foundation, Copenhagen Center for Glycomics.
University of Copenhagen
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New research provides direct evidence that genetic variations in some African Americans with chronic kidney disease contribute to a more rapid decline in kidney function compared with white Americans. The research, led by investigators from the University of Maryland School of Medicine and Johns Hopkins University, may help explain, in part, why even after accounting for differences in socio-economic background, end-stage kidney disease is twice as prevalent among blacks as whites.
‘What we found is pretty remarkable — that variations in a single gene account for a large part of the racial disparity in kidney disease progression and risk for end-stage kidney disease,’ says co-lead author and nephrologist Afshin Parsa, M.D., M.P.H., assistant professor of medicine and member of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine. ‘If it were possible to reduce the effect of this gene, there could be a very meaningful decrease in progressive kidney and end-stage kidney disease within blacks.’
Previous landmark discoveries revealed that two common variants within a gene called apolipoprotein L1 (APOL1) were strongly associated with non-diabetic end-stage renal disease in blacks. Having only one copy of the variant APOL1 gene variant is associated with a health benefit – protection against African sleeping sickness, a potentially lethal parasitic infection transmitted by the tsetse fly, found only in sub-Saharan Africa. However, people with two copies of the variant are at a higher risk for kidney disease.
The current research expands on these prior findings and demonstrates the effect of these variants on the progression of established kidney disease and development of end-stage renal disease; analyses their role in black-versus-white renal disease disparities; investigates their effect in patients with diabetes and observes the impact of blood pressure control on APOL1-associated disease progression.
According to Dr. Parsa, approximately 13 percent of the African American population has two copies of the risk variants. Fortunately, most of those at risk do not develop kidney disease. The researchers analysed the role of APOL1 gene variants in two longitudinal studies of patients with kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension (AASK), both sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). Dr. Parsa examined the CRIC study data, while co-lead author and Johns Hopkins epidemiologist W.H. Linda Kao, Ph.D., M.H.S., analysed the AASK data.
University of Maryland Medical Center
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A pilot study by a multi-disciplinary team of investigators at Georgetown University suggests that a simple dot test could help doctors gauge the extent of dopamine loss in individuals with Parkinson’s disease (PD).
‘It is very difficult now to assess the extent of dopamine loss — a hallmark of Parkinson’s disease — in people with the disease,’ says lead author Katherine R. Gamble, a psychology PhD student working with two Georgetown psychologists, a psychiatrist and a neurologist. ‘Use of this test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,’ she adds.
Gamble works in the Cognitive Aging Laboratory, led by the study’s senior investigator, Darlene Howard, PhD, Davis Family Distinguished Professor in the department of psychology and member of the Georgetown Center for Brain Plasticity and Recovery.
The TLT tests implicit learning, a type of learning that occurs without awareness or intent, which relies on the caudate nucleus, an area of the brain affected by loss of dopamine.
The test is a sequential learning task that does not require complex motor skills, which tend to decline in people with PD. In the TLT, participants see four open circles, see two red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.
Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, PD participants implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively impact that learning compared to healthy older adults.
‘Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,’ says Gamble.
In this study of 27 people with PD, the research team is now testing how implicit learning may differ by different PD stages and drug doses.
‘This work is important in that it may be a non-invasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,’ explains Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center, and a co-author of the study.
They hope the TLT may one day be a tool to help determine levels of dopamine loss in PD.
EurekAlert
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For years, scientists have observed that tumour cells from certain breast cancer patients with aggressive forms of the disease contained low levels of mitochondrial DNA. But, until recently, no one was able to explain how this characteristic influenced disease progression.
Now, University of Pennsylvania researchers have revealed how a reduction in mitochondrial DNA content leads human breast cancer cells to take on aggressive, metastatic properties. The work breaks new ground in understanding why some cancers progress and spread faster than others and may offer clinicians a biomarker that would distinguish patients with particularly aggressive forms of disease, helping personalise treatment approaches.
The study was led by the Penn School of Veterinary Medicine’s Manti Guha, a senior research investigator, and Narayan Avadhani, Harriet Ellison Woodward Professor of Biochemistry in the Department of Animal Biology. Additional Penn Vet collaborators included Satish Srinivasan, Gordon Ruthel, Anna K. Kashina and Thomas Van Winkle. They teamed with Russ P. Carstens of Penn’s Perelman School of Medicine and Arnulfo Mendoza and Chand Khanna of the National Cancer Institute.
Mitochondria, the ‘powerhouses’ of mammalian cells, are also a signalling hub. They are heavily involved in cellular metabolism as well as in apoptosis, the process of programmed cell death by which potentially cancerous cells can be killed before they multiply and spread. In addition, mitochondria contain their own genomes, which code for specific proteins and are expressed in co-ordination with nuclear DNA to regulate the provision of energy to cells.
In mammals, each cell contains between 100 and 1,000 copies of mitochondrial DNA, but previous research had found that as many as 80 percent of people with breast cancer have low mitochondrial DNA, or mtDNA, content.
To gain an understanding of the mechanism that connects low mtDNA levels with a cellular change that leads to cancer and metastasis, Guha, Avadhani and their colleagues set up two systems by which they could purposefully reduce the amount of mtDNA in a cell. One used a chemical to deplete the DNA content, and another altered mtDNA levels genetically. They compared normal, non-cancer-forming human breast tissue cells with cancerous breast cells using both of these treatments, contrasting them with cells with unmanipulated mtDNA.
The differences between cells with unmodified and reduced mtDNA levels were striking, the researchers found. The cells in which mtDNA was reduced had altered metabolism and their structure appeared disorganised, more like that of a metastatic cancer cell. Even the non-tumour-forming breast cells became invasive and more closely resembled cancer cells. Significantly, cells with reduced mtDNA became self-renewing and expressed specific cell surface markers characteristic of breast cancer stem cells.
‘Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells,’ Avadhani said. ‘These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body.’
‘Most patients who had low copy numbers of mitochondrial DNA have a poor disease prognosis,’ Guha said. ‘We’ve shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease. In the future, mtDNA and the factors involved in mitochondrial signalling may serve as markers of metastatic potential and novel points for therapeutic intervention of cancer stem cells. Since the specific inducers of cancer stem cells, which are key drivers of metastasis, remain elusive, our current findings are a significant advancement in this area.’
No two breast cancers are exactly alike, so having a way to recognise patients who are at high-risk for developing particularly invasive and rapidly metastasising cancers could help physicians customise treatments. In addition, researchers are currently filling in the unknown components of the signalling pathway linking a cell’s mitochondrial DNA levels and its involvement in metastatic disease.
University of Pennsylvania
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The sensitivity of the GLP-1 hormone, which is secreted by the gastrointestinal tract, can predict the metabolic efficacy of a gastric bypass. The use of a GLP1 challenge could thus function as a novel predictive biomarker for personalised treatment of type 2 diabetes and obesity
The gastric bypass is one of the most commonly performed surgical procedures in the treatment of obesity. In most patients, it quickly produces substantial body weight loss. Moreover, even before the weight loss, the procedure leads to improved glucose tolerance. However, these metabolic improvements vary considerably from patient to patient.
A hormone test may be able to predict the extent of metabolic improvement caused by the gastric bypass. These are the results of a study on a rodent model conducted by Prof. Dr. Matthias Tschöp and his colleagues from the Institute of Diabetes and Obesity (IDO), Helmholtz Diabetes Center at Helmholtz Zentrum München together with a team of researchers led by Dr. Kirk Habegger at the Metabolic Disease Institute of the University of Cincinnati.
After gastric bypass surgery, the concentration of the gut hormone GLP-1 (glucagon-like peptide 1) in the blood rises significantly. GLP-1 increases insulin secretion and contributes to improved blood glucose levels and blood lipids. As the rat studies by the Tschöp and Habegger research teams showed, GLP-1 responsiveness varied considerably with regard to glucose metabolism. More importantly, the more responsive the animals were to GLP-1, the greater the efficacy of the gastric bypass turned out to be regarding glucose metabolism improvements.
Thus, the responsiveness to GLP-1 could be a key indicator for the success of the gastric bypass. ‘If our results are confirmed in clinical trials with patients, the hormone response could be tested before the planned surgery and surgeons would be able to predict how much an individual patient’s glucose metabolism would benefit,’ said Tschöp. ‘This will contribute to the development of personalized therapies for type 2 diabetes and obesity. For surgical procedures such as gastric bypass this is particularly compelling because such operations are complex and cannot be easily reversed.’
The numerous secondary diseases related to excess weight and obesity, such as type 2 diabetes, are among the most common diseases in Germany. These diseases are the focus of research at Helmholtz Zentrum München, a partner in the German Center for Diabetes Research (DZD).
Helmholtz Zentrum München
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The absence of a protein called SMG1 could be a contributing factor in the development of Parkinson’s disease and other related neurological disorders, according to a study led by the Translational Genomics Research Institute (TGen).
The study screened 711 human kinases (key regulators of cellular functions) and 206 phosphatases (key regulators of metabolic processes) to determine which might have the greatest relationship to the aggregation of a protein known as alpha-synuclein, which has been previously implicated in Parkinson’s disease. Previous studies have shown that hyperphosphorylation of the α-synuclein protein on serine 129 is related to this aggregation.
‘Identifying the kinases and phosphates that regulate this critical phosphorylation event may ultimately prove beneficial in the development of new drugs that could prevent synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies,’ said Dr. Travis Dunckley, a TGen Assistant Professor and senior author of the study.
Synucleinopathies are neurodegenerative disorders characterised
by aggregates of α-synuclein protein. They include Parkinson’s, various forms of dementia and multiple systems atrophy (MSA).
By using the latest in genomic technologies, Dr. Dunckley and collaborators found that expression of the protein SMG1 was ‘significantly reduced’ in tissue samples of patients with Parkinson’s and dementia.
‘These results suggest that reduced SMG1 expression may be a contributor to α-synuclein pathology in these diseases,’ Dr. Dunckley said.
TGen collaborators in this study included researchers from Banner Sun Health Institute and Mayo Clinic Scottsdale.
Translational Genomics Research Institute
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A way of using nanoparticles to investigate the mechanisms underlying ‘mystery’ cases of infertility has been developed by scientists at Oxford University.
The technique `could eventually help researchers to discover the causes behind cases of unexplained infertility and develop treatments for affected couples. The method involves loading porous silica nanoparticle ‘envelopes’ with compounds to identify, diagnose or treat the causes of infertility.
The researchers demonstrated that the nanoparticles could be attached to boar sperm with no detrimental effects on their function.
‘An attractive feature of nanoparticles is that they are like an empty envelope that can be loaded with a variety of compounds and inserted into cells,’ says Dr Natalia Barkalina, lead author of the study from the Nuffield Department of Obstetrics and Gynaecology at Oxford University. ‘The nanoparticles we use don’t appear to interfere with the sperm, making them a perfect delivery vessel.’
Dr Barkalina added: ‘We will start with compounds to investigate the biology of infertility, and within a few years may be able to explain or even diagnose rare cases in patients. In future we could even deliver treatments in a similar way.’
Sperm are difficult to study owing to their small size, unusual shape and short lifetime outside of the body. Yet this is a vital part of infertility research, as senior author Dr Kevin Coward explains: ‘To discover the causes of infertility, we need to investigate sperm to see where the problems start. Previous methods involved complicated procedures in animals and introduced months of delays before the sperm could be used.
‘Now, we can simply expose sperm to nanoparticles in a petri dish. It’s so simple that it can all be done quickly enough for the sperm to survive perfectly unharmed.’
The team, based at the Institute of Reproductive Sciences, used boar sperm because of its similarities to human sperm, as study co-author Celine Jones explains: ‘It is similar in size, shape and activity. Now that we have proved the system in boar sperm, we hope to replicate our findings in human sperm and eventually see if we can use them to deliver compounds to eggs as well.’
Oxford University
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Researchers have linked a species of intestinal bacteria known as Prevotella copri to the onset of rheumatoid arthritis, the first demonstration in humans that the chronic inflammatory joint disease may be mediated in part by specific intestinal bacteria. The new findings by laboratory scientists and clinical researchers in rheumatology at NYU School of Medicine add to the growing evidence that the trillions of microbes in our body play an important role in regulating our health.
Using sophisticated DNA analysis to compare gut bacteria from faecal samples of patients with rheumatoid arthritis and healthy individuals, the researchers found that P. copri was more abundant in patients newly diagnosed with rheumatoid arthritis than in healthy individuals or patients with chronic, treated rheumatoid arthritis. Moreover, the overgrowth of P. copri was associated with fewer beneficial gut bacteria belonging to the genera Bacteroides.
‘Studies in rodent models have clearly shown that the intestinal microbiota contribute significantly to the causation of systemic autoimmune diseases,’ says Dan R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Pathology and Microbiology and a Howard Hughes Medical Institute investigator.
‘Our own results in mouse studies encouraged us to take a closer look at patients with rheumatoid arthritis, and we found this remarkable and surprising association,’ says Dr. Littman, whose basic science laboratory at NYU School of Medicine’s Skirball Institute of Biomolecular Medicine collaborated with clinical investigators led by Steven Abramson, MD, senior vice president and vice dean for education, faculty, and academic affairs; the Frederick H. King Professor of Internal Medicine; chair of the Department of Medicine; and professor of medicine and pathology at NYU School of Medicine.
‘At this stage, however, we cannot conclude that there is a causal link between the abundance of P. copri and the onset of rheumatoid arthritis,’ Dr. Littman says. ‘We are developing new tools that will hopefully allow us to ask if this is indeed the case.’
NYU Langone Medical Center
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Researchers identify seven types of breast cancer for more accurate prognosis
, /in E-News /by 3wmediaA study by researchers in Nottingham has identified seven distinct types of breast cancer, a discovery which could lead to new and improved prognostic tests for patients with the disease.
The findings could revolutionise the way in which breast cancer patients are treated by giving clinicians more detailed information about a patient’s breast cancer type and helping them create a more personalised treatment plan, avoiding over or under-treatment.
Dr Green said: ‘With an increasing number of treatment options available for breast cancer patients, decision making regarding the choice of the most appropriate treatment method is becoming increasingly complex. Improvements in care and outcome for patients with breast cancer will involve improved targeting of effective therapies to appropriate patients.
‘Equally important should be improvement in parallel strategies to avoid unnecessary or inappropriate treatment and side effects.’
Breast cancer is a biologically complex disease and each tumour can have very different properties, so the more information that doctors have about each patient’s cancer, the better they can plan treatments. Currently just two proteins are tested for as standard in breast cancer cells (known as biomarkers): the oestrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2), alongside information about the tumour size, spread and grade.
Dr Green and colleagues, who also included Professor Ian Ellis in the Division of Oncology and Jon Garibaldi and Daniele Soria in the University’s School of Computer Science, wanted to see if, by testing for more biomarkers, but keeping the number of biomarkers as low as possible to make an affordable test a realistic proposition, they could devise categories that better reflect the diversity of breast cancer and, importantly, better predict how a patient’s cancer is likely to progress.
Using tissue that now forms part of the Breast Cancer Campaign Tissue Bank, the team tested 1073 tumour samples and from these, 997 (93%) fitted perfectly into one of seven classes, whereas 76 (7%) had mixed characteristics and couldn’t be put into a distinct category. They then verified these classes in another 238 tumour samples.
The seven classes are defined by different combinations and levels of ten biomarkers found in breast cancer cells. These biomarkers include ER and HER2, the two biomarkers currently tested for in clinics, but also others that are not currently tested for, such as p53, cytokeratins, HER3 and HER4.
To test whether the new classes could give doctors more information about prognosis, Dr Green’s team compared the classes to survival outcomes from the patient samples. Each of the seven classes was found to have its own unique survival outcome. This indicates that the classes can tell us more about prognosis and help doctors to fine-tune treatment plans to improve survival.
Importantly, the technology required to measure protein biomarkers in tumour samples is already in place in most pathology laboratories across the UK, whereas newly developed genetic profiling tests such as Oncotype DX need to be sent to specialist laboratories, which brings additional costs. University of Nottingham
Toxin-emitting bacteria being evaluated as a potential multiple sclerosis trigger
, /in E-News /by 3wmediaA research team from Weill Cornell Medical College and The Rockefeller University has identified a bacterium it believes may trigger multiple sclerosis (MS), a chronic, debilitating disorder that damages myelin forming cells in the brain and spinal cord.
Their study is the first to identify the bacterium, Clostridium (C.) perfringens type B, in humans.
The scientists say their study is small and must be expanded before a definitive connection between the pathogen and MS can be made, but they also say their findings are so intriguing that they have already begun to work on new treatments for the disease.
‘This bacterium produces a toxin that we normally think humans never encounter. That we identified this bacterium in a human is important enough, but the fact that it is present in MS patients is truly significant because the toxin targets the exact tissues damaged during the acute MS disease process,’ say the study’s first author, K. Rashid Rumah, an MD/PhD student at Weill Cornell Medical College, and the study’s senior investigator, Dr. Timothy Vartanian, professor of neurology and neuroscience at Weill Cornell Medical College and director of the Judith Jaffe Multiple Sclerosis Center at New York-Presbyterian Hospital/Weill Cornell Medical Center.
‘While it is clear that new MS disease activity requires an environmental trigger, the identity of this trigger has eluded the MS scientific community for decades,’ Dr. Vartanian says. ‘Work is underway to test our hypothesis that the environmental trigger for MS lays within the microbiome, the ecosystem of bacteria that populates the gastrointestinal tract and other body habitats of MS patients.’
The study describes discovery of C. perfringens type B in a 21-year-old woman who was experiencing a flare-up of her MS.
The woman was part of the Harboring the Initial Trigger for MS (HITMS) observational trial launched by Dr. Vartanian and K. Rashid Rumah, who works both with Dr. Vartanian and with co-author Dr. Vincent Fischetti at The Rockefeller University.
C. perfringens, found in soil, is one of the most common bacteria in the world. It is divided into five types. C. perfringens type A is commonly found in the human gastrointestinal tract and is believed to be largely harmless.
C. perfringens types B and D carry a gene (epsilon toxin) that emits a protoxin — a non-active precursor form of the toxin — which is turned into the potent ‘epsilon’ toxin within the intestines of grazing animals. The epsilon toxin travels through the blood to the brain, where it damages brain blood vessels and myelin, the insulation protecting neurons, resulting in MS-like symptoms in the animals. While the D subtype has only been found in two people, based on prior studies by other investigators, the B subtype had never been found in humans.
Nevertheless, Rumah and the research team set out to see if subtypes B or D exist in humans and if they are associated with MS. They tested banked blood and spinal fluid from both MS patients and healthy controls for antibody reactivity to the epsilon toxin. Investigators found that levels of epsilon toxin antibodies in MS patients were 10 times higher than in the healthy controls — the blood of only one out of 100 control participants showed an immune reaction to the toxin.
The team also examined stool samples from both MS patients and healthy controls enrolled in the HITMS clinical study, and found that 52 percent of healthy controls carried the A subtype compared to 23 percent of MS patients. ‘This is important because it is believed that the type A bacterium competes with the other subtypes for resources, so that makes it potentially protective against being colonised by epsilon toxin secreting subtypes and developing MS,’ say Rumah and Vartanian.
The search by investigators for evidence of C. perfringens type B paid off in the case of a young MS patient. Co-author Dr. Jennifer Linden, a microbiologist at Weill Cornell Medical College, isolated the actual bacterium from the patient’s stool.
The authors suspect that once a human is infected with C. perfringens type B or D, the pathogen usually lives in the gut as an endospore, a seed-like structure that allows some bacteria to remain dormant for long periods. ‘The human gastrointestinal tract is host to approximately 1,000 different bacterial species, but is not a hospitable environment for C. perfringens type B or D, so it does not grow well there. It hibernates in a protective spore. When it does grow, we anticipate it generates a small quantity of epsilon toxin, which travels through the blood into the brain,’ Dr. Vartanian says. ‘We believe the bacterium’s growth is episodic, meaning the environmental trigger is always present, and it rears its ugly head from time to time.’
He says researchers do not know how humans are infected with C. perfringens type B or D, but they are studying potential routes of exposure. The scientists are also in the first stages of investigating potential treatments against the pathogen. Weill Cornell Medical College
New knowledge about serious muscle disease
, /in E-News /by 3wmediaRecent research from University of Copenhagen sheds light on previously unknown facts about muscular dystrophy at molecular level. The breakthrough is hoped to improve future diagnosis and treatment of the disease. Researchers have developed a method that will make it easier to map the proteins that have an important kind of sugar monomer, mannose, attached. This is an important finding, as mannose deficiency can lead to diseases such as muscular dystrophy.
About 3,000 people in Denmark suffer from one of the serious muscle-related diseases that come under the heading of muscular dystrophy. Some patients diagnosed with muscular dystrophy die shortly after birth, others become severely retarded and develop eye problems, while certain groups are confined to life in a wheelchair. Common to all muscular dystrophy sufferers is the difficulty of their muscle cells to attach themselves to each other and to the surrounding tissue. However, little is actually known about the root causes of the disease.
New basic research from University of Copenhagen now offers insight into previously unknown facts about muscular dystrophy that may improve future diagnosis and treatment of the disease.
‘Our new research findings may shed light on some of the cellular processes that take place in connection with, for example, muscular dystrophy. This is important information because it is crucial for us to gain as detailed an understanding as possible about the individual cell components. Although the journey from the current basic research to any potential treatment options or diagnostic tools is a long one, our discoveries give grounds for optimism,’ says postdoc Malene Bech Vester-Christensen – who carried out the new experiments from her base at the Faculty of Health and Medical Sciences, University of Copenhagen, and has since taken up a research position at Novo Nordisk.
The new method developed by researchers makes it easier to map the proteins that The protein previously associated with muscular dystrophy is a so-called glycoprotein – a protein with chains of sugar molecules attached. The special kind of sugar attached to these glycoproteins is called mannose. A functional pathway for binding mannose to the proteins is key to the functioning of the human organism, and genetic defects in the process that attaches mannose to the proteins – known as O-mannosylation – can lead to diseases such as muscular dystrophy.
‘To date, only one single protein has been identified and characterised where the mannose deficiency on the protein leads to muscular dystrophy, but our method enables us to faster identify many new proteins that have mannose attached and therefore potentially play a key role for the disease,’ says Adnan Halim, who is associated with the research project and a postdoc with the Danish National Research Foundation, Copenhagen Center for Glycomics. University of Copenhagen
Genetic variation increases risk of kidney disease progression in African Americans
, /in E-News /by 3wmediaNew research provides direct evidence that genetic variations in some African Americans with chronic kidney disease contribute to a more rapid decline in kidney function compared with white Americans. The research, led by investigators from the University of Maryland School of Medicine and Johns Hopkins University, may help explain, in part, why even after accounting for differences in socio-economic background, end-stage kidney disease is twice as prevalent among blacks as whites.
‘What we found is pretty remarkable — that variations in a single gene account for a large part of the racial disparity in kidney disease progression and risk for end-stage kidney disease,’ says co-lead author and nephrologist Afshin Parsa, M.D., M.P.H., assistant professor of medicine and member of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine. ‘If it were possible to reduce the effect of this gene, there could be a very meaningful decrease in progressive kidney and end-stage kidney disease within blacks.’
Previous landmark discoveries revealed that two common variants within a gene called apolipoprotein L1 (APOL1) were strongly associated with non-diabetic end-stage renal disease in blacks. Having only one copy of the variant APOL1 gene variant is associated with a health benefit – protection against African sleeping sickness, a potentially lethal parasitic infection transmitted by the tsetse fly, found only in sub-Saharan Africa. However, people with two copies of the variant are at a higher risk for kidney disease.
The current research expands on these prior findings and demonstrates the effect of these variants on the progression of established kidney disease and development of end-stage renal disease; analyses their role in black-versus-white renal disease disparities; investigates their effect in patients with diabetes and observes the impact of blood pressure control on APOL1-associated disease progression.
According to Dr. Parsa, approximately 13 percent of the African American population has two copies of the risk variants. Fortunately, most of those at risk do not develop kidney disease. The researchers analysed the role of APOL1 gene variants in two longitudinal studies of patients with kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension (AASK), both sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). Dr. Parsa examined the CRIC study data, while co-lead author and Johns Hopkins epidemiologist W.H. Linda Kao, Ph.D., M.H.S., analysed the AASK data. University of Maryland Medical Center
Simple dot test may help gauge the progression of dopamine loss in Parkinson’s disease
, /in E-News /by 3wmediaA pilot study by a multi-disciplinary team of investigators at Georgetown University suggests that a simple dot test could help doctors gauge the extent of dopamine loss in individuals with Parkinson’s disease (PD).
‘It is very difficult now to assess the extent of dopamine loss — a hallmark of Parkinson’s disease — in people with the disease,’ says lead author Katherine R. Gamble, a psychology PhD student working with two Georgetown psychologists, a psychiatrist and a neurologist. ‘Use of this test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,’ she adds.
Gamble works in the Cognitive Aging Laboratory, led by the study’s senior investigator, Darlene Howard, PhD, Davis Family Distinguished Professor in the department of psychology and member of the Georgetown Center for Brain Plasticity and Recovery.
The TLT tests implicit learning, a type of learning that occurs without awareness or intent, which relies on the caudate nucleus, an area of the brain affected by loss of dopamine.
The test is a sequential learning task that does not require complex motor skills, which tend to decline in people with PD. In the TLT, participants see four open circles, see two red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.
Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, PD participants implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively impact that learning compared to healthy older adults.
‘Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,’ says Gamble.
In this study of 27 people with PD, the research team is now testing how implicit learning may differ by different PD stages and drug doses.
‘This work is important in that it may be a non-invasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,’ explains Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center, and a co-author of the study.
They hope the TLT may one day be a tool to help determine levels of dopamine loss in PD. EurekAlert
New trigger for breast cancer metastasis
, /in E-News /by 3wmediaFor years, scientists have observed that tumour cells from certain breast cancer patients with aggressive forms of the disease contained low levels of mitochondrial DNA. But, until recently, no one was able to explain how this characteristic influenced disease progression.
Now, University of Pennsylvania researchers have revealed how a reduction in mitochondrial DNA content leads human breast cancer cells to take on aggressive, metastatic properties. The work breaks new ground in understanding why some cancers progress and spread faster than others and may offer clinicians a biomarker that would distinguish patients with particularly aggressive forms of disease, helping personalise treatment approaches.
The study was led by the Penn School of Veterinary Medicine’s Manti Guha, a senior research investigator, and Narayan Avadhani, Harriet Ellison Woodward Professor of Biochemistry in the Department of Animal Biology. Additional Penn Vet collaborators included Satish Srinivasan, Gordon Ruthel, Anna K. Kashina and Thomas Van Winkle. They teamed with Russ P. Carstens of Penn’s Perelman School of Medicine and Arnulfo Mendoza and Chand Khanna of the National Cancer Institute.
Mitochondria, the ‘powerhouses’ of mammalian cells, are also a signalling hub. They are heavily involved in cellular metabolism as well as in apoptosis, the process of programmed cell death by which potentially cancerous cells can be killed before they multiply and spread. In addition, mitochondria contain their own genomes, which code for specific proteins and are expressed in co-ordination with nuclear DNA to regulate the provision of energy to cells.
In mammals, each cell contains between 100 and 1,000 copies of mitochondrial DNA, but previous research had found that as many as 80 percent of people with breast cancer have low mitochondrial DNA, or mtDNA, content.
To gain an understanding of the mechanism that connects low mtDNA levels with a cellular change that leads to cancer and metastasis, Guha, Avadhani and their colleagues set up two systems by which they could purposefully reduce the amount of mtDNA in a cell. One used a chemical to deplete the DNA content, and another altered mtDNA levels genetically. They compared normal, non-cancer-forming human breast tissue cells with cancerous breast cells using both of these treatments, contrasting them with cells with unmanipulated mtDNA.
The differences between cells with unmodified and reduced mtDNA levels were striking, the researchers found. The cells in which mtDNA was reduced had altered metabolism and their structure appeared disorganised, more like that of a metastatic cancer cell. Even the non-tumour-forming breast cells became invasive and more closely resembled cancer cells. Significantly, cells with reduced mtDNA became self-renewing and expressed specific cell surface markers characteristic of breast cancer stem cells.
‘Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells,’ Avadhani said. ‘These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body.’
‘Most patients who had low copy numbers of mitochondrial DNA have a poor disease prognosis,’ Guha said. ‘We’ve shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease. In the future, mtDNA and the factors involved in mitochondrial signalling may serve as markers of metastatic potential and novel points for therapeutic intervention of cancer stem cells. Since the specific inducers of cancer stem cells, which are key drivers of metastasis, remain elusive, our current findings are a significant advancement in this area.’
No two breast cancers are exactly alike, so having a way to recognise patients who are at high-risk for developing particularly invasive and rapidly metastasising cancers could help physicians customise treatments. In addition, researchers are currently filling in the unknown components of the signalling pathway linking a cell’s mitochondrial DNA levels and its involvement in metastatic disease. University of Pennsylvania
Gut hormone test predicts individual efficacy of gastric bypass
, /in E-News /by 3wmediaThe sensitivity of the GLP-1 hormone, which is secreted by the gastrointestinal tract, can predict the metabolic efficacy of a gastric bypass. The use of a GLP1 challenge could thus function as a novel predictive biomarker for personalised treatment of type 2 diabetes and obesity
The gastric bypass is one of the most commonly performed surgical procedures in the treatment of obesity. In most patients, it quickly produces substantial body weight loss. Moreover, even before the weight loss, the procedure leads to improved glucose tolerance. However, these metabolic improvements vary considerably from patient to patient.
A hormone test may be able to predict the extent of metabolic improvement caused by the gastric bypass. These are the results of a study on a rodent model conducted by Prof. Dr. Matthias Tschöp and his colleagues from the Institute of Diabetes and Obesity (IDO), Helmholtz Diabetes Center at Helmholtz Zentrum München together with a team of researchers led by Dr. Kirk Habegger at the Metabolic Disease Institute of the University of Cincinnati.
After gastric bypass surgery, the concentration of the gut hormone GLP-1 (glucagon-like peptide 1) in the blood rises significantly. GLP-1 increases insulin secretion and contributes to improved blood glucose levels and blood lipids. As the rat studies by the Tschöp and Habegger research teams showed, GLP-1 responsiveness varied considerably with regard to glucose metabolism. More importantly, the more responsive the animals were to GLP-1, the greater the efficacy of the gastric bypass turned out to be regarding glucose metabolism improvements.
Thus, the responsiveness to GLP-1 could be a key indicator for the success of the gastric bypass. ‘If our results are confirmed in clinical trials with patients, the hormone response could be tested before the planned surgery and surgeons would be able to predict how much an individual patient’s glucose metabolism would benefit,’ said Tschöp. ‘This will contribute to the development of personalized therapies for type 2 diabetes and obesity. For surgical procedures such as gastric bypass this is particularly compelling because such operations are complex and cannot be easily reversed.’
The numerous secondary diseases related to excess weight and obesity, such as type 2 diabetes, are among the most common diseases in Germany. These diseases are the focus of research at Helmholtz Zentrum München, a partner in the German Center for Diabetes Research (DZD). Helmholtz Zentrum München
Absence of the SMG1 protein could contribute to Parkinson’s and other neurological disorders
, /in E-News /by 3wmediaThe absence of a protein called SMG1 could be a contributing factor in the development of Parkinson’s disease and other related neurological disorders, according to a study led by the Translational Genomics Research Institute (TGen).
The study screened 711 human kinases (key regulators of cellular functions) and 206 phosphatases (key regulators of metabolic processes) to determine which might have the greatest relationship to the aggregation of a protein known as alpha-synuclein, which has been previously implicated in Parkinson’s disease. Previous studies have shown that hyperphosphorylation of the α-synuclein protein on serine 129 is related to this aggregation.
‘Identifying the kinases and phosphates that regulate this critical phosphorylation event may ultimately prove beneficial in the development of new drugs that could prevent synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies,’ said Dr. Travis Dunckley, a TGen Assistant Professor and senior author of the study.
Synucleinopathies are neurodegenerative disorders characterised
by aggregates of α-synuclein protein. They include Parkinson’s, various forms of dementia and multiple systems atrophy (MSA).
By using the latest in genomic technologies, Dr. Dunckley and collaborators found that expression of the protein SMG1 was ‘significantly reduced’ in tissue samples of patients with Parkinson’s and dementia.
‘These results suggest that reduced SMG1 expression may be a contributor to α-synuclein pathology in these diseases,’ Dr. Dunckley said.
TGen collaborators in this study included researchers from Banner Sun Health Institute and Mayo Clinic Scottsdale. Translational Genomics Research Institute
Nanoparticles to probe mystery sperm defects behind infertility
, /in E-News /by 3wmediaA way of using nanoparticles to investigate the mechanisms underlying ‘mystery’ cases of infertility has been developed by scientists at Oxford University.
The technique `could eventually help researchers to discover the causes behind cases of unexplained infertility and develop treatments for affected couples. The method involves loading porous silica nanoparticle ‘envelopes’ with compounds to identify, diagnose or treat the causes of infertility.
The researchers demonstrated that the nanoparticles could be attached to boar sperm with no detrimental effects on their function.
‘An attractive feature of nanoparticles is that they are like an empty envelope that can be loaded with a variety of compounds and inserted into cells,’ says Dr Natalia Barkalina, lead author of the study from the Nuffield Department of Obstetrics and Gynaecology at Oxford University. ‘The nanoparticles we use don’t appear to interfere with the sperm, making them a perfect delivery vessel.’
Dr Barkalina added: ‘We will start with compounds to investigate the biology of infertility, and within a few years may be able to explain or even diagnose rare cases in patients. In future we could even deliver treatments in a similar way.’
Sperm are difficult to study owing to their small size, unusual shape and short lifetime outside of the body. Yet this is a vital part of infertility research, as senior author Dr Kevin Coward explains: ‘To discover the causes of infertility, we need to investigate sperm to see where the problems start. Previous methods involved complicated procedures in animals and introduced months of delays before the sperm could be used.
‘Now, we can simply expose sperm to nanoparticles in a petri dish. It’s so simple that it can all be done quickly enough for the sperm to survive perfectly unharmed.’
The team, based at the Institute of Reproductive Sciences, used boar sperm because of its similarities to human sperm, as study co-author Celine Jones explains: ‘It is similar in size, shape and activity. Now that we have proved the system in boar sperm, we hope to replicate our findings in human sperm and eventually see if we can use them to deliver compounds to eggs as well.’ Oxford University
Study links intestinal bacteria to rheumatoid arthritis
, /in E-News /by 3wmediaResearchers have linked a species of intestinal bacteria known as Prevotella copri to the onset of rheumatoid arthritis, the first demonstration in humans that the chronic inflammatory joint disease may be mediated in part by specific intestinal bacteria. The new findings by laboratory scientists and clinical researchers in rheumatology at NYU School of Medicine add to the growing evidence that the trillions of microbes in our body play an important role in regulating our health.
Using sophisticated DNA analysis to compare gut bacteria from faecal samples of patients with rheumatoid arthritis and healthy individuals, the researchers found that P. copri was more abundant in patients newly diagnosed with rheumatoid arthritis than in healthy individuals or patients with chronic, treated rheumatoid arthritis. Moreover, the overgrowth of P. copri was associated with fewer beneficial gut bacteria belonging to the genera Bacteroides.
‘Studies in rodent models have clearly shown that the intestinal microbiota contribute significantly to the causation of systemic autoimmune diseases,’ says Dan R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Pathology and Microbiology and a Howard Hughes Medical Institute investigator.
‘Our own results in mouse studies encouraged us to take a closer look at patients with rheumatoid arthritis, and we found this remarkable and surprising association,’ says Dr. Littman, whose basic science laboratory at NYU School of Medicine’s Skirball Institute of Biomolecular Medicine collaborated with clinical investigators led by Steven Abramson, MD, senior vice president and vice dean for education, faculty, and academic affairs; the Frederick H. King Professor of Internal Medicine; chair of the Department of Medicine; and professor of medicine and pathology at NYU School of Medicine.
‘At this stage, however, we cannot conclude that there is a causal link between the abundance of P. copri and the onset of rheumatoid arthritis,’ Dr. Littman says. ‘We are developing new tools that will hopefully allow us to ask if this is indeed the case.’ NYU Langone Medical Center