A team of researchers from the Hospital Universitario La Paz Research Institute (IdiPAZ, Madrid), LifeSequencing S.L. (Valencia), Era7 Bioinformatics (Madrid) and Roche Spain (Barcelona) announced on March 14th the sequencing of the whole genome of three antibiotic resistant strains of Klebsiella pneunomiae isolated from a recent outbreak in a Spanish hospital. The sequence data, generated using Roche’s 454 GS FLX+ System, is some of the first for this particular bacterial species, providing new insights into how antibiotic resistance evolves within this microorganism and can lead to hospital outbreaks.
Klebsiella pneumoniae is a bacterium frequently found in the mouth and gut of healthy humans. In most instances, it does not lead to disease but it can mutate opportunistically and cause diverse types of infections. The bacterium also has a significant capacity to acquire antibiotic resistance. Three closely related isolates of a pathogenic strain of K. pneumonia with increasing degrees of antibiotic resistance were obtained in the Microbiology department at Hospital Universitario La Paz and sequenced at LifeSequencing in Valencia, Spain using the long read GS FLX+ System, developed by 454 Life Sciences, a Roche Company. The sequencing data was assembled using the GS De Novo Assembler software and functional annotation was performed to identify the relevant genes codified in the three genomes with BG7, the optimized system developed by Era 7 Bioinformatics, providing rich functional annotation of 454 Sequencing data.
The researchers found that the three bacteria strains showed an increasing resistance pattern to a wide range of the antibiotics most commonly used at the hospital. Comparison of the genomes will give insights regarding how antibiotic resistance evolves within K. pneumonia and will aid in efforts to reduce the increasing prevalence of antibiotic resistance worldwide. In addition, the comparison of these genomes with other previously studied bacteria will help to understand how a microorganism that is part of our normal microbiome can become a dangerous pathogen.
“Fast and affordable sequencing of pathogenic bacteria is a huge qualitative and quantitative advance that is radically changing the way researchers and clinicians view the infectious disease process,” said Dr. Jesús Mingorance lead researcher at the Hospital Universitario La Paz. The GS FLX+ and GS Junior Systems from Roche are aiding in these pathogen detection and bacterial comparative genomics efforts worldwide. For life science research only. Not for use in diagnostic procedures.
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Women 65 or older who have even mild retinopathy, a disease of blood vessels in the retina, are more likely to have cognitive decline and related vascular changes in the brain, according to a multi-institutional study led by scientists at the University of California, San Francisco (UCSF).
The findings suggest that a relatively simple eye screening could serve as a marker for cognitive changes related to vascular disease, allowing for early diagnosis and treatment, potentially reducing the progression of cognitive impairment to dementia.
As retinopathy usually is caused by Type II diabetes or hypertension, a diagnosis could indicate early stages of these diseases, before they are clinically detectable. Early diagnosis could allow for lifestyle or drug interventions when they might be most effective.
‘Lots of people who are pre-diabetic or pre-hypertensive develop retinopathy,’ said the lead author of the study, Mary Haan, DrPH, MPH, UCSF professor of epidemiology and biostatistics. ‘Early intervention might reduce the progression to full onset diabetes or hypertension.’
The results were based on data from the Women’s Health Initiative Memory Study and the Site Examination study, two ancillary studies of the Women’s Health Initiative Clinical Trial of Hormone Therapy.
In the study, the team followed 511 women with an average starting age of 69, for 10 years. Each year, the women took a cognition test focused on short-term memory and thinking processes. In the fourth year, they received an exam to assess eye health. In the eighth year, they received a brain scan.
Of the full group of women, 39 women, or 7.6 percent, were diagnosed with retinopathy. On average, these women scored worse on the cognition test than the other women. They had more difficulty, for instance, recalling a list of several words five minutes after hearing them.
The women with retinopathy also had more damage to the blood vessels of the brain. They had 47 percent more ischemic lesions, or holes, in the vasculature overall and 68 percent more lesions in the parietal lobe. The lesions, associated with vascular disease and sometimes stroke, are believed to be caused by high blood pressure. They also had more thickening of the white matter tracks that transmit signals in the brain, which also appear to be caused by high blood pressure.
Notably, the women did not have more brain atrophy, which is associated with Alzheimer’s disease. This result indicates that retinopathy is a marker of neurovascular disease rather than Alzheimer’s disease, according to Haan.
University of California, San Francisco,
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The addition of changes in inflammatory biomarkers to established clinical variables improves the prediction of mortality in patients with chronic obstructive pulmonary disease (COPD), according to a new study.
‘COPD is characterised by low-grade inflammation, so we hypothesised that the addition of inflammatory biomarkers to established predictive factors would improve the prediction of mortality,’ said lead author Bartolome Celli, lecturer in medicine at Harvard Medical School and member of the Pulmonary and Critical Care Division of Brigham and Women’s Hospital in Boston. ‘We found that the addition of a panel of selected biomarkers to clinical variables significantly improved the ability of clinical variables to predict mortality in these patients.’
The researchers analysed prospectively collected data on 1,843 COPD patients from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Of these 1,843 patients, 168 (9.1%) died during the three-year follow-up.
Clinical predictors of morality included age, BODE (Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity) index , and incidence of hospitalisations due to exacerbation’s of COPD in the year prior to the study. A predictive model for mortality using these clinical variables had a C-statistic (which measures the ability of how well a clinical prediction rule can correctly rank-order patients by risk) of 0.686. Adding interleukin-6 (IL-6) to the predictive model significantly improved the C-statistic to 0.708, and the addition of a panel of biomarkers including white blood cell counts, IL-6, C-reactive protein (CRP), interleukin-8 (IL-8), fibrinogen, chemokine (C-C-motif) ligand 18 (CCL-18), and surfactant protein D (SP-D) further improved the C-statistic to 0.726.
‘This panel of selected biomarkers was not only elevated in non-survivors in our cohort, but was associated with mortality over three years of follow-up after adjusting for clinical variables known to predict mortality in patients with COPD,’ said Dr. Celli. ‘Except for IL-6, these biomarkers improved the predictive value of our model only marginally when considered individually, but they improved the model significantly when analyzed as a group.’
The study had several limitations, including the lack of a study adjudication committee to specify causes of death, the exclusion of some biomarkers thought to be important in the pathobiology of COPD, and the lack of a validating cohort.
‘Adding white blood cell counts and measurement of changes in systemic levels of IL-6, CRP, IL-8, fibrinogen, CCL-18, and SP-D significantly improves the ability of clinical variables to predict mortality in patients with COPD,’ said Dr. Celli. ‘This is the first study to show that the addition of biomarker levels to clinical predictors in COPD patients adds relevant prognostic information.’
EurekAlert
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Widely used antibiotics may increase incidence and severity of allergic asthma in early life, according to a University of British Columbia study.
The study shows that certain antibiotics that affect intestinal bacteria also had a profound impact on allergic asthma.
‘It has long been suspected that kids exposed to more antibiotics – like those in developed countries – are more prone to allergic asthma,’ says the study’s author, UBC microbiologist Brett Finlay. ‘Our study is the first experimental proof that shows how.’
Finlay’s team at UBC’s Dept. of Microbiology and Immunology and Michael Smith Laboratories examined how two widely used antibiotics – streptomycin and vancomycin – affected the bacterial ‘ecosystem’ in the gut. They found that vancomycin profoundly alters the bacterial communities in the intestine and increases severity of asthma in mouse models.
The same antibiotics do not impact adult mice’s susceptibility to asthma, indicating that early life is a critical period of establishing a healthy immune system.
Allergic asthma affects more than 100 million people worldwide and its prevalence is increasing on average by 50 per cent every decade, particularly among children in industrialized countries. According to the Asthma Society of Canada, asthma affects at least 12 per cent of Canadian children.
The human gut is colonised by approximately 100 trillion bacteria, and contains upwards of 1,000 bacterial species. While not fully understood, these micro-organisms, known as ‘gut flora,’ perform a host of useful functions, says Finlay.
‘Modern societal practices, such as improved sanitation methods and widespread antibiotic use, are causing the disappearance of ancestral species of bacteria in our gut that may be critical to a healthy immune system,’ says Finlay.
‘Our study shows this is the case with certain antibiotics and allergic asthma, and the gut-lung connection is also consistent with observations that incidence of asthma has not increased significantly in developing countries where antibiotic use is less prevalent – and in turn, the gut flora is permitted to fully develop.’
University of British Columbia
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Retinoic acid (vitamin A) and steroids are hormones found in our body that protect against oxidative stress, reduce inflammation and are involved in cellular differentiation processes. One of the characteristics of tumours is that their cells have lost the ability to differentiate; therefore these hormones have useful properties to prevent cancer. Currently, retinoic acid and steroids are being used to treat some types of leukemia.
A study led by the research group on Genes and Cancer of the Bellvitge Biomedical Research Institute (IDIBELL) has shown that loss of BRG1 gene implies a lack of response of cells to these hormones, and therefore the tumour may continue growing.
The IDIBELL research group on Genes and Cancer led by Montse Sanchez-Cespedes discovered some years ago that the BRG1 gene, a tumour suppressor, is inactivated in non-small cell lung cancer by genetic mutations. ‘The BRG1 protein is part of a chromatin remodelling complex that regulates the expression of several genes,’ said the researcher, ‘and is related to the differentiation of lung cells, allowing cells response to certain hormones and environment vitamins like vitamin A or steroids.’
When BRG1 is mutated and therefore inactive, tumour cells do not respond to the presence of these hormones and they continue growing and spreading. For this reason, these types of tumours are refractory to treatment with these substances.
‘At the moment,’ says Montse Sanchez-Cespedes, ‘we are not able to restore the functionality of a tumour suppressor gene as BRG1 in patients. Therefore, we are still far from a therapeutic application but the discovery enables us to better understand the biology of tumours. What we will try to do in the immediate future is to look for agents that specifically destroy the cells with mutated BRG1, following the strategy of lethal synthetics’.
In any case, this finding it can be useful in advancing personalised medicine, because ‘it explains why lung cancer patients are resistant to these treatments and may serve to rule out therapies with lipid-derived hormones in patients with BRG1 mutations, not just in lung cancer but also in breast and prostate, among others. ‘
IDIBELL
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A collaborative discovery involving Kansas State University researchers may improve animal health and save the U.S. pork industry millions of dollars each year.
Raymond ‘Bob’ Rowland, a virologist and professor of diagnostic medicine and pathobiology, was part of the collaborative effort that discovered a genetic marker that identifies pigs with reduced susceptibility to porcine reproductive and respiratory syndrome, or PRRS. This virus costs the U.S. pork industry more than $600 million each year.
‘This discovery is what you call a first-first,’ Rowland said. ‘This discovery is the first of its kind for PRRS but also for any large food animal infectious disease. I have worked in the field for 20 years and this is one of the biggest advances I have seen.’
Rowland and researchers Jack Dekkers from Iowa State University and Joan Lunney from the Agricultural Research Service discovered a genetic marker called a quantitative trait locus, or QTL, which is associated with porcine reproductive and respiratory syndrome virus susceptibility. This discovery is a first step in controlling and eliminating the virus.
The project’s beginning and future centre around Kansas State University, Rowland said.
It begins at the university because Rowland is involved with an organisation called the PRRS Host Genetics Consortium, or PHGC, which initiated and provided more than $5 million for the research. Rowland is co-director of the consortium, which is a collaboration among the United States Department of Agriculture, the National Pork Board and Genome Canada as well as universities and industry members. Rowland is also director of the USDA-funded PRRS Coordinated Agriculture Project, known as PRRS CAP.
‘The PRRS Host Genetics Consortium takes fundamental science and turns it into utility,’ Rowland said.
Kansas State University’s new Large Animal Research Center is the site of much of the project’s experimental work. The researchers obtain multiple measurements — including growth, weight gain, performance and virus measurements — over time. They have collected samples from more than 2,000 pigs since they began the study in 2007, for a total of more than 100,000 samples that are stored or distributed to the consortium’s collaborators.
The university shipped samples to the Agricultural Research Service for genomic DNA preparations to identify differences among more than 60,000 genes. The data was transferred to Iowa State University for genetic analysis that led to the discovery of the QTL.
The collaborators at Iowa State University created a common database so that all the data collected during the project can be accessed at multiple locations by researchers and the breeding industry for the next several decades.
‘A unique aspect of this project is that we have been looking at genes that may provide long-term resistance to a lot of infections,’ Rowland said. ‘This is very important for animal health because there are a lot of diseases for which there are no cures and no vaccines. Now we have a tool to study these diseases.’
These findings open new possibilities with Kansas State University’s Biosecurity Research Institute and the future National Bio and Agro-defense Facility. Scientists can take this new genetic tool and study different infectious diseases in these world-class research facilities.
Sex-deprived fruit flies’ alcohol preference could uncover answers for human addictions
Kansas State University
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Researchers from the Perelman School of Medicine at the University of Pennsylvania have identified an abnormal amount a protein called Prostaglandin D2 in the bald scalp of men with male pattern baldness, a discovery that may lead directly to new treatments for the most common cause of hair loss in men. In both human and animal models, researchers found that a prostaglandin known as PGD2 and its derivative, 15-dPGJ2, inhibit hair growth. The PGD2-related inhibition occurred through a receptor called GPR44, which is a promising therapeutic target for androgenetic alopecia in both men and women with hair loss and thinning.
Male pattern baldness strikes 8 of 10 men under 70 years old, and causes hair follicles to shrink and produce microscopic hairs, which grow for a shorter duration of time than normal follicles.
Researchers took an unbiased approach when scanning for potential biological causes of baldness, looking in scalp tissue from balding and non-bald spots from men with male pattern baldness and then corroborating findings in mouse models. They found that levels of PGD2 were elevated in bald scalp tissue at levels 3 times greater than what was found in comparative haired scalp of men with androgenetic alopecia. When PGD2 was added to cultured hair follicles, PGD2-treated hair was significantly shortened, while PGD2’s derivative, 15-dPGJ2, completely inhibited hair growth.
‘Although a different prostaglandin was known to increase hair growth, our findings were unexpected, as prostaglandins haven’t been thought about in relation to hair loss, yet it made sense that there was an inhibitor of hair growth, based on our earlier work looking at hair follicle stem cells,’ said George Cotsarelis, MD, chair and professor of Dermatology, and senior author on the studies. In a Penn study published in the Journal of Clinical Investigation last year, underlying hair follicle stem cells were found intact, suggesting that the scalp was lacking an activator or something was inhibiting hair follicle growth.
Prostaglandins are well characterised for their role in many bodily functions — controlling cell growth, constricting and dilating smooth muscle tissue — and a different prostaglandin (F2alpha) is known to increase hair growth. Researchers found that as PGD2 inhibits hair growth, other prostaglandins work in opposition, enhancing and regulating the speed of hair growth.
While these studies looked at AGA in men, the researchers noted that prostaglandins may represent a common pathway shared by both men and women with AGA. Future studies, potentially testing topical treatments that may target GPR44, can determine whether targeting prostaglandins will benefit woman with AGA as well.
Penn University
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No one really wants the short end of the stick, in this case the short end of a chromosome. Telomeres, which are DNA-protein complexes at the ends of chromosomes, can be thought of as protein ‘caps’ that protect chromosomes from deteriorating and fusing with neighbouring chromosomes.
It is typical for telomeres to shorten as cells divide and chromosomes replicate over time. Now a new study from Brigham and Women’s Hospital (BWH) suggest a strong link between telomere shortening and poor cardiovascular outcomes in patients with acute coronary syndrome.
Scientists measured telomere length in 5,044 patients with an acute coronary syndrome who were followed for 18 months.
They evaluated the risk of cardiovascular death or heart attack based on telomere length and other characteristics.
Shorter telomeres were associated with older age, male gender, smoking, prior heart attack and heart failure; although, the correlation between each individual factor and telomere length was modest. Age, for example, only accounts for seven percent of the variability in telomere length.
Telomere length was strongly associated with risk of cardiovascular death or heart attack. Patients with shorter telomeres had the highest risk. This relationship was consistent across various age groups.
‘We know that many different genetic and environmental factors, like diabetes, high cholesterol and smoking predispose patients to suffering cardiovascular events,’ said Christian T. Ruff, MD, MPH, Cardiovascular Division, BWH Department of Medicine, and lead study investigator. ‘Even when accounting for all of these other known risk factors, patients with short telomeres have an increased risk of having a heart attack or dying from heart disease.’
Taking the research findings from bench to bedside, Ruff points out that measuring telomere length may be useful in a clinical setting, providing a sort of predictor for cardiovascular events.
‘Telomere shortening may represent some sort of ‘biological clock’ which integrates the cumulative effect of environmental and genetic stresses on the body, both of which can contribute to cardiovascular events.’ said Ruff.
The researchers will continue to validate their findings to see if the relationship between telomere length and cardiovascular outcomes holds true in broader populations of patients. They also plan on experimenting on whether the rate of telomere shortening over time also predicts adverse cardiovascular events.
‘In the future, we hope to identify clinical, biochemical and genetic characteristics that predict telomere shortening,’ said Ruff. ‘We hope to have the ability to determine if therapies and medications that impact these processes may delay telomere attrition and lessen the risk of cardiovascular events in these patients.’
EurekAlert
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An international team of researchers have developed a new method for measurement of aggregated beta-amyloid – a protein complex believed to cause major nerve cell damage and dysfunction in Alzheimer’s disease. The new method might facilitate diagnosis and detection as well as development of drugs directed against aggregated beta-amyloid.
Alzheimer’s disease (AD) is the most common cause of memory decline and dementia. According to the Alzheimer World Report 2011, today around 36 million people suffer from Dementia (around 20 – 25 million are Alzheimer’s patients). These numbers will dramatically increase with the ageing populations over the next few decades. For the year 2050 the expected number of dementia patients will be 115 – 200 million (70 – 150 million Alzheimer’s cases). It is therefore important to develop new therapies and diagnostic methods to detect and treat this complex chronic neurodegenerative brain disease.
Alzheimer’s disease is characterised by aggregates in the brain, containing a protein called beta-amyloid. The neuropathology of Alzheimer’s disease has recently been linked to the neurotoxic amyloid-β (Aβ) oligomers. The crucial role of Aβ oligomers in the early events of AD is experimentally underlined. Several recent results suggest that those oligomers may cause the death of neurons and neurological dysfunctions relevant to memory. Furthermore Aβ oligomers levels are increased in brain and cerebrospinal fluid samples from people with Alzheimer’s disease. This reflects the potential of Aβ oligomers as a marker for the early diagnosis of the disease.
An international team of scien
He analysed the cerebrospinal fluid of 30 neurological patients, including 14 Alzheimer’s patients. ‘These samples provided from leading expert academic memory clinics in Germany and Sweden are of the best quality and are highly characterised in order to provide robust and reliable results on promising novel biomarker candidates’, Professor Harald Hampel of Frankfurt University, a lead investigator comments.
‘Because of the limited number of samples, however, further study is needed to confirm the results,’ said Dr. Oskar Hansson of Lund University. The study was an international co-operation with the University of California in the U.S., the Goteborg and Malmö Universities from Sweden and the University of Frankfurt in Germany.
The test might not only be used fo
tists from Germany, Sweden and the U.S. have used a new method to quantify soluble variants of aggregated beta-amyloid (Aβ oligomers) in cerebrospinal fluid by flow cytometry. "We found that patients with a greater number of Aβ oligomers in the cerebrospinal fluid had a more pronounced disease," says Dr. Alexander Navarrete Santos (the developer of this method and now employee of the Research Laboratory of the University of Halle, Department of Cardiothoracic Surgery), and first author of the study.r the early detection of AD but can also be used when developing new and effective therapies for AD. A decline in the number of Aβ oligomers in cerebrospinal fluids could be a hint for the effectiveness of new drug therapies.
EurekAlert
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An international group of researchers, including those from Moffitt Cancer Center in Tampa, Fla., have published a paper reviewing the results of a study that analysed mutations in 18 genes of 398 patients who had acute myeloid leukemia (AML). They found that several mutated genes predicted improved outcomes when patients with certain gene mutations were given high-dose induction chemotherapy. Their findings suggest that mutational profiling could potentially be used for both risk stratification and also in helping health care providers make therapeutic decisions for some AML patients.
‘Previous studies have found that AML is a highly heterogenic disorder,’ said study co-author Hugo F. Fernandez, a senior member at Moffitt and associate chief of Moffitt’s Blood and Marrow Transplantation Division. ‘Moreover, recent studies have revealed that a number of genetic mutations in AML patients might have prognostic value. The question of the presence of these gene mutations altering outcomes based on current therapy had not been answered to date.’
Their paper cites a clinical trial carried out by the Eastern Co-operative Oncology Group (ECOG) in which dose-intensified chemotherapy improved outcomes in two age sets of AML patients. Based on these findings, the research team hypothesised that carrying out mutational analysis of all known molecular alterations occurring in more than 5 percent of patients with AML might allow for the identification of distinct, molecularly defined subgroups of patients who might benefit from dose-intensified chemotherapy.
The laboratory research team subsequently performed a mutational analysis on diagnostic samples from 398 patients enrolled in the ECOG clinical trial they cited and used patients’ frozen sample cells for extraction and profiling. The researchers validated the results of this latter group of 104 patients.
‘We found that intensification of the dose of anthracycline significantly improved outcomes and overall survival in patients with mutations in DNMT3A, NPM1 or MLL translocations,’ said Fernandez. ‘This finding suggests that mutational profiling could be used to determine which AML patients will benefit from dose-intensive induction therapy.’
‘Most importantly,’ said Fernandez, ‘this study demonstrates how integrated mutational profiling of samples from a clinical trial cohort can advance understanding of the biologic characteristics of AML.’
Moffitt Cancer Center
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Spanish research team announce the sequencing of antibiotic resistance bacteria in recent hospital outbreak
, /in E-News /by 3wmediaA team of researchers from the Hospital Universitario La Paz Research Institute (IdiPAZ, Madrid), LifeSequencing S.L. (Valencia), Era7 Bioinformatics (Madrid) and Roche Spain (Barcelona) announced on March 14th the sequencing of the whole genome of three antibiotic resistant strains of Klebsiella pneunomiae isolated from a recent outbreak in a Spanish hospital. The sequence data, generated using Roche’s 454 GS FLX+ System, is some of the first for this particular bacterial species, providing new insights into how antibiotic resistance evolves within this microorganism and can lead to hospital outbreaks.
Klebsiella pneumoniae is a bacterium frequently found in the mouth and gut of healthy humans. In most instances, it does not lead to disease but it can mutate opportunistically and cause diverse types of infections. The bacterium also has a significant capacity to acquire antibiotic resistance. Three closely related isolates of a pathogenic strain of K. pneumonia with increasing degrees of antibiotic resistance were obtained in the Microbiology department at Hospital Universitario La Paz and sequenced at LifeSequencing in Valencia, Spain using the long read GS FLX+ System, developed by 454 Life Sciences, a Roche Company. The sequencing data was assembled using the GS De Novo Assembler software and functional annotation was performed to identify the relevant genes codified in the three genomes with BG7, the optimized system developed by Era 7 Bioinformatics, providing rich functional annotation of 454 Sequencing data.
The researchers found that the three bacteria strains showed an increasing resistance pattern to a wide range of the antibiotics most commonly used at the hospital. Comparison of the genomes will give insights regarding how antibiotic resistance evolves within K. pneumonia and will aid in efforts to reduce the increasing prevalence of antibiotic resistance worldwide. In addition, the comparison of these genomes with other previously studied bacteria will help to understand how a microorganism that is part of our normal microbiome can become a dangerous pathogen.
“Fast and affordable sequencing of pathogenic bacteria is a huge qualitative and quantitative advance that is radically changing the way researchers and clinicians view the infectious disease process,” said Dr. Jesús Mingorance lead researcher at the Hospital Universitario La Paz. The GS FLX+ and GS Junior Systems from Roche are aiding in these pathogen detection and bacterial comparative genomics efforts worldwide.
www.roche.comwww.idipaz.eswww.era7bioinformatics.comwww.lifesequencing.comFor life science research only. Not for use in diagnostic procedures.
Blood vessel disease of retina may be marker of cognitive decline
, /in E-News /by 3wmediaWomen 65 or older who have even mild retinopathy, a disease of blood vessels in the retina, are more likely to have cognitive decline and related vascular changes in the brain, according to a multi-institutional study led by scientists at the University of California, San Francisco (UCSF).
The findings suggest that a relatively simple eye screening could serve as a marker for cognitive changes related to vascular disease, allowing for early diagnosis and treatment, potentially reducing the progression of cognitive impairment to dementia.
As retinopathy usually is caused by Type II diabetes or hypertension, a diagnosis could indicate early stages of these diseases, before they are clinically detectable. Early diagnosis could allow for lifestyle or drug interventions when they might be most effective.
‘Lots of people who are pre-diabetic or pre-hypertensive develop retinopathy,’ said the lead author of the study, Mary Haan, DrPH, MPH, UCSF professor of epidemiology and biostatistics. ‘Early intervention might reduce the progression to full onset diabetes or hypertension.’
The results were based on data from the Women’s Health Initiative Memory Study and the Site Examination study, two ancillary studies of the Women’s Health Initiative Clinical Trial of Hormone Therapy.
In the study, the team followed 511 women with an average starting age of 69, for 10 years. Each year, the women took a cognition test focused on short-term memory and thinking processes. In the fourth year, they received an exam to assess eye health. In the eighth year, they received a brain scan.
Of the full group of women, 39 women, or 7.6 percent, were diagnosed with retinopathy. On average, these women scored worse on the cognition test than the other women. They had more difficulty, for instance, recalling a list of several words five minutes after hearing them.
The women with retinopathy also had more damage to the blood vessels of the brain. They had 47 percent more ischemic lesions, or holes, in the vasculature overall and 68 percent more lesions in the parietal lobe. The lesions, associated with vascular disease and sometimes stroke, are believed to be caused by high blood pressure. They also had more thickening of the white matter tracks that transmit signals in the brain, which also appear to be caused by high blood pressure.
Notably, the women did not have more brain atrophy, which is associated with Alzheimer’s disease. This result indicates that retinopathy is a marker of neurovascular disease rather than Alzheimer’s disease, according to Haan. University of California, San Francisco,
Inflammatory biomarkers improve the clinical prediction of mortality in COPD
, /in E-News /by 3wmediaThe addition of changes in inflammatory biomarkers to established clinical variables improves the prediction of mortality in patients with chronic obstructive pulmonary disease (COPD), according to a new study.
‘COPD is characterised by low-grade inflammation, so we hypothesised that the addition of inflammatory biomarkers to established predictive factors would improve the prediction of mortality,’ said lead author Bartolome Celli, lecturer in medicine at Harvard Medical School and member of the Pulmonary and Critical Care Division of Brigham and Women’s Hospital in Boston. ‘We found that the addition of a panel of selected biomarkers to clinical variables significantly improved the ability of clinical variables to predict mortality in these patients.’
The researchers analysed prospectively collected data on 1,843 COPD patients from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Of these 1,843 patients, 168 (9.1%) died during the three-year follow-up.
Clinical predictors of morality included age, BODE (Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity) index , and incidence of hospitalisations due to exacerbation’s of COPD in the year prior to the study. A predictive model for mortality using these clinical variables had a C-statistic (which measures the ability of how well a clinical prediction rule can correctly rank-order patients by risk) of 0.686. Adding interleukin-6 (IL-6) to the predictive model significantly improved the C-statistic to 0.708, and the addition of a panel of biomarkers including white blood cell counts, IL-6, C-reactive protein (CRP), interleukin-8 (IL-8), fibrinogen, chemokine (C-C-motif) ligand 18 (CCL-18), and surfactant protein D (SP-D) further improved the C-statistic to 0.726.
‘This panel of selected biomarkers was not only elevated in non-survivors in our cohort, but was associated with mortality over three years of follow-up after adjusting for clinical variables known to predict mortality in patients with COPD,’ said Dr. Celli. ‘Except for IL-6, these biomarkers improved the predictive value of our model only marginally when considered individually, but they improved the model significantly when analyzed as a group.’
The study had several limitations, including the lack of a study adjudication committee to specify causes of death, the exclusion of some biomarkers thought to be important in the pathobiology of COPD, and the lack of a validating cohort.
‘Adding white blood cell counts and measurement of changes in systemic levels of IL-6, CRP, IL-8, fibrinogen, CCL-18, and SP-D significantly improves the ability of clinical variables to predict mortality in patients with COPD,’ said Dr. Celli. ‘This is the first study to show that the addition of biomarker levels to clinical predictors in COPD patients adds relevant prognostic information.’ EurekAlert
Exposure to antibiotics linked to severity of allergic asthma
, /in E-News /by 3wmediaWidely used antibiotics may increase incidence and severity of allergic asthma in early life, according to a University of British Columbia study.
The study shows that certain antibiotics that affect intestinal bacteria also had a profound impact on allergic asthma.
‘It has long been suspected that kids exposed to more antibiotics – like those in developed countries – are more prone to allergic asthma,’ says the study’s author, UBC microbiologist Brett Finlay. ‘Our study is the first experimental proof that shows how.’
Finlay’s team at UBC’s Dept. of Microbiology and Immunology and Michael Smith Laboratories examined how two widely used antibiotics – streptomycin and vancomycin – affected the bacterial ‘ecosystem’ in the gut. They found that vancomycin profoundly alters the bacterial communities in the intestine and increases severity of asthma in mouse models.
The same antibiotics do not impact adult mice’s susceptibility to asthma, indicating that early life is a critical period of establishing a healthy immune system.
Allergic asthma affects more than 100 million people worldwide and its prevalence is increasing on average by 50 per cent every decade, particularly among children in industrialized countries. According to the Asthma Society of Canada, asthma affects at least 12 per cent of Canadian children.
The human gut is colonised by approximately 100 trillion bacteria, and contains upwards of 1,000 bacterial species. While not fully understood, these micro-organisms, known as ‘gut flora,’ perform a host of useful functions, says Finlay.
‘Modern societal practices, such as improved sanitation methods and widespread antibiotic use, are causing the disappearance of ancestral species of bacteria in our gut that may be critical to a healthy immune system,’ says Finlay.
‘Our study shows this is the case with certain antibiotics and allergic asthma, and the gut-lung connection is also consistent with observations that incidence of asthma has not increased significantly in developing countries where antibiotic use is less prevalent – and in turn, the gut flora is permitted to fully develop.’ University of British Columbia
BRG1 mutations confer resistance to hormones in lung cancer
, /in E-News /by 3wmediaRetinoic acid (vitamin A) and steroids are hormones found in our body that protect against oxidative stress, reduce inflammation and are involved in cellular differentiation processes. One of the characteristics of tumours is that their cells have lost the ability to differentiate; therefore these hormones have useful properties to prevent cancer. Currently, retinoic acid and steroids are being used to treat some types of leukemia.
A study led by the research group on Genes and Cancer of the Bellvitge Biomedical Research Institute (IDIBELL) has shown that loss of BRG1 gene implies a lack of response of cells to these hormones, and therefore the tumour may continue growing.
The IDIBELL research group on Genes and Cancer led by Montse Sanchez-Cespedes discovered some years ago that the BRG1 gene, a tumour suppressor, is inactivated in non-small cell lung cancer by genetic mutations. ‘The BRG1 protein is part of a chromatin remodelling complex that regulates the expression of several genes,’ said the researcher, ‘and is related to the differentiation of lung cells, allowing cells response to certain hormones and environment vitamins like vitamin A or steroids.’
When BRG1 is mutated and therefore inactive, tumour cells do not respond to the presence of these hormones and they continue growing and spreading. For this reason, these types of tumours are refractory to treatment with these substances.
‘At the moment,’ says Montse Sanchez-Cespedes, ‘we are not able to restore the functionality of a tumour suppressor gene as BRG1 in patients. Therefore, we are still far from a therapeutic application but the discovery enables us to better understand the biology of tumours. What we will try to do in the immediate future is to look for agents that specifically destroy the cells with mutated BRG1, following the strategy of lethal synthetics’.
In any case, this finding it can be useful in advancing personalised medicine, because ‘it explains why lung cancer patients are resistant to these treatments and may serve to rule out therapies with lipid-derived hormones in patients with BRG1 mutations, not just in lung cancer but also in breast and prostate, among others. ‘ IDIBELL
Research uncovers genetic marker that could help control, eliminate PRRS virus
, /in E-News /by 3wmediaA collaborative discovery involving Kansas State University researchers may improve animal health and save the U.S. pork industry millions of dollars each year.
Raymond ‘Bob’ Rowland, a virologist and professor of diagnostic medicine and pathobiology, was part of the collaborative effort that discovered a genetic marker that identifies pigs with reduced susceptibility to porcine reproductive and respiratory syndrome, or PRRS. This virus costs the U.S. pork industry more than $600 million each year.
‘This discovery is what you call a first-first,’ Rowland said. ‘This discovery is the first of its kind for PRRS but also for any large food animal infectious disease. I have worked in the field for 20 years and this is one of the biggest advances I have seen.’
Rowland and researchers Jack Dekkers from Iowa State University and Joan Lunney from the Agricultural Research Service discovered a genetic marker called a quantitative trait locus, or QTL, which is associated with porcine reproductive and respiratory syndrome virus susceptibility. This discovery is a first step in controlling and eliminating the virus.
The project’s beginning and future centre around Kansas State University, Rowland said.
It begins at the university because Rowland is involved with an organisation called the PRRS Host Genetics Consortium, or PHGC, which initiated and provided more than $5 million for the research. Rowland is co-director of the consortium, which is a collaboration among the United States Department of Agriculture, the National Pork Board and Genome Canada as well as universities and industry members. Rowland is also director of the USDA-funded PRRS Coordinated Agriculture Project, known as PRRS CAP.
‘The PRRS Host Genetics Consortium takes fundamental science and turns it into utility,’ Rowland said.
Kansas State University’s new Large Animal Research Center is the site of much of the project’s experimental work. The researchers obtain multiple measurements — including growth, weight gain, performance and virus measurements — over time. They have collected samples from more than 2,000 pigs since they began the study in 2007, for a total of more than 100,000 samples that are stored or distributed to the consortium’s collaborators.
The university shipped samples to the Agricultural Research Service for genomic DNA preparations to identify differences among more than 60,000 genes. The data was transferred to Iowa State University for genetic analysis that led to the discovery of the QTL.
The collaborators at Iowa State University created a common database so that all the data collected during the project can be accessed at multiple locations by researchers and the breeding industry for the next several decades.
‘A unique aspect of this project is that we have been looking at genes that may provide long-term resistance to a lot of infections,’ Rowland said. ‘This is very important for animal health because there are a lot of diseases for which there are no cures and no vaccines. Now we have a tool to study these diseases.’
These findings open new possibilities with Kansas State University’s Biosecurity Research Institute and the future National Bio and Agro-defense Facility. Scientists can take this new genetic tool and study different infectious diseases in these world-class research facilities.
Sex-deprived fruit flies’ alcohol preference could uncover answers for human addictions Kansas State University
Experts identify inhibitor causing male pattern baldness and target for hair loss treatments
, /in E-News /by 3wmediaResearchers from the Perelman School of Medicine at the University of Pennsylvania have identified an abnormal amount a protein called Prostaglandin D2 in the bald scalp of men with male pattern baldness, a discovery that may lead directly to new treatments for the most common cause of hair loss in men. In both human and animal models, researchers found that a prostaglandin known as PGD2 and its derivative, 15-dPGJ2, inhibit hair growth. The PGD2-related inhibition occurred through a receptor called GPR44, which is a promising therapeutic target for androgenetic alopecia in both men and women with hair loss and thinning.
Male pattern baldness strikes 8 of 10 men under 70 years old, and causes hair follicles to shrink and produce microscopic hairs, which grow for a shorter duration of time than normal follicles.
Researchers took an unbiased approach when scanning for potential biological causes of baldness, looking in scalp tissue from balding and non-bald spots from men with male pattern baldness and then corroborating findings in mouse models. They found that levels of PGD2 were elevated in bald scalp tissue at levels 3 times greater than what was found in comparative haired scalp of men with androgenetic alopecia. When PGD2 was added to cultured hair follicles, PGD2-treated hair was significantly shortened, while PGD2’s derivative, 15-dPGJ2, completely inhibited hair growth.
‘Although a different prostaglandin was known to increase hair growth, our findings were unexpected, as prostaglandins haven’t been thought about in relation to hair loss, yet it made sense that there was an inhibitor of hair growth, based on our earlier work looking at hair follicle stem cells,’ said George Cotsarelis, MD, chair and professor of Dermatology, and senior author on the studies. In a Penn study published in the Journal of Clinical Investigation last year, underlying hair follicle stem cells were found intact, suggesting that the scalp was lacking an activator or something was inhibiting hair follicle growth.
Prostaglandins are well characterised for their role in many bodily functions — controlling cell growth, constricting and dilating smooth muscle tissue — and a different prostaglandin (F2alpha) is known to increase hair growth. Researchers found that as PGD2 inhibits hair growth, other prostaglandins work in opposition, enhancing and regulating the speed of hair growth.
While these studies looked at AGA in men, the researchers noted that prostaglandins may represent a common pathway shared by both men and women with AGA. Future studies, potentially testing topical treatments that may target GPR44, can determine whether targeting prostaglandins will benefit woman with AGA as well. Penn University
The long, err, short of it
, /in E-News /by 3wmediaNo one really wants the short end of the stick, in this case the short end of a chromosome. Telomeres, which are DNA-protein complexes at the ends of chromosomes, can be thought of as protein ‘caps’ that protect chromosomes from deteriorating and fusing with neighbouring chromosomes.
It is typical for telomeres to shorten as cells divide and chromosomes replicate over time. Now a new study from Brigham and Women’s Hospital (BWH) suggest a strong link between telomere shortening and poor cardiovascular outcomes in patients with acute coronary syndrome.
Scientists measured telomere length in 5,044 patients with an acute coronary syndrome who were followed for 18 months.
They evaluated the risk of cardiovascular death or heart attack based on telomere length and other characteristics.
Shorter telomeres were associated with older age, male gender, smoking, prior heart attack and heart failure; although, the correlation between each individual factor and telomere length was modest. Age, for example, only accounts for seven percent of the variability in telomere length.
Telomere length was strongly associated with risk of cardiovascular death or heart attack. Patients with shorter telomeres had the highest risk. This relationship was consistent across various age groups.
‘We know that many different genetic and environmental factors, like diabetes, high cholesterol and smoking predispose patients to suffering cardiovascular events,’ said Christian T. Ruff, MD, MPH, Cardiovascular Division, BWH Department of Medicine, and lead study investigator. ‘Even when accounting for all of these other known risk factors, patients with short telomeres have an increased risk of having a heart attack or dying from heart disease.’
Taking the research findings from bench to bedside, Ruff points out that measuring telomere length may be useful in a clinical setting, providing a sort of predictor for cardiovascular events.
‘Telomere shortening may represent some sort of ‘biological clock’ which integrates the cumulative effect of environmental and genetic stresses on the body, both of which can contribute to cardiovascular events.’ said Ruff.
The researchers will continue to validate their findings to see if the relationship between telomere length and cardiovascular outcomes holds true in broader populations of patients. They also plan on experimenting on whether the rate of telomere shortening over time also predicts adverse cardiovascular events.
‘In the future, we hope to identify clinical, biochemical and genetic characteristics that predict telomere shortening,’ said Ruff. ‘We hope to have the ability to determine if therapies and medications that impact these processes may delay telomere attrition and lessen the risk of cardiovascular events in these patients.’ EurekAlert
A new test might facilitate diagnosis and drug development for Alzheimer’s disease
, /in E-News /by 3wmediaAn international team of researchers have developed a new method for measurement of aggregated beta-amyloid – a protein complex believed to cause major nerve cell damage and dysfunction in Alzheimer’s disease. The new method might facilitate diagnosis and detection as well as development of drugs directed against aggregated beta-amyloid.
Alzheimer’s disease (AD) is the most common cause of memory decline and dementia. According to the Alzheimer World Report 2011, today around 36 million people suffer from Dementia (around 20 – 25 million are Alzheimer’s patients). These numbers will dramatically increase with the ageing populations over the next few decades. For the year 2050 the expected number of dementia patients will be 115 – 200 million (70 – 150 million Alzheimer’s cases). It is therefore important to develop new therapies and diagnostic methods to detect and treat this complex chronic neurodegenerative brain disease.
Alzheimer’s disease is characterised by aggregates in the brain, containing a protein called beta-amyloid. The neuropathology of Alzheimer’s disease has recently been linked to the neurotoxic amyloid-β (Aβ) oligomers. The crucial role of Aβ oligomers in the early events of AD is experimentally underlined. Several recent results suggest that those oligomers may cause the death of neurons and neurological dysfunctions relevant to memory. Furthermore Aβ oligomers levels are increased in brain and cerebrospinal fluid samples from people with Alzheimer’s disease. This reflects the potential of Aβ oligomers as a marker for the early diagnosis of the disease.
An international team of scien
He analysed the cerebrospinal fluid of 30 neurological patients, including 14 Alzheimer’s patients. ‘These samples provided from leading expert academic memory clinics in Germany and Sweden are of the best quality and are highly characterised in order to provide robust and reliable results on promising novel biomarker candidates’, Professor Harald Hampel of Frankfurt University, a lead investigator comments.
‘Because of the limited number of samples, however, further study is needed to confirm the results,’ said Dr. Oskar Hansson of Lund University. The study was an international co-operation with the University of California in the U.S., the Goteborg and Malmö Universities from Sweden and the University of Frankfurt in Germany.
The test might not only be used fo
tists from Germany, Sweden and the U.S. have used a new method to quantify soluble variants of aggregated beta-amyloid (Aβ oligomers) in cerebrospinal fluid by flow cytometry. "We found that patients with a greater number of Aβ oligomers in the cerebrospinal fluid had a more pronounced disease," says Dr. Alexander Navarrete Santos (the developer of this method and now employee of the Research Laboratory of the University of Halle, Department of Cardiothoracic Surgery), and first author of the study.r the early detection of AD but can also be used when developing new and effective therapies for AD. A decline in the number of Aβ oligomers in cerebrospinal fluids could be a hint for the effectiveness of new drug therapies. EurekAlert
Identifying acute myeloid leukemia gene mutations may indicate risk, best treatment
, /in E-News /by 3wmediaAn international group of researchers, including those from Moffitt Cancer Center in Tampa, Fla., have published a paper reviewing the results of a study that analysed mutations in 18 genes of 398 patients who had acute myeloid leukemia (AML). They found that several mutated genes predicted improved outcomes when patients with certain gene mutations were given high-dose induction chemotherapy. Their findings suggest that mutational profiling could potentially be used for both risk stratification and also in helping health care providers make therapeutic decisions for some AML patients.
‘Previous studies have found that AML is a highly heterogenic disorder,’ said study co-author Hugo F. Fernandez, a senior member at Moffitt and associate chief of Moffitt’s Blood and Marrow Transplantation Division. ‘Moreover, recent studies have revealed that a number of genetic mutations in AML patients might have prognostic value. The question of the presence of these gene mutations altering outcomes based on current therapy had not been answered to date.’
Their paper cites a clinical trial carried out by the Eastern Co-operative Oncology Group (ECOG) in which dose-intensified chemotherapy improved outcomes in two age sets of AML patients. Based on these findings, the research team hypothesised that carrying out mutational analysis of all known molecular alterations occurring in more than 5 percent of patients with AML might allow for the identification of distinct, molecularly defined subgroups of patients who might benefit from dose-intensified chemotherapy.
The laboratory research team subsequently performed a mutational analysis on diagnostic samples from 398 patients enrolled in the ECOG clinical trial they cited and used patients’ frozen sample cells for extraction and profiling. The researchers validated the results of this latter group of 104 patients.
‘We found that intensification of the dose of anthracycline significantly improved outcomes and overall survival in patients with mutations in DNMT3A, NPM1 or MLL translocations,’ said Fernandez. ‘This finding suggests that mutational profiling could be used to determine which AML patients will benefit from dose-intensive induction therapy.’
‘Most importantly,’ said Fernandez, ‘this study demonstrates how integrated mutational profiling of samples from a clinical trial cohort can advance understanding of the biologic characteristics of AML.’ Moffitt Cancer Center