Scientists say they have developed a breath-test that can accurately tell if a person has bowel cancer. The test, which looks for exhaled chemicals linked to tumour activity, was able to identify a majority of patients with the disease.
The British Journal of Surgery reported an overall accuracy of 76%.
However, another scientist said it was unlikely a fully functioning and reliable breath-test would be available soon for the general public. Scientists are working on breath-tests for a host of other diseases, including several types of cancer, TB and diabetes.
If diagnosed and treated early, the chances of stopping cancer can be good, but there is often little or no outward sign of the disease until it has progressed significantly.
The current screening test for bowel cancer looks for signs of blood in the faeces, but only a small proportion of those who test positive actually have colorectal cancer, which means unnecessary and invasive further testing for many people.
The breath-test technology relies on the idea that the biology of tumours can lead to the production of specific ‘volatile organic compounds’, combinations of chemicals unlikely in a healthy person.
These can be found in small amounts in the breath of the patient, and early studies found dogs could be trained to identify them – although the latest study relies an electronic device to analyse breath gases.
The team from a hospital in Bari, southern Italy, compared the breath of 37 patients known to have bowel cancer with that of 41 ‘controls’ who were thought to be healthy.
The initial test identified the cancer patients with 85% accuracy, and although, when combined with a follow-up test, the overall result fell to 76%, the researchers were upbeat about its potential.
‘The present findings further support the value of breath-testing as a screening tool,’ they say.
It might be possible that the technique could help identify patients whose cancer was returning after treatment.
Bigger studies with a greater number of patients were now needed to fine-tune the test and confirm it worked, said Dr Donato Altomare and colleagues.
BBC
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The study, led by King’s College London’s Institute of Psychiatry (IoP) provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.
Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.
Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: ‘People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.’
Approximately 6 out of 10 young people aged 11-15 in England report drinking, a figure which has remained relatively stable over the past 20 years. However, binge drinking has become more common, with teenagers reportedly drinking an average of 6 units per week in 1994 and 13 units per week in 2007. In the UK, around 5,000 teenagers are admitted to hospital every year for alcohol-related reasons. Teenage alcohol abuse is also linked to poor brain development, health problems in later life, risk taking behaviour (drunk driving, unsafe sex) and antisocial behaviour.
The study initially looked at mouse models without the RASGRF2 gene to see how they reacted to alcohol. They found that the absence of the RASGRF-2 gene was linked to a significant reduction in alcohol-seeking activity. Upon intake of alcohol, the absence of the RASGRF-2 impaired the activity of dopamine-releasing neurons in a region of the brain called the ventral tegmental area (VTA) and prevented the brain from releasing dopamine, and hence any sense of reward.
The research team then analysed the brain scans of 663 14 year old boys – who at that age had not been exposed to significant amounts of alcohol. They found that individuals with genetic variations to the RASGRF2 gene had higher activation of the ventral striatum area of the brain (closely linked to the VTA and involved in dopamine release) when anticipating reward in a cognitive task. This suggests that individuals with a genetic variation on the RASGRF-2 gene release more dopamine when anticipating a reward, and hence derive more pleasure from the experience.
To confirm these findings, the researchers analysed drinking behaviour from the same group of boys at 16 years old, when many had already begun drinking frequently. They found that individuals with the variation on the RASGRF-2 gene drank more frequently at the age of 16 than those with no variation on the gene.
Professor Schumann concludes: ‘Identifying risk factors for early alcohol abuse is important in designing prevention and treatment interventions for alcohol addiction.’
King’s College London
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Children with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’
European Society of Cardiology
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An international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis — premature closure of the bony plates of the skull. The team of geneticists, paediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.
During foetal and early childhood development, the skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary ‘soft spots’ at the intersection of the seams.
If the bones fuse too early — the condition called craniosynostosis — a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.
About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis — affecting about 1 in 5,000 newborns — involves the sagittal suture, the main seam that runs down the centre of the top of the skull. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.
To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.
The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.
Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analysed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analysed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.
The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.
‘Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate,’ said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. ‘The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented.’
He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned.
Penn State
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About 10 percent of kids born with kidney defects have large alterations in their genomes known to be linked with neuro-developmental delay and mental illness, a new study by Columbia University Medical Center (CUMC) researchers has shown.
Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the US and are present in about 1 in every 200 births. Eventually, an evaluation for genomic alterations will be part of the standard clinical workup. Patients with congenital kidney disease—who are currently lumped into one category—will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis.
‘This changes the way we should handle these kids,’ said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital.’
‘If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neuro-developmental delay or mental illness later in life,’ he said. ‘This is a major opportunity for personalising medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.’
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC’s Department of Medicine.
Until now, no studies have linked congenital kidney disease with neuro-developmental disorders.
‘If you talk to clinicians, they tell you that some of these kids behave differently,’ Dr. Sanna-Cherchi said. ‘There has been a general assumption, though, that behavioural or cognitive issues in children with chronic illnesses such as kidney disease stem from the child’s difficulty in coping with the illness. Our study suggests that in some cases, neuro-developmental issues may be attributable to an underlying genomic disorder, not the kidney disease.’
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the ‘dose’ of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
Until the mid-2000s, when effective techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders—including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centres in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said.
University of Columbia
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Unfortunately, newspaper articles about young athletes dying suddenly on the field are not unheard of. Such reports fuel discussions about compulsory screening, for example of young footballers, for heart failure. Research by scientists from Ghent (VIB/UGent) and Italy will benefit these screening methods. They have discovered a link between mutations in a certain gene and the heart condition Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).
ARVC is a hereditary heart condition in which the heart muscle (particularly the right ventricle) is partly replaced by fatty tissue and connective tissue. Cardiac arrhythmias can occur as a result of the changes in the heart muscle. Severe arrhythmias can cause dizziness or even lead to fainting or an acute cardiac arrest (= sudden death). ARVC is a progressive disease that usually presents during the teenage years.
Mutations in various genes have already been linked to ARVC. These are primarily genes that are responsible for the production of proteins in the desmosomes. Desmosomes are structures in the heart that ensure that the heart muscle cells remain connected to each other. Therefore, it was assumed that defects in the desmosomes were the most important factors in developing ARVC.
Together with Italian scientists, Jolanda van Hengel, studied patients with ARVC who did not exhibit mutations in the desmosomal genes. The scientists identified mutations in the CTNNA3 gene in these patients, which codes for the protein αT-catenin – a component of the area composita. The area composita is a structure specifically modified to the heart, where extra strong connections between cardiac muscle cells occur.
The scientists’ findings indicate that there is a link between mutations in the CTNNA3 gene and ARVC. It was demonstrated for the first time that – in addition to desmosomal genes – an area composita gene also plays a role in the development of ARVC. Future genetic screening tests for ARVC should include the CTNNA3 gene as a standard part of the test. This would increase the value of the screening.
VIB
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Hot flushes are not ‘in the head,’ but new research suggests they may start there. A UA research team has identified a region in the brain that may trigger the uncomfortable surges of heat most women experience in the first few years of menopause.
Hot flushes – also called hot flashes – affect millions of people, and not just women. Yet, it is still unclear what causes the episodes of temperature discomfort, often accompanied by profuse sweating.
Now a team of researchers around Dr. Naomi Rance, a professor in the department of pathology at the UA College of Medicine, has come closer to understanding the mechanism of hot flushes, a necessary step for potential treatment options down the road.
The team identified a group of brain cells known as KNDy neurons as a likely control switch of hot flushes. KNDy neurons (pronounced ‘candy’) are located in the hypothalamus, a portion of the brain controlling vital functions that also serves as the switchboard between the central nervous system and hormone signals.
‘Although the KNDy neurons are a very small population of cells, our research reveals that they play extremely important roles in how the body controls its energy resources, reproduction and temperature,’ said Melinda Mittelman-Smith, who led the study as part of her doctoral thesis. ‘They are true multitaskers.’
By studying KNDy neurons in rats, the research team created an animal model of menopause to elucidate the biological mechanisms of temperature control in response to withdrawal of the hormone oestrogen, the main trigger of the changes that go along with menopause.
They discovered that tail skin temperature was consistently lower in rats whose KNDy neurons were inactivated, suggesting the neurons control a process known as vasodilation, or widening of the blood vessels to increase blood flow through the skin.
‘The hallmark of hot flushes is vasodilation,’ explained Rance, who also is a neuropathologist at The University of Arizona Medical Center. ‘When you flush, your skin gets hot and you can see the redness of the skin. It is an attempt of the body to get rid of heat, just like sweating. Except that if you were to measure core temperature at that point, you would find it is not even elevated.’
Although the results are not yet directly applicable in helping individuals affected by hot flushes, they mark a necessary first step, Rance said.
‘Obviously we can’t do these studies in women, and only if we understand the mechanism is there a chance of developing therapies. All that is known so far is that dwindling estrogen levels have something to do with it but anything after that is a black box.’
University of Arizona
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A research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper. The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as ‘astrocyte activation.’ The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial.
University of Kentucky
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New research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection.
George Washington University
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A review in the December issue of the journal Archives of Pathology & Laboratory Medicine by Paul Bunn Jr, MD, University of Colorado Cancer Center investigator and past president of ASCO, IASLC and AACI describes the current state of lung cancer care.
‘We’re in a new paradigm in which we realize this top cause of cancer deaths is actually a number of related diseases, each potentially with its own cause and cure,’ Bunn says.
The review describes the shift from blanketing lung cancer with radiation and chemotherapy, to targeting the specific genetic mutations that cause lung cancer’s many varieties. The first of these oncogenic lung cancer mutations to be exploited by a drug was the epidermal growth factor receptor (EGFR), described in 2004 and targeted by the drugs erlotinib and gefitinib. Then in 2007 the oncogenic ALK/EML4 fusion protein was described, and is now targeted by the drug crizotinib, which earned FDA approval in 2011. Drugs in the development pipeline target a handful of additional lung-cancer-causing mutations including KRAS, HER2/neu, BRAF, NRAF, and ROS.
‘Pathologists used to define lung cancer as one of four types, based on its appearance,’ Bunn says, ‘but it’s much more heterogenous than that. Some of these driver mutations may only be present in 1 or 2 percent of the lung cancer population, and mutations in combination may make for hundreds of species of the disease, each with its own response characteristics to targeted drugs and drug combinations.’
‘Whole exome sequencing shows there are about 300 mutations in the average lung cancer,’ Bunn says. ‘You may have an EGFR mutation driving the cancer, but then the other 299 mutations may help define who will do well on an EGFR inhibitor.’
Bunn points out that in the lung cancer varieties whose driver oncogenes can be matched with targeted therapy, we tend to see 70-80 percent patient response as opposed to 20-30 percent response to traditional chemotherapies, and with much reduced side effects.
But with this great promise of picking off cancer varieties one-by-one according to their oncogenes comes the challenge of testing drugs that are effective in perhaps only one of every 100 lung cancer patients. The challenge is twofold: enrolling enough patients on a clinical trial to make the results meaningful, and securing funding for a trial in which the drug will only be marketable to a small slice of the lung cancer population.
‘How do you get drug approvals for what we’d normally call orphan diseases?’ Bunn asks.
Then, Bunn points to the major challenge of staying ahead of lung cancer as it mutates in response to these targeted first-line drugs. ‘Targeted therapies don’t cure patients yet,’ Bunn says. Instead, lung cancer eventually mutates around the drug’s effectiveness. ‘And so we have to discover the most rational combinations and see if these combinations allow complete response,’ Bunn says.
In addition to therapies targeting oncogenes, Bunn describes completely new approaches to treating the disease, including Phase III clinical trials of lung cancer vaccines that aid the body’s immune response against the cancer, and the search for ways to promote the function of tumour-suppressor genes that are commonly turned off in cancers.
What is clear is that after many years of chemotherapy and radiation, we’re in the midst of an explosion in novel lung cancer treatment options.
University of Colorado Cancer Center
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‘Promising results’ for bowel cancer breath-test
, /in E-News /by 3wmediaScientists say they have developed a breath-test that can accurately tell if a person has bowel cancer. The test, which looks for exhaled chemicals linked to tumour activity, was able to identify a majority of patients with the disease.
The British Journal of Surgery reported an overall accuracy of 76%.
However, another scientist said it was unlikely a fully functioning and reliable breath-test would be available soon for the general public. Scientists are working on breath-tests for a host of other diseases, including several types of cancer, TB and diabetes.
If diagnosed and treated early, the chances of stopping cancer can be good, but there is often little or no outward sign of the disease until it has progressed significantly.
The current screening test for bowel cancer looks for signs of blood in the faeces, but only a small proportion of those who test positive actually have colorectal cancer, which means unnecessary and invasive further testing for many people.
The breath-test technology relies on the idea that the biology of tumours can lead to the production of specific ‘volatile organic compounds’, combinations of chemicals unlikely in a healthy person.
These can be found in small amounts in the breath of the patient, and early studies found dogs could be trained to identify them – although the latest study relies an electronic device to analyse breath gases.
The team from a hospital in Bari, southern Italy, compared the breath of 37 patients known to have bowel cancer with that of 41 ‘controls’ who were thought to be healthy.
The initial test identified the cancer patients with 85% accuracy, and although, when combined with a follow-up test, the overall result fell to 76%, the researchers were upbeat about its potential.
‘The present findings further support the value of breath-testing as a screening tool,’ they say.
It might be possible that the technique could help identify patients whose cancer was returning after treatment.
Bigger studies with a greater number of patients were now needed to fine-tune the test and confirm it worked, said Dr Donato Altomare and colleagues. BBC
Research reveals why some teenagers more prone to binge drinking
, /in E-News /by 3wmediaThe study, led by King’s College London’s Institute of Psychiatry (IoP) provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.
Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.
Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: ‘People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.’
Approximately 6 out of 10 young people aged 11-15 in England report drinking, a figure which has remained relatively stable over the past 20 years. However, binge drinking has become more common, with teenagers reportedly drinking an average of 6 units per week in 1994 and 13 units per week in 2007. In the UK, around 5,000 teenagers are admitted to hospital every year for alcohol-related reasons. Teenage alcohol abuse is also linked to poor brain development, health problems in later life, risk taking behaviour (drunk driving, unsafe sex) and antisocial behaviour.
The study initially looked at mouse models without the RASGRF2 gene to see how they reacted to alcohol. They found that the absence of the RASGRF-2 gene was linked to a significant reduction in alcohol-seeking activity. Upon intake of alcohol, the absence of the RASGRF-2 impaired the activity of dopamine-releasing neurons in a region of the brain called the ventral tegmental area (VTA) and prevented the brain from releasing dopamine, and hence any sense of reward.
The research team then analysed the brain scans of 663 14 year old boys – who at that age had not been exposed to significant amounts of alcohol. They found that individuals with genetic variations to the RASGRF2 gene had higher activation of the ventral striatum area of the brain (closely linked to the VTA and involved in dopamine release) when anticipating reward in a cognitive task. This suggests that individuals with a genetic variation on the RASGRF-2 gene release more dopamine when anticipating a reward, and hence derive more pleasure from the experience.
To confirm these findings, the researchers analysed drinking behaviour from the same group of boys at 16 years old, when many had already begun drinking frequently. They found that individuals with the variation on the RASGRF-2 gene drank more frequently at the age of 16 than those with no variation on the gene.
Professor Schumann concludes: ‘Identifying risk factors for early alcohol abuse is important in designing prevention and treatment interventions for alcohol addiction.’ King’s College London
Atherosclerosis found in HIV children
, /in E-News /by 3wmediaChildren with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’ European Society of Cardiology
Genetic differences discovered in kids with premature skull closure
, /in E-News /by 3wmediaAn international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis — premature closure of the bony plates of the skull. The team of geneticists, paediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.
During foetal and early childhood development, the skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary ‘soft spots’ at the intersection of the seams.
If the bones fuse too early — the condition called craniosynostosis — a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.
About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis — affecting about 1 in 5,000 newborns — involves the sagittal suture, the main seam that runs down the centre of the top of the skull. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.
To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.
The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.
Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analysed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analysed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.
The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.
‘Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate,’ said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. ‘The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented.’
He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned. Penn State
Surprising link between kidney defects and neuro-developmental disorders in kids
, /in E-News /by 3wmediaAbout 10 percent of kids born with kidney defects have large alterations in their genomes known to be linked with neuro-developmental delay and mental illness, a new study by Columbia University Medical Center (CUMC) researchers has shown.
Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the US and are present in about 1 in every 200 births. Eventually, an evaluation for genomic alterations will be part of the standard clinical workup. Patients with congenital kidney disease—who are currently lumped into one category—will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis.
‘This changes the way we should handle these kids,’ said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital.’
‘If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neuro-developmental delay or mental illness later in life,’ he said. ‘This is a major opportunity for personalising medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.’
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC’s Department of Medicine.
Until now, no studies have linked congenital kidney disease with neuro-developmental disorders.
‘If you talk to clinicians, they tell you that some of these kids behave differently,’ Dr. Sanna-Cherchi said. ‘There has been a general assumption, though, that behavioural or cognitive issues in children with chronic illnesses such as kidney disease stem from the child’s difficulty in coping with the illness. Our study suggests that in some cases, neuro-developmental issues may be attributable to an underlying genomic disorder, not the kidney disease.’
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the ‘dose’ of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
Until the mid-2000s, when effective techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders—including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centres in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said. University of Columbia
Discovery in Ghent could improve screening for sudden cardiac death
, /in E-News /by 3wmediaUnfortunately, newspaper articles about young athletes dying suddenly on the field are not unheard of. Such reports fuel discussions about compulsory screening, for example of young footballers, for heart failure. Research by scientists from Ghent (VIB/UGent) and Italy will benefit these screening methods. They have discovered a link between mutations in a certain gene and the heart condition Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).
ARVC is a hereditary heart condition in which the heart muscle (particularly the right ventricle) is partly replaced by fatty tissue and connective tissue. Cardiac arrhythmias can occur as a result of the changes in the heart muscle. Severe arrhythmias can cause dizziness or even lead to fainting or an acute cardiac arrest (= sudden death). ARVC is a progressive disease that usually presents during the teenage years.
Mutations in various genes have already been linked to ARVC. These are primarily genes that are responsible for the production of proteins in the desmosomes. Desmosomes are structures in the heart that ensure that the heart muscle cells remain connected to each other. Therefore, it was assumed that defects in the desmosomes were the most important factors in developing ARVC.
Together with Italian scientists, Jolanda van Hengel, studied patients with ARVC who did not exhibit mutations in the desmosomal genes. The scientists identified mutations in the CTNNA3 gene in these patients, which codes for the protein αT-catenin – a component of the area composita. The area composita is a structure specifically modified to the heart, where extra strong connections between cardiac muscle cells occur.
The scientists’ findings indicate that there is a link between mutations in the CTNNA3 gene and ARVC. It was demonstrated for the first time that – in addition to desmosomal genes – an area composita gene also plays a role in the development of ARVC. Future genetic screening tests for ARVC should include the CTNNA3 gene as a standard part of the test. This would increase the value of the screening. VIB
What causes hot flushes during menopause?
, /in E-News /by 3wmediaHot flushes are not ‘in the head,’ but new research suggests they may start there. A UA research team has identified a region in the brain that may trigger the uncomfortable surges of heat most women experience in the first few years of menopause.
Hot flushes – also called hot flashes – affect millions of people, and not just women. Yet, it is still unclear what causes the episodes of temperature discomfort, often accompanied by profuse sweating.
Now a team of researchers around Dr. Naomi Rance, a professor in the department of pathology at the UA College of Medicine, has come closer to understanding the mechanism of hot flushes, a necessary step for potential treatment options down the road.
The team identified a group of brain cells known as KNDy neurons as a likely control switch of hot flushes. KNDy neurons (pronounced ‘candy’) are located in the hypothalamus, a portion of the brain controlling vital functions that also serves as the switchboard between the central nervous system and hormone signals.
‘Although the KNDy neurons are a very small population of cells, our research reveals that they play extremely important roles in how the body controls its energy resources, reproduction and temperature,’ said Melinda Mittelman-Smith, who led the study as part of her doctoral thesis. ‘They are true multitaskers.’
By studying KNDy neurons in rats, the research team created an animal model of menopause to elucidate the biological mechanisms of temperature control in response to withdrawal of the hormone oestrogen, the main trigger of the changes that go along with menopause.
They discovered that tail skin temperature was consistently lower in rats whose KNDy neurons were inactivated, suggesting the neurons control a process known as vasodilation, or widening of the blood vessels to increase blood flow through the skin.
‘The hallmark of hot flushes is vasodilation,’ explained Rance, who also is a neuropathologist at The University of Arizona Medical Center. ‘When you flush, your skin gets hot and you can see the redness of the skin. It is an attempt of the body to get rid of heat, just like sweating. Except that if you were to measure core temperature at that point, you would find it is not even elevated.’
Although the results are not yet directly applicable in helping individuals affected by hot flushes, they mark a necessary first step, Rance said.
‘Obviously we can’t do these studies in women, and only if we understand the mechanism is there a chance of developing therapies. All that is known so far is that dwindling estrogen levels have something to do with it but anything after that is a black box.’
University of ArizonaUK team inhibits Alzheimer’s biomarkers in animal model by targeting astrocytes
, /in E-News /by 3wmediaA research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper. The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as ‘astrocyte activation.’ The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial. University of Kentucky
New research helps predict susceptibility to Burkitt Lymphoma
, /in E-News /by 3wmediaNew research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection. George Washington University
The current state of lung cancer treatment
, /in E-News /by 3wmediaA review in the December issue of the journal Archives of Pathology & Laboratory Medicine by Paul Bunn Jr, MD, University of Colorado Cancer Center investigator and past president of ASCO, IASLC and AACI describes the current state of lung cancer care.
‘We’re in a new paradigm in which we realize this top cause of cancer deaths is actually a number of related diseases, each potentially with its own cause and cure,’ Bunn says.
The review describes the shift from blanketing lung cancer with radiation and chemotherapy, to targeting the specific genetic mutations that cause lung cancer’s many varieties. The first of these oncogenic lung cancer mutations to be exploited by a drug was the epidermal growth factor receptor (EGFR), described in 2004 and targeted by the drugs erlotinib and gefitinib. Then in 2007 the oncogenic ALK/EML4 fusion protein was described, and is now targeted by the drug crizotinib, which earned FDA approval in 2011. Drugs in the development pipeline target a handful of additional lung-cancer-causing mutations including KRAS, HER2/neu, BRAF, NRAF, and ROS.
‘Pathologists used to define lung cancer as one of four types, based on its appearance,’ Bunn says, ‘but it’s much more heterogenous than that. Some of these driver mutations may only be present in 1 or 2 percent of the lung cancer population, and mutations in combination may make for hundreds of species of the disease, each with its own response characteristics to targeted drugs and drug combinations.’
‘Whole exome sequencing shows there are about 300 mutations in the average lung cancer,’ Bunn says. ‘You may have an EGFR mutation driving the cancer, but then the other 299 mutations may help define who will do well on an EGFR inhibitor.’
Bunn points out that in the lung cancer varieties whose driver oncogenes can be matched with targeted therapy, we tend to see 70-80 percent patient response as opposed to 20-30 percent response to traditional chemotherapies, and with much reduced side effects.
But with this great promise of picking off cancer varieties one-by-one according to their oncogenes comes the challenge of testing drugs that are effective in perhaps only one of every 100 lung cancer patients. The challenge is twofold: enrolling enough patients on a clinical trial to make the results meaningful, and securing funding for a trial in which the drug will only be marketable to a small slice of the lung cancer population.
‘How do you get drug approvals for what we’d normally call orphan diseases?’ Bunn asks.
Then, Bunn points to the major challenge of staying ahead of lung cancer as it mutates in response to these targeted first-line drugs. ‘Targeted therapies don’t cure patients yet,’ Bunn says. Instead, lung cancer eventually mutates around the drug’s effectiveness. ‘And so we have to discover the most rational combinations and see if these combinations allow complete response,’ Bunn says.
In addition to therapies targeting oncogenes, Bunn describes completely new approaches to treating the disease, including Phase III clinical trials of lung cancer vaccines that aid the body’s immune response against the cancer, and the search for ways to promote the function of tumour-suppressor genes that are commonly turned off in cancers.
What is clear is that after many years of chemotherapy and radiation, we’re in the midst of an explosion in novel lung cancer treatment options. University of Colorado Cancer Center