The occurrence of chemotherapy resistance is one of the major reasons for failure in cancer treatment. A study led by Óscar Fernández-Capetillo, Head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), has identified a new determinant of chemotherapy resistance. In this regard, they employed ATR kinase inhibitors, which were previously described by the group as a cancer treatment strategy, and that could be tested on humans as early as 2017, according to the researcher. The determining factor is a protein that often appears increased in cancer cells, CDC25A. This discovery opens up new avenues for novel and more effective treatments as well as a way to predict which patients will particularly benefit from a therapy with ATR inhibitors.
Most chemotherapy agents are drugs that destroy the DNA of cancer cells. In this case, the CNIO’s strategy is targeting ATR kinase; a protein that is responsible for repairing the genome. This protein, ‘is present in all cells, both in healthy and cancerous cells; however, its function in tumour cells is even more vital because their genome is highly fragmented and needs to be repaired frequently so as not to become unstable and die,’ says Fernández-Capetillo. Disabling this genome guardian element in tumour cells is catastrophic for them, he adds, ‘it is like killing the fireman in the middle of a forest fire.’ This explains why this treatment is more toxic to tumour cells and not so toxic in the healthy tissues surrounding them.
In this project, the researchers have tried to anticipate the potential for the emergence of resistance during therapy in the clinic. In order to identify possible mutations that may confer resistance to ATR inhibitors in cells, the researchers made use of a new ally: the CRISPR genome editing technology. By implementing this technology, they generated a collection of cells, in which each cell contained a different mutated gene. ‘Taking into account that a mouse has around 20,000 different genes, it would have taken much longer to generate a collection of mutants like these using any other modification technique,’ explain Sergio Ruiz and Cristina Mayor-Ruiz, first authors of the study.
By subjecting the cells to treatment with ATR inhibitors, they were able to isolate some that were resistant to the treatment and subsequently identify the mutation they were carrying. It was demonstrated that cells with mutations in the CDC25A gene survived.
‘CDC25A is a protein that is normally highly expressed in tumours,’ explains Fernández-Capetillo. ‘This paper suggests that a way of identifying patients who will respond more successfully to treatment is by determining those whose tumours have higher levels of CDC25A.’ In addition to finding a mutation that allows cells to become resistant to treatment, the researchers also identified a treatment capable of eliminating resistant cells.
EurekAlert
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Coeliac disease is a chronic, immunological disease that is manifested as intolerance to gluten proteins present in wheat, rye and barley. This intolerance leads to an inflammatory reaction in the small intestine that hampers the absorption of nutrients. The only treatment is a strict, life-long, gluten-free diet.
It has been known for some time that coeliac disease develops in people who have a genetic susceptibility, but despite the fact that 40% of the population carry the most decisive risk factor (the HLA-DQ2 and DQ8 polymorphisms), only 1% go on to develop the disease. ‘What we have here is a complex genetic disease in which many polymorphisms play a role, each making a very small contribution to its development,’ explained the UPV/EHU researcher Ainara Castellanos, who has led the work published in Science.
One of the added risk factors is to be found, according to this research, in the so-called ‘junk’ DNA, in other words, in 95% of the DNA. It is the least-known part because, unlike the remaining 5%, it is not involved in synthesising proteins. Nevertheless, light is gradually being shed on its role in the control of the overall functioning of the genome, in other words, it regulates important processes in our organism such as immune response and that is where it might be possible to find the causes of auto-immune diseases such as coeliac disease.
A key gene in the regulating of the inflammatory response observed in coeliac patients has been found in one of the regions of the junk genome: it is the 1nc13. The ribonucleic acid produced by this gene belongs to the family of long, non-coding RNAs or lncRNA and is responsible for maintaining the normal levels of expression of pro-inflammatory genes. In coeliacs, this non-coding RNA is hardly produced at all so the levels of these inflammatory genes are not properly regulated and their expression is increased. But besides being produced in low quantities, the 1nc13 produced by coeliac patients has a variant that alters the way it functions. ‘That way an inflammatory environment is created and the development of the disease is encouraged,’ said Ainara Castellanos.
‘This study confirms the importance of the regions of the genome previously regarded as ‘junk’ in the development of common complaints such as coeliac disease and opens up the door to a new possibility for diagnosis. Right now, we are interested in finding out whether the low levels of this RNA are an early feature of coeliac disease (and of other immune diseases), which could be used as a diagnostic tool before its onset,’ explained the UPV/EHU’s lecturer in Genetics José Ramón Bilbao, another of the authors of the work.
University of the Basque Country
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Newcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver – even before someone may feel ill. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).
NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.
The Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.
Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: “This scientific breakthrough has great promise because the majority of patients show no symptoms.
“Routine blood tests can’t detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages – by examining a piece of the liver under the microscope.
“We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it’s important to be able to detect liver scarring at an early stage.”
In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of “cell-free” DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγthat controls scar formation are then used to stratify patients by fibrosis severity.
Senior author Dr Jelena Mann of Newcastle University’s Institute for Cellular Medicine added: “This is the first time that a DNA methylation ‘signature’ from the blood has been shown to match the severity of a liver disease.
“It opens up the possibility of an improved blood test for liver fibrosis in the future.”
Newcastle University
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The babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.
Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.
Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.
Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.
Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.
The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.
“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.
“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”
Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus.
Cambridge University
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While research has identified hundreds of genes required for normal memory formation, genes that suppress memory are of special interest because they offer insights into how the brain prioritizes and manages all of the information, including memories, that it takes in every day. These genes also provide clues for how scientists might develop new treatments for cognitive disorders such as Alzheimer’s disease.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, a widely recognized substitute for human memory studies.
The study, which was led by Ron Davis, chair of TSRI’s Department of Neuroscience].
Davis and his colleagues screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts. One of these suppressor genes, in particular, caught their attention.
“When we knocked out this gene, the flies had a better memory—a nearly two-fold better memory,” said Davis. “The fact that this gene is active in the same pathway as several cognitive enhancers currently used for the treatment of Alzheimer’s disease suggests it could be a potential new therapeutic target.”
When the scientists disabled this gene, known as DmSLC22A, flies’ memory of smells (the most widely studied form of memory in this model) was enhanced—while overexpression of the gene inhibited that same memory function.
“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said Research Associate Ze Liu, co-first author of the study. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”
The gene in question belongs to a family of “plasma membrane transporters,” which produce proteins that move molecules, large and small, across cell walls. In the case of DmSLC22A, the new study indicates that the gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. When DmSLC22A functions normally, the protein removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When the protein is missing, more acetylcholine persists in the synapse, making the synaptic signal stronger and more persistent, leading to enhanced memory.
“DmSLC22A serves as a bottleneck in memory formation,” said Research Associate Yunchao Gai, the study’s other co-first author. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”
The next step, Davis added, is to develop a screen for inhibitors of this pathway that, independently or in concert with other treatments, may offer a more effective way to deal with the problems of memory loss due to Alzheimer’s and other neurodegenerative diseases.
Scripps Florida
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Genomic makeup of colorectal cancers predicts immune system ability to fight tumours
Colorectal cancers heavily bedecked with tumour-related proteins called neoantigens are likely to be permeated with disease-fighting white blood cells, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard report in a new study. Because such an influx of white blood cells often signifies an immune system attack on cancer, the discovery will sharpen research into therapies that make tumours more vulnerable to such an attack.
The discovery was made by combining several data sets from patients in two large health-tracking studies, the Nurses’ Health Study and the Health Professionals Follow-up Study. Researchers first performed whole-exome sequencing on colorectal tumour samples from 619. This information was merged with data from tests of the immune system’s response to the tumours and with patient clinical data, including length of survival.
“We were looking for genetic features that predict how extensively a tumour is infiltrated by lymphocytes [certain white blood cells] and which types of lymphocytes are present,” said study co-lead author, Marios Giannakis, MD, PhD, medical oncologist and clinical investigator at the Dana-Farber Gastrointestinal Cancer Treatment Center, and researcher at the Broad Institute of MIT and Harvard. “We found that tumours with a high ‘neoantigen load’ – which carry large quantities of neoantigens – tended to be infiltrated by a large number of lymphocytes, including memory T cells, which provide protection against previously encountered infections and diseases. Patients whose tumours had high numbers of neoantigens also survived longer than those with lower neoantigen loads.”
Neoantigens are deviant forms of protein antigens, which are found on normal cells. Genetic mutations often cause cancer cells to produce abnormal proteins, some of which get lifted to the cell surface, where they serve as a red flag to the immune system that something is amiss with the cell.
“There can be hundreds or thousands of neoantigens on tumour cells,” Giannakis explained. “Only a few of these may actually provoke T cells to infiltrate a tumour. But the more neoantigens on display, the greater the chance that some of them will spark an immune system response.”
Therapies known as immune checkpoint inhibitors work by removing some of the barriers to an immune system attack on cancer. Although these agents have produced astonishing results in some cases, they’re generally effective only in patients whose immune system has already launched an immune response to cancer. By showing that tumours with high antigen loads are apt to be laced with T cells – and therefore to have provoked an immune response – the study may help investigators identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.
The study’s genomic analysis of colorectal tumour samples also found several often-mutated genes that had not previously been strongly associated with the disease, including BCL9L, RBM10, CTCF, and KLF5. The discovery of their prevalence in colorectal cancer suggests that they may be valuable targets for new therapies.
Dana-Farber Cancer Institute
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Led by researchers at the University of Pittsburgh School of Medicine, an international panel of pathologists and clinicians has reclassified a type of thyroid cancer to reflect that it is non-invasive and has a low risk of recurrence. The name change is expected to reduce the psychological and medical consequences of a cancer diagnosis, potentially affecting thousands of people worldwide.
The incidence of thyroid cancer has been rising partly due to early detection of tumours that are indolent or non-progressing, despite the presence of certain cellular abnormalities that are traditionally considered cancerous, explained senior investigator Yuri Nikiforov, M.D., Ph.D., professor of pathology and director of Pitt’s Division of Molecular and Genomic Pathology.
“This phenomenon is known as over-diagnosis,” Dr. Nikiforov said. “To my knowledge, this is the first time in the modern era a type of cancer is being reclassified as a non-cancer. I hope that it will set an example for other expert groups to address nomenclature of various cancer types that have indolent behaviour to prevent inappropriate and costly treatment.”
University of Pittsburgh School of Medicine
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Imagine attempting to bake a cake—except you have to go to different stores for flour and milk, drive across town to get eggs and call a friend to borrow a cake pan.
This is the kind of disjointed scenario many scientists face when they attempt to gather data scattered across small databases and hard-to-search PDF files.
“It’s not that the data doesn’t exist,” said Andrew Su, associate professor at The Scripps Research Institute (TSRI). “The data just isn’t stored in a way that scientists can easily access.”
“Open data is vital for progress and research,” added TSRI Assistant Professor of Molecular and Experimental Medicine Ben Good. “We need to break down those barriers.”
To solve this problem, Su, Good and their colleagues at TSRI have integrated biomedical data into Wikidata, a public, editable database where researchers can easily link genes, proteins and more.
Technological breakthroughs in the last 10 years have led to rapid increases in the volume and rate of biomedical research, which in turn has led to a rapid growth in biomedical knowledge. However, this knowledge is currently fragmented across countless resources—from online databases to supplementary data files to individual facts in individual papers.
“As a research community, we spend a lot of time searching for good resources and trying to link them together,” said TSRI Research Associate Tim Putman, who was first author of one of the studies. “It’s cringeworthy.”
Even when databases are open to the public, current knowledge isn’t always organized in a uniform way, Putman explained.
Rather than leave each research group to tackle data integration individually, Wikidata offers a new model for organizing all this information. Built on the same principles as Wikipedia, Wikidata enables anyone to add new information to an open community database.
While other Wikidata editors have added information on millions of items as diverse as works of art to U.S. cities, the TSRI team has focused on adding information on biomedical concepts.
TSRI Research Associate Sebastian Burgstaller-Muehlbacher, first author on one study, added data on all human and mouse genes, all human diseases and all drugs approved by the U.S. Food and Drug Administration.
Putman then extended Wikidata with a focus on microbial genomes. With all this information collected in one system, researchers can more easily spot connections between diseases, pathogens and biological processes. As an example, Putman used the model to show that other microorganisms in the body can influence chlamydia infections.
As a proof of concept, Putman led the development of a genome browser based on Wikidata. Rather than having to develop one browser for every sequenced genome, this genome browser allows users to browse any genome that has been loaded into Wikidata.
“You can zoom in on a gene, click on it and the sequence will pop up,” said Good. The genome browser will then link back to the original Wikidata entry.
In the end, the researchers plan to have a comprehensive, uniform database that is easy to search and open to anyone who wants to add data and link related concepts.
“We think this data should all be open,” said Su. “This just makes intuitive sense.”
The Scripps Research Institute
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Researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.
Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.
“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”
In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.
The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.
“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.”
University of Pennsylvania Health System
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A quick, reliable and cost-effective mobility assessment tool may help to identify elderly patients at risk for adverse post-surgery outcomes, according to Wake Forest Baptist Medical Center researchers.
In their study of 197 men and woman over age 69 who underwent elective, non-cardiac, inpatient surgery at Wake Forest Baptist over a 20-month period, the researchers found that the participants’ preoperative scores on the Mobility Assessment Tool: Short Form (MAT-sf) were predictive of early postoperative complications, longer hospital stays and discharges to nursing homes.
“Preoperative assessment of patient characteristics that may lead to adverse postoperative outcomes is important to patients, their families and their surgeons, especially with older adults, in whom complications are more likely,” said Leanne Groban, M.D., professor of anaesthesiology at Wake Forest Baptist and lead author of the study.
“Mobility is a powerful indicator of overall health in the elderly, and our results indicate that self-reported mobility, as measured by the MAT-sf, can complement existing assessment tools in determining which patients are at risk of adverse postoperative outcomes.”
The MAT-sf features animated video clips of 10 common physical activities, each followed by questions about the participant’s ability to perform the particular task. In addition to the MAT-sf, participants in the study also underwent four other commonly employed preoperative risk assessments. After controlling for factors such as the participants’ age, sex and body mass index and their scores on the other tests, the researchers found that low (poor) scores on the MAT-sf were associated with short-term complications, later time to discharge and increased nursing home placement to a greater degree than any of the other indicators.
“The traditional risk assessments may be too comprehensive, too focused on single organ systems or too impractical to be effective in this setting,” Groban said.
The next steps, she said, are to validate these findings in a larger, multi-centre study and to test whether preoperative strength and balance training might limit undesirable postoperative outcomes in older adults with mobility limitations.
“Studies such as this will help determine future clinical pathways aimed at reducing adverse outcomes while improving patients’ functionality and speeding their return to independence,” Groban said.
Wake Forest University
www.wakehealth.edu/News-Releases/2016/Mobility_Assessment_Tool_May_Help_Predict_Early_Postoperative_Outcomes_for_Older_Adults.htm
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New mechanism of resistance to chemotherapy
, /in E-News /by 3wmediaThe occurrence of chemotherapy resistance is one of the major reasons for failure in cancer treatment. A study led by Óscar Fernández-Capetillo, Head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), has identified a new determinant of chemotherapy resistance. In this regard, they employed ATR kinase inhibitors, which were previously described by the group as a cancer treatment strategy, and that could be tested on humans as early as 2017, according to the researcher. The determining factor is a protein that often appears increased in cancer cells, CDC25A. This discovery opens up new avenues for novel and more effective treatments as well as a way to predict which patients will particularly benefit from a therapy with ATR inhibitors.
Most chemotherapy agents are drugs that destroy the DNA of cancer cells. In this case, the CNIO’s strategy is targeting ATR kinase; a protein that is responsible for repairing the genome. This protein, ‘is present in all cells, both in healthy and cancerous cells; however, its function in tumour cells is even more vital because their genome is highly fragmented and needs to be repaired frequently so as not to become unstable and die,’ says Fernández-Capetillo. Disabling this genome guardian element in tumour cells is catastrophic for them, he adds, ‘it is like killing the fireman in the middle of a forest fire.’ This explains why this treatment is more toxic to tumour cells and not so toxic in the healthy tissues surrounding them.
In this project, the researchers have tried to anticipate the potential for the emergence of resistance during therapy in the clinic. In order to identify possible mutations that may confer resistance to ATR inhibitors in cells, the researchers made use of a new ally: the CRISPR genome editing technology. By implementing this technology, they generated a collection of cells, in which each cell contained a different mutated gene. ‘Taking into account that a mouse has around 20,000 different genes, it would have taken much longer to generate a collection of mutants like these using any other modification technique,’ explain Sergio Ruiz and Cristina Mayor-Ruiz, first authors of the study.
By subjecting the cells to treatment with ATR inhibitors, they were able to isolate some that were resistant to the treatment and subsequently identify the mutation they were carrying. It was demonstrated that cells with mutations in the CDC25A gene survived.
‘CDC25A is a protein that is normally highly expressed in tumours,’ explains Fernández-Capetillo. ‘This paper suggests that a way of identifying patients who will respond more successfully to treatment is by determining those whose tumours have higher levels of CDC25A.’ In addition to finding a mutation that allows cells to become resistant to treatment, the researchers also identified a treatment capable of eliminating resistant cells. EurekAlert
A key gene in the development of coeliac disease has been found in ‘junk’ DNA
, /in E-News /by 3wmediaCoeliac disease is a chronic, immunological disease that is manifested as intolerance to gluten proteins present in wheat, rye and barley. This intolerance leads to an inflammatory reaction in the small intestine that hampers the absorption of nutrients. The only treatment is a strict, life-long, gluten-free diet.
It has been known for some time that coeliac disease develops in people who have a genetic susceptibility, but despite the fact that 40% of the population carry the most decisive risk factor (the HLA-DQ2 and DQ8 polymorphisms), only 1% go on to develop the disease. ‘What we have here is a complex genetic disease in which many polymorphisms play a role, each making a very small contribution to its development,’ explained the UPV/EHU researcher Ainara Castellanos, who has led the work published in Science.
One of the added risk factors is to be found, according to this research, in the so-called ‘junk’ DNA, in other words, in 95% of the DNA. It is the least-known part because, unlike the remaining 5%, it is not involved in synthesising proteins. Nevertheless, light is gradually being shed on its role in the control of the overall functioning of the genome, in other words, it regulates important processes in our organism such as immune response and that is where it might be possible to find the causes of auto-immune diseases such as coeliac disease.
A key gene in the regulating of the inflammatory response observed in coeliac patients has been found in one of the regions of the junk genome: it is the 1nc13. The ribonucleic acid produced by this gene belongs to the family of long, non-coding RNAs or lncRNA and is responsible for maintaining the normal levels of expression of pro-inflammatory genes. In coeliacs, this non-coding RNA is hardly produced at all so the levels of these inflammatory genes are not properly regulated and their expression is increased. But besides being produced in low quantities, the 1nc13 produced by coeliac patients has a variant that alters the way it functions. ‘That way an inflammatory environment is created and the development of the disease is encouraged,’ said Ainara Castellanos.
‘This study confirms the importance of the regions of the genome previously regarded as ‘junk’ in the development of common complaints such as coeliac disease and opens up the door to a new possibility for diagnosis. Right now, we are interested in finding out whether the low levels of this RNA are an early feature of coeliac disease (and of other immune diseases), which could be used as a diagnostic tool before its onset,’ explained the UPV/EHU’s lecturer in Genetics José Ramón Bilbao, another of the authors of the work. University of the Basque Country
Promising new blood test is first of its kind to detect liver scarring
, /in E-News /by 3wmediaNewcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver – even before someone may feel ill. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).
NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.
The Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.
Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: “This scientific breakthrough has great promise because the majority of patients show no symptoms.
“Routine blood tests can’t detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages – by examining a piece of the liver under the microscope.
“We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it’s important to be able to detect liver scarring at an early stage.”
In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of “cell-free” DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγthat controls scar formation are then used to stratify patients by fibrosis severity.
Senior author Dr Jelena Mann of Newcastle University’s Institute for Cellular Medicine added: “This is the first time that a DNA methylation ‘signature’ from the blood has been shown to match the severity of a liver disease.
“It opens up the possibility of an improved blood test for liver fibrosis in the future.” Newcastle University
Maternal obesity and diabetes in pregnancy result in early overgrowth of the baby in the womb
, /in E-News /by 3wmediaThe babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.
Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.
Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.
Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.
Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.
The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.
“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.
“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”
Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus. Cambridge University
Memory suppressor gene that could hold key to new Alzheimer’s Disease treatments
, /in E-News /by 3wmediaWhile research has identified hundreds of genes required for normal memory formation, genes that suppress memory are of special interest because they offer insights into how the brain prioritizes and manages all of the information, including memories, that it takes in every day. These genes also provide clues for how scientists might develop new treatments for cognitive disorders such as Alzheimer’s disease.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, a widely recognized substitute for human memory studies.
The study, which was led by Ron Davis, chair of TSRI’s Department of Neuroscience].
Davis and his colleagues screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts. One of these suppressor genes, in particular, caught their attention.
“When we knocked out this gene, the flies had a better memory—a nearly two-fold better memory,” said Davis. “The fact that this gene is active in the same pathway as several cognitive enhancers currently used for the treatment of Alzheimer’s disease suggests it could be a potential new therapeutic target.”
When the scientists disabled this gene, known as DmSLC22A, flies’ memory of smells (the most widely studied form of memory in this model) was enhanced—while overexpression of the gene inhibited that same memory function.
“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said Research Associate Ze Liu, co-first author of the study. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”
The gene in question belongs to a family of “plasma membrane transporters,” which produce proteins that move molecules, large and small, across cell walls. In the case of DmSLC22A, the new study indicates that the gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. When DmSLC22A functions normally, the protein removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When the protein is missing, more acetylcholine persists in the synapse, making the synaptic signal stronger and more persistent, leading to enhanced memory.
“DmSLC22A serves as a bottleneck in memory formation,” said Research Associate Yunchao Gai, the study’s other co-first author. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”
The next step, Davis added, is to develop a screen for inhibitors of this pathway that, independently or in concert with other treatments, may offer a more effective way to deal with the problems of memory loss due to Alzheimer’s and other neurodegenerative diseases. Scripps Florida
Genomic makeup of colorectal cancers predicts immune system ability to fight tumours
, /in E-News /by 3wmediaGenomic makeup of colorectal cancers predicts immune system ability to fight tumours
Colorectal cancers heavily bedecked with tumour-related proteins called neoantigens are likely to be permeated with disease-fighting white blood cells, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard report in a new study. Because such an influx of white blood cells often signifies an immune system attack on cancer, the discovery will sharpen research into therapies that make tumours more vulnerable to such an attack.
The discovery was made by combining several data sets from patients in two large health-tracking studies, the Nurses’ Health Study and the Health Professionals Follow-up Study. Researchers first performed whole-exome sequencing on colorectal tumour samples from 619. This information was merged with data from tests of the immune system’s response to the tumours and with patient clinical data, including length of survival.
“We were looking for genetic features that predict how extensively a tumour is infiltrated by lymphocytes [certain white blood cells] and which types of lymphocytes are present,” said study co-lead author, Marios Giannakis, MD, PhD, medical oncologist and clinical investigator at the Dana-Farber Gastrointestinal Cancer Treatment Center, and researcher at the Broad Institute of MIT and Harvard. “We found that tumours with a high ‘neoantigen load’ – which carry large quantities of neoantigens – tended to be infiltrated by a large number of lymphocytes, including memory T cells, which provide protection against previously encountered infections and diseases. Patients whose tumours had high numbers of neoantigens also survived longer than those with lower neoantigen loads.”
Neoantigens are deviant forms of protein antigens, which are found on normal cells. Genetic mutations often cause cancer cells to produce abnormal proteins, some of which get lifted to the cell surface, where they serve as a red flag to the immune system that something is amiss with the cell.
“There can be hundreds or thousands of neoantigens on tumour cells,” Giannakis explained. “Only a few of these may actually provoke T cells to infiltrate a tumour. But the more neoantigens on display, the greater the chance that some of them will spark an immune system response.”
Therapies known as immune checkpoint inhibitors work by removing some of the barriers to an immune system attack on cancer. Although these agents have produced astonishing results in some cases, they’re generally effective only in patients whose immune system has already launched an immune response to cancer. By showing that tumours with high antigen loads are apt to be laced with T cells – and therefore to have provoked an immune response – the study may help investigators identify which patients are most likely to benefit in new clinical trials of immune checkpoint inhibitors.
The study’s genomic analysis of colorectal tumour samples also found several often-mutated genes that had not previously been strongly associated with the disease, including BCL9L, RBM10, CTCF, and KLF5. The discovery of their prevalence in colorectal cancer suggests that they may be valuable targets for new therapies. Dana-Farber Cancer Institute
Panel reclassifies thyroid tumour to curb over-diagnosis of cancer
, /in E-News /by 3wmediaLed by researchers at the University of Pittsburgh School of Medicine, an international panel of pathologists and clinicians has reclassified a type of thyroid cancer to reflect that it is non-invasive and has a low risk of recurrence. The name change is expected to reduce the psychological and medical consequences of a cancer diagnosis, potentially affecting thousands of people worldwide.
The incidence of thyroid cancer has been rising partly due to early detection of tumours that are indolent or non-progressing, despite the presence of certain cellular abnormalities that are traditionally considered cancerous, explained senior investigator Yuri Nikiforov, M.D., Ph.D., professor of pathology and director of Pitt’s Division of Molecular and Genomic Pathology.
“This phenomenon is known as over-diagnosis,” Dr. Nikiforov said. “To my knowledge, this is the first time in the modern era a type of cancer is being reclassified as a non-cancer. I hope that it will set an example for other expert groups to address nomenclature of various cancer types that have indolent behaviour to prevent inappropriate and costly treatment.” University of Pittsburgh School of Medicine
Researcher help build a biomedical knowledgebase
, /in E-News /by 3wmediaImagine attempting to bake a cake—except you have to go to different stores for flour and milk, drive across town to get eggs and call a friend to borrow a cake pan.
This is the kind of disjointed scenario many scientists face when they attempt to gather data scattered across small databases and hard-to-search PDF files.
“It’s not that the data doesn’t exist,” said Andrew Su, associate professor at The Scripps Research Institute (TSRI). “The data just isn’t stored in a way that scientists can easily access.”
“Open data is vital for progress and research,” added TSRI Assistant Professor of Molecular and Experimental Medicine Ben Good. “We need to break down those barriers.”
To solve this problem, Su, Good and their colleagues at TSRI have integrated biomedical data into Wikidata, a public, editable database where researchers can easily link genes, proteins and more.
Technological breakthroughs in the last 10 years have led to rapid increases in the volume and rate of biomedical research, which in turn has led to a rapid growth in biomedical knowledge. However, this knowledge is currently fragmented across countless resources—from online databases to supplementary data files to individual facts in individual papers.
“As a research community, we spend a lot of time searching for good resources and trying to link them together,” said TSRI Research Associate Tim Putman, who was first author of one of the studies. “It’s cringeworthy.”
Even when databases are open to the public, current knowledge isn’t always organized in a uniform way, Putman explained.
Rather than leave each research group to tackle data integration individually, Wikidata offers a new model for organizing all this information. Built on the same principles as Wikipedia, Wikidata enables anyone to add new information to an open community database.
While other Wikidata editors have added information on millions of items as diverse as works of art to U.S. cities, the TSRI team has focused on adding information on biomedical concepts.
TSRI Research Associate Sebastian Burgstaller-Muehlbacher, first author on one study, added data on all human and mouse genes, all human diseases and all drugs approved by the U.S. Food and Drug Administration.
Putman then extended Wikidata with a focus on microbial genomes. With all this information collected in one system, researchers can more easily spot connections between diseases, pathogens and biological processes. As an example, Putman used the model to show that other microorganisms in the body can influence chlamydia infections.
As a proof of concept, Putman led the development of a genome browser based on Wikidata. Rather than having to develop one browser for every sequenced genome, this genome browser allows users to browse any genome that has been loaded into Wikidata.
“You can zoom in on a gene, click on it and the sequence will pop up,” said Good. The genome browser will then link back to the original Wikidata entry.
In the end, the researchers plan to have a comprehensive, uniform database that is easy to search and open to anyone who wants to add data and link related concepts.
“We think this data should all be open,” said Su. “This just makes intuitive sense.” The Scripps Research Institute
Genetic variation that predicted type and rate of physical decline in patients with Parkinson’s Disease
, /in E-News /by 3wmediaResearchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.
Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.
“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”
In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.
The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.
“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.” University of Pennsylvania Health System
Mobility assessment tool may help predict early postoperative outcomes for older adults
, /in E-News /by 3wmediaA quick, reliable and cost-effective mobility assessment tool may help to identify elderly patients at risk for adverse post-surgery outcomes, according to Wake Forest Baptist Medical Center researchers.
In their study of 197 men and woman over age 69 who underwent elective, non-cardiac, inpatient surgery at Wake Forest Baptist over a 20-month period, the researchers found that the participants’ preoperative scores on the Mobility Assessment Tool: Short Form (MAT-sf) were predictive of early postoperative complications, longer hospital stays and discharges to nursing homes.
“Preoperative assessment of patient characteristics that may lead to adverse postoperative outcomes is important to patients, their families and their surgeons, especially with older adults, in whom complications are more likely,” said Leanne Groban, M.D., professor of anaesthesiology at Wake Forest Baptist and lead author of the study.
“Mobility is a powerful indicator of overall health in the elderly, and our results indicate that self-reported mobility, as measured by the MAT-sf, can complement existing assessment tools in determining which patients are at risk of adverse postoperative outcomes.”
The MAT-sf features animated video clips of 10 common physical activities, each followed by questions about the participant’s ability to perform the particular task. In addition to the MAT-sf, participants in the study also underwent four other commonly employed preoperative risk assessments. After controlling for factors such as the participants’ age, sex and body mass index and their scores on the other tests, the researchers found that low (poor) scores on the MAT-sf were associated with short-term complications, later time to discharge and increased nursing home placement to a greater degree than any of the other indicators.
“The traditional risk assessments may be too comprehensive, too focused on single organ systems or too impractical to be effective in this setting,” Groban said.
The next steps, she said, are to validate these findings in a larger, multi-centre study and to test whether preoperative strength and balance training might limit undesirable postoperative outcomes in older adults with mobility limitations.
“Studies such as this will help determine future clinical pathways aimed at reducing adverse outcomes while improving patients’ functionality and speeding their return to independence,” Groban said.
Wake Forest University www.wakehealth.edu/News-Releases/2016/Mobility_Assessment_Tool_May_Help_Predict_Early_Postoperative_Outcomes_for_Older_Adults.htm