Investigators at The Feinstein Institute for Medical Research discovered dozens of new genetic variations associated with a person’s general cognitive ability. The findings have the potential to help researchers develop more targeted treatment for cognitive and memory disorders. “For the first time, we were able to use genetic information to point us towards specific drugs that might aid in cognitive disorders of the brain, including Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder,” said Todd Lencz, PhD, senior author of the study and professor at the Feinstein Institute and the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. In the largest peer-reviewed study of its kind, an international team of 65 scientists, led by Dr. Lencz, studied the genomes of more than 100,000 individuals who had their brain function measured by neuropsychological tests. These data were then combined with genomes from 300,000 people measured for the highest level of education achieved, which serves as an estimate for cognitive ability, or how the brain acquires knowledge. While profiling cognitive ability, researchers also discovered a genetic overlap with longevity. They found when examining an individual’s family that a genetic predisposition towards higher cognitive ability was associated with longer lifespan. A new genetic overlap between cognitive ability and risk for autoimmune disease was also identified. This study appears less than a year after Dr. Lencz and his colleagues published a similar, smaller study that was only able to identify a few key genes associated with cognitive ability. “The field of genomics is growing by leaps and bounds,” Dr. Lencz said. “Because the number of genes we can discover is a direct function of the sample size available, further research with additional samples is likely to provide even more insight into how our genes play a role in cognitive ability.”
Feinstein Institute – Northwell Healthhttps://tinyurl.com/y8649b9o
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:55Researchers identify new genes associated with cognitive ability
A simple blood test that detects tumour cells circulating in the blood shows promise as a new way to predict high or low risk of a breast cancer relapse. “Late recurrence five or more years after surgery accounts for at least one-half of recurrences of breast cancer, and there are no tests that identify who is at highest risk. We found that in women who were cancer-free five years after diagnosis, about 5 percent had a positive circulating tumour cells (CTC) test,” said lead researcher Joseph A. Sparano, MD, vice chair of the ECOG-ACRIN Cancer Research Group, Philadelphia, and associate director for clinical research at Montefiore Medical Center, Albert Einstein Cancer Center, New York. “More importantly …”, Dr. Sparano continued, “…we also found that a positive test was associated with a 35 percent recurrence risk after two years, compared with only 2 percent for those with a negative CTC test.” The concept is to explore the use of the CTC blood test in a new way. Currently, the test is FDA-approved for use by physicians to monitor response to treatment in patients with advanced breast, colon or prostate cancer, but not early stage cancer. A rise in the number of circulating tumour cells in the blood in patients with advanced disease may indicate trouble before it shows up on a scan. In this study, the research team evaluated this test in a different setting—individuals alive and cancer-free about five years after their diagnosis and potentially cured, but still at risk for having a recurrence of their disease. ”Our ultimate goal is to use blood tests like this to tailor treatment in a way that minimizes recurrence risk for those at high risk, and spare treatment for those at low risk who may be unlikely to benefit from it,” Dr. Sparano said. “The findings of this analysis provide strong evidence to further evaluate this new risk assessment approach using CTC and other blood-based tests in this setting”. The test was done on a single blood sample provided by 547 breast cancer patients who had been diagnosed more than five years prior and treated as part of a large ECOG-ACRIN breast cancer treatment trial, E5103. This group of patients had stage two or three breast cancer, and the cells in their tumours were HER2-negative. Many women in E5103 remain cancer free and are being followed for their breast cancer status as part of standard care. Dr. Sparano and colleagues set up a biobank and invited these patients to contribute additional specimens for future research into the reasons for late recurrence. The biobank was established by ECOG-ACRIN and the Coalition of Cancer Cooperative Groups with funding from the Breast Cancer Research Foundation, National Cancer Institute, and Susan G. Komen.
ECOG-ACRIN Cancer Research Grouphttps://tinyurl.com/ydgym4c3
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:55Simple blood test may predict recurrence of breast cancer
Clearbridge BioMedics and Leica Biosystems have today announced a partnership, co-marketing each other’s products to support circulating tumour cell (CTC) research. This is specifically for the Clearbridge BioMedics ClearCell® FX CTC enrichment system and the Leica Biosystems’ BOND RX staining platform. This new partnership provides an integrated and automated workflow for CTC enrichment and immunostaining, improving on major challenges in CTC liquid biopsy testing, such as handling and standardization. The ClearCell® FX System is an automated CTC enrichment system, powered by the patented CTChip® FR1 microfluidics biochip. Using a label-free approach, the ClearCell® FX System retrieves wholly-intact and viable CTCs from a standard blood draw. The gentle sorting principle retains high cell integrity and cell surface antigen expression. This coupled with single-step CTC retrieval, provides a seamless integration into pathology lab workflows. Automated CTC staining on a glass slide is then performed on Leica Biosystems’ BOND RX. The BOND RX platform is an open and flexible system that efficiently automates staining for immunofluorescence (IF), immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) assays. It provides a high-throughput workflow with exceptional consistency and minimal hands-on time. Linking these two advanced technologies will empower researchers and laboratories with an integrated solution for CTC enrichment and immunostaining, accelerating the development of clinical applications using CTCs. “The global liquid biopsy market has been growing significantly and will continue to grow, due to trends such as rising prevalence of cancer, preference for personalized medicine and the move towards non-invasive procedures. Today’s partnership announcement between Leica Biosystems and Clearbridge BioMedics provides clinical research laboratories with a seamless end-to-end enrichment and immunostaining solution for CTCs. This will support the development of new therapies and diagnostics for cancer patients,” said Dr Michael Paumen, CEO of Clearbridge BioMedics.
www.clearbridgebiomedics.comwww.leicabiosystems.com
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:54Clearbridge BioMedics and Leica Biosystems to co-market automated solutions for circulating tumour cell (CTC) analysis
Siemens Healthineers has now confirmed that it has completed the acquisition of Epocal Inc. from Abbott to complete its blood gas portfolio. The closing of the deal occurred October 31, 2017. Financial details of the transaction were not disclosed. In integrating Epocal Inc.’s offerings into its POC Ecosystem™ solution, Siemens Healthineers enables customized testing offerings based on individual facility needs – whether that is handheld testing, benchtop solutions or central lab applications – to help improve process efficiency. The epoc® product line will integrate seamlessly into the Siemens Healthineers POC Ecosystem solution for easy connection from many manufacturers’ point-of-care analysers to hospital information systems, providing a flexible, long-term solution. “Health networks have varying needs for blood gas testing across physicians’ offices, clinics, emergency departments, laboratories and even in ambulances. Having any one solution is limiting and may not meet all patient needs, which is why customized testing solutions are so important for improving patient care,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “With a complete offering for blood gas diagnostics, we can help healthcare providers and point-of-care coordinators improve their workflows by offering the right test in the right setting at the right time.”
www.siemens.com/epoc
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:54Siemens Healthineers announces closing of Epocal acquisition
EKF Diagnostics announces that its Stanbio Chemistry Procalcitonin (PCT) LiquiColor® assay has been FDA cleared and validated for use on Beckman AU 480, 680 and 5800 clinical chemistry analysers. EKF is pleased to confirm the immediate availability of a user-defined application (UDA) for running this 10-minute test for bacterial infection and sepsis on these Beckman AU analysers. PCT is a widely accepted marker for use in conjunction with other tests to quickly identify sepsis and monitor progression/severity over time. EKF’s PCT test is designed to be used on an open channel of most main brand clinical chemistry analysers, including Roche Cobas, Abbott Architect and Hitachi systems. Therefore, the availability of the user-defined application (UDA) on Beckman AU analysers further increases the breadth of application of the LiquiColor PCT assay. Trevor McCarthy, Sales Manager, EKF Central Laboratory Products, EMEA/APAC said, “The news regarding the FDA clearance and Beckman AU analyser validated application for the PCT LiquiColor assay will bolster trust in the quality and reliability of our product. Having EKF’s PCT assay validated on Beckman AU chemistry analysers allows us to provide a competitive alternative product for hospital labs and should open up new markets and opportunities for us to support improved and early detection of sepsis.” The cost-effective, immunoturbidimetric assay, which features the use of monoclonal antibodies coated to latex particles, can determine PCT from just 20µL of serum and plasma specimens. Conveniently, the reagent set requires no reagent preparation and is designed to be used on open chemistry systems. It is available in a liquid-stable format, meaning that it can remain on-board a clinical chemistry analyser for up to four weeks. PCT is a quick and effective adjunct marker in sepsis diagnosis which helps to differentiate between viral and bacterial infections, so enabling early administration of antimicrobial therapy. It is an important test, as the Surviving Sepsis Campaign (SSC) estimates that the incidence of sepsis is 3 per 1,000 worldwide. There has been a steady rise in the number of patients with sepsis; globally there are now over 18 million cases per year. Due to its high mortality, sepsis is a primary cause of death, accounting for over 60% of deaths per year in the developing world. It kills over 6 million new-borns and children each year and there are over 100,000 cases of maternal sepsis. In addition to improving sepsis survival rates and improving antibiotic stewardship, studies have also shown that PCT testing reduces hospital costs and length of stay. For example, a recent large cohort study examined whether PCT testing helps to more effectively manage sepsis care. The study found that use of PCT testing on day one of admission into the ICU lead to an average of 1.2 fewer hospital days than patients who were not screened and saved an average of $2,759 (€2,337) on their total hospital costs.
www.ekfdiagnostics.com
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:54EKF procalcitonin assay validated for Beckman AU chemistry analysers
A research team led by National University Health System (NUHS) and Duke-NUS Medical School has used genomic technologies to better understand intestinal metaplasia (IM), a known risk factor for gastric (stomach) cancer. Patients with IM are six times more likely to develop stomach cancer than those without. This study is an important part of an ambitious investigation to understand why some people develop stomach cancer, while others do not. The research could also help detect patients who are infected with the Helicobacter pylori bacteria, which is also linked to the disease. Stomach cancer is the third deadliest cancer in the world according to World Health Organization (WHO) statistics, and claims more than 300 lives yearly in Singapore. The disease is believed to be caused by infection with Helicobacter pylori but is potentially treatable if detected early. Unfortunately, more than two-thirds of stomach cancer patients are only diagnosed at an advanced stage. "Previous genetic studies on IM have mainly focused on patients who were already diagnosed with stomach cancer but these are limited in their ability to predict who are likely to develop the disease and how the disease will progress," said Professor Patrick Tan, co-lead investigator and Professor, Duke-NUS Medical School. Professor Tan is also Deputy Executive Director, Biomedical Research Council, Agency for Science, Technology, and Research, and a Senior Principal Investigator at the Cancer Science Institute of Singapore. "This new study is the first to comprehensively map out the genetic changes in IM in a cohort of stomach cancer-free subjects, which helps us better predict the possible occurrence and progression of the disease." Dr Yeoh Khay Guan, co-lead investigator and Deputy Chief Executive, NUHS as well as Dean, NUS Yong Loo Lin School of Medicine added, "Our study is the largest series of IM to be studied in detail by genetic analysis. These new findings help us understand why some people have a higher risk of progression to stomach cancer, and identify those who may benefit from closer follow-up to prevent cancer or to detect it early so that it can be cured." The researchers leveraged the near 3,000 participants-strong Gastric Cancer Epidemiology Programme (GCEP) cohort, recruited with the support of patients and doctors from four local public hospitals (National University Hospital, Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital), to show that a comprehensive analysis of the genetic patterns of IM can predict its subsequent progression towards stomach cancer. The genetic analysis of IM helps to identify those with a higher risk of progression to stomach cancer, adding further information to what is available by microscopic examination alone. The research team is using this new information to identify biomarkers that can be applied in future in the clinic to identify people who have a high risk of progression to stomach cancer. EurekAlertwww.eurekalert.org/pub_releases/2018-01/nuos-lgs010518.php
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:54Landmark genetic study better predicts stomach cancer
A pioneering study has found that patients with Parkinson’s disease have more errors in the mitochondrial DNA within the brainstem, leading to increased cell death in that area. Experts at Newcastle and Sussex universities also revealed that surviving brain cells in the brainstem have more copies of mitochondrial DNA and this has not been identified before. The study’s deeper understanding into Parkinson’s disease suggests a new target for therapies for patients with the debilitating condition. Researchers say their findings are “surprising” as the results differ from what has been seen in studies of brain regions that harbour other brain cell-types. Dr Joanna Elson, a mitochondrial geneticist at Newcastle University, said: “Our study is a major step forwards in gaining an enhanced insight into the serious condition. Research shows that in Parkinson’s disease a brainstem region called the pedunculopontine nucleus (PPN) develops changes in DNA found in mitochondria – the batteries of the cell – as they produce and store energy that cells can use. This study looked at cholinergic neurons that are responsible for producing the brain chemical acetylcholine, which is released by cholinergic nerve cells to send signals from one neuron to another. Death of these cells in the PPN is believed to be the cause of some of the symptoms of Parkinson’s disease, such as problems with attention, walking and posture. Identifying changes in the mitochondrial DNA in PPN cholinergic neurons has the potential to allow the development of more effective treatments targeted to specific cell-types. The PPN is an understudied part of the brain and researchers used post-mortem tissue from the Newcastle Brain Tissue Resource, based at Newcastle University, to isolate single neurons for in-depth analysis. Dr Ilse Pienaar, a neuroscientist at Sussex University, said: “At present, treatments are aimed at the whole brain of patient’s with Parkinson’s disease. “Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments be produced. “We believe that not only would cell-specific targeted treatments be more effective, but they would also be associated with fewer side-effects.” The PPN was of interest because, in previous studies, patients with Parkinson’s disease displayed lower levels of mitochondrial DNA (mtDNA) in remaining dopaminergic neurons. This study showed that mtDNA levels are higher in the surviving cholinergic neurons of the brainstem, but with both cell-types that undergo profound degeneration during Parkinson’s disease. The finding identifies how vulnerable cell groups react and respond differently to the accumulation of mitochondrial DNA damage seen in the disease, highlighting the need for cell-specific treatments. Newcastle Universitywww.ncl.ac.uk/press/articles/latest/2018/01/parkinsonsdiseaseresearch/
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:53New brainstem changes identified in Parkinson’s disease
Hong Kong Baptist University (HKBU) Chemistry scholars have invented a new class of multifunctional cyanine compounds that can be used for detection, imaging and thus treatment of Alzheimer’s disease. The discovery has been granted four US patents and a patent by the Chinese government. The research team was jointly led by Professor Ricky Wong Man-shing and Associate Professor Dr Li Hung-wing with members from the Department of Chemistry of HKBU. By making use of the proprietary compounds, the HKBU team, on one hand, has proved that the cyanine compounds applied onto a “nano”-detection platform can quantify trace amounts of Alzheimer’s disease related protein biomarkers present in human fluids such as cerebrospinal fluid, serum, saliva, and urine. It is a rapid, low-cost and ultrasensitive detection assay. On the other hand, the compounds also serve as an imaging agent for in vivo detection and monitoring of disease progression and understanding the disease pathogenesis as well as a drug candidate for treatment of the disease. Alzheimer’s disease is the most common neurodegenerative disorder, it is incurable and the underlying cause is still not well understood. Alzheimer’s disease is characterized by the formation of amyloid plaque in human brains. Clinical evaluation, cognitive tests and neuroimaging (monitoring the brain’s structural changes) are commonly used to diagnose Alzheimer’s disease, but are only effective after symptoms appear. Moreover, neuroimaging, such as magnetic resonance imaging (MRI), requires injecting contrast agents into a person that may bring health risks. The proteins of interest, namely beta amyloid peptide, tau, and p-tau, in human’s cerebrospinal fluid are linked to Alzheimer’s disease. The versatile detection assay using the compounds developed by the team requires only a minute amount of the sample fluids (a few microliters) to reliably quantify the target proteins. The detection assay developed by the team is fast, cheaper and more sensitive than traditional commercially available biological methods. Detection is based on the specific immuno-interactions between the target antigen and detection antibody that is immobilised on the surface of magnetic nanoparticles. The sandwiched immuno-assembly is then labelled with a newly developed turn-on cyanine compound that enhances the fluorescence signal, which is quantified by an imaging system. Dr Li said, “This newly developed assay will be particularly useful as a low-cost yet accurate diagnostic and prognostic tool for Alzheimer’s disease. It can also serve as a novel alternative non-invasive tool for population-wide screening for the disease. This scientific detection assay has a high potential to serve as a practical diagnosis tool.” Dr Li said that the new approach is universal and general enough to be readily modified and elaborated further, such as replacing the antibodies with other disease-associated antibodies, nucleic acids, for a broad range of biomedical research and disease diagnostics. Hong Kong Baptist Universityhkbuenews.hkbu.edu.hk/?t=press_release_details/2196
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:53World-first array of multifunctional compounds for detection, imaging and treatment of Alzheimer’s Disease
Visualizing cellular components and processes at the molecular level is important for understanding the basis of any biological activity. Fluorescent proteins (FPs) are one of the most useful tools for investigating intracellular molecular dynamics. However, FPs have usage limitations for imaging in low pH environments, such as in acidic organelles, including endosomes, lysosomes, and plant vacuoles. In environments of pH less than 6, most FPs lose their brightness and stability due to their neutral pKa. pKa is the measure of acid strength; the smaller the pKa is, the more acidic the substance is. “Although there are reports of several acid-tolerant green FPs (GFPs), most have serious drawbacks. Furthermore, there is a lack of acid-tolerant GFPs that are practically applicable to bioimaging,” says Hajime Shinoda, lead author of an Osaka University study that aimed to design acid-tolerant monomeric GFP that is practically applicable to live-cell imaging in acidic organelles. “In the current study, we developed an acid-tolerant GFP. We called it Gamillus.” Gamillus is a GFP cloned from Olindias formosa (flower hat jellyfish) and exhibits superior acid tolerance (pKa=3.4) and nearly twice as much brightness compared with the reported GFPs. The fluorescence spectrum is constant between pH4.5 and 9.0, which falls between the intracellular range in most cell types. X-ray crystallography (a technique used for determining the atomic and molecular structure of a crystal, in this case, a Gamillus crystal) and point mutagenesis suggest the acid tolerance of Gamillus is attributed to stabilization of deprotonation in its chemical structure. “The applicability of Gamillus as a molecular tag was shown by the correct localization pattern of Gamillus fusions in a variety of cellular structures, including ones that are difficult to target,” corresponding author Takeharu Nagai says. “We believe Gamillus can be a powerful molecular tool for investigating unknown biological phenomena involving acidic organelles, such as autophagy.” Osaka Universityresou.osaka-u.ac.jp/en/research/2017/20171229_1
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:53New acid-tolerant green fluorescent protein for bioimaging
An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors. The scientists say the findings reveal potential new drug targets and might aid efforts to extend the benefits of immunotherapy treatment to more patients and additional types of cancer. One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, led by Eliezer Van Allen, MD, of Dana-Farber and the Broad, and Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber. The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, MD, PhD, director of Dana-Farber’s Center for Cancer Immunotherapy Research, and Shirley Liu, PhD, of Dana-Farber. The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodelling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins. Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit — sometimes durable — from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t. The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive "neoantigens" that help the patient’s immune system recognize and attack tumours, and make the cancer cells’ “microenvironment” hospitable to tumour-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy. To search for other characteristics of ccRCC tumours that influence immunotherapy response or resistance, the researchers used whole-exome DNA sequencing to analyse tumour samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analysed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs. When the data was sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumours lacked a functioning PRBM1 gene. (About 41 percent of patients with ccRCC kidney cancer have a non-functioning PRBM1 gene.) That gene encodes a protein called BAF 180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodelling complex. Loss of the PRBM1 gene function caused the cancer cells to have increased expression of other genes, including a gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation. While the finding does not directly lead to a test for immunotherapy response yet, Choueiri said, "We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations." In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 technique to sift the genomes of melanoma cells for changes that made tumours resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells. The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodelling complex — the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells — as being involved in resistance to immune T cells. When the PRBM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex — ARID2 and BRD7 — are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors note, "represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack." Finding ways to alter those target molecules, they add, "will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy." Dana-Farber Cancer Institutewww.dana-farber.org/newsroom/news-releases/2018/mechanism-for-resistance-to-immunotherapy-treatment-discovered/
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:53Mechanism for resistance to immunotherapy treatment discovered
We may ask you to place cookies on your device. We use cookies to let us know when you visit our websites, how you interact with us, to enrich your user experience and to customise your relationship with our website.
Click on the different sections for more information. You can also change some of your preferences. Please note that blocking some types of cookies may affect your experience on our websites and the services we can provide.
Essential Website Cookies
These cookies are strictly necessary to provide you with services available through our website and to use some of its features.
Because these cookies are strictly necessary to provide the website, refusing them will affect the functioning of our site. You can always block or delete cookies by changing your browser settings and block all cookies on this website forcibly. But this will always ask you to accept/refuse cookies when you visit our site again.
We fully respect if you want to refuse cookies, but to avoid asking you each time again to kindly allow us to store a cookie for that purpose. You are always free to unsubscribe or other cookies to get a better experience. If you refuse cookies, we will delete all cookies set in our domain.
We provide you with a list of cookies stored on your computer in our domain, so that you can check what we have stored. For security reasons, we cannot display or modify cookies from other domains. You can check these in your browser's security settings.
.
Google Analytics Cookies
These cookies collect information that is used in aggregate form to help us understand how our website is used or how effective our marketing campaigns are, or to help us customise our website and application for you to improve your experience.
If you do not want us to track your visit to our site, you can disable this in your browser here:
.
Other external services
We also use various external services such as Google Webfonts, Google Maps and external video providers. Since these providers may collect personal data such as your IP address, you can block them here. Please note that this may significantly reduce the functionality and appearance of our site. Changes will only be effective once you reload the page
Google Webfont Settings:
Google Maps Settings:
Google reCaptcha settings:
Vimeo and Youtube videos embedding:
.
Privacy Beleid
U kunt meer lezen over onze cookies en privacy-instellingen op onze Privacybeleid-pagina.
Researchers identify new genes associated with cognitive ability
, /in E-News /by 3wmediaInvestigators at The Feinstein Institute for Medical Research discovered dozens of new genetic variations associated with a person’s general cognitive ability. The findings have the potential to help researchers develop more targeted treatment for cognitive and memory disorders.
“For the first time, we were able to use genetic information to point us towards specific drugs that might aid in cognitive disorders of the brain, including Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder,” said Todd Lencz, PhD, senior author of the study and professor at the Feinstein Institute and the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
In the largest peer-reviewed study of its kind, an international team of 65 scientists, led by Dr. Lencz, studied the genomes of more than 100,000 individuals who had their brain function measured by neuropsychological tests. These data were then combined with genomes from 300,000 people measured for the highest level of education achieved, which serves as an estimate for cognitive ability, or how the brain acquires knowledge.
While profiling cognitive ability, researchers also discovered a genetic overlap with longevity. They found when examining an individual’s family that a genetic predisposition towards higher cognitive ability was associated with longer lifespan. A new genetic overlap between cognitive ability and risk for autoimmune disease was also identified.
This study appears less than a year after Dr. Lencz and his colleagues published a similar, smaller study that was only able to identify a few key genes associated with cognitive ability.
“The field of genomics is growing by leaps and bounds,” Dr. Lencz said. “Because the number of genes we can discover is a direct function of the sample size available, further research with additional samples is likely to provide even more insight into how our genes play a role in cognitive ability.”
Feinstein Institute – Northwell Healthhttps://tinyurl.com/y8649b9o
Simple blood test may predict recurrence of breast cancer
, /in E-News /by 3wmediaA simple blood test that detects tumour cells circulating in the blood shows promise as a new way to predict high or low risk of a breast cancer relapse.
“Late recurrence five or more years after surgery accounts for at least one-half of recurrences of breast cancer, and there are no tests that identify who is at highest risk. We found that in women who were cancer-free five years after diagnosis, about 5 percent had a positive circulating tumour cells (CTC) test,” said lead researcher Joseph A. Sparano, MD, vice chair of the ECOG-ACRIN Cancer Research Group, Philadelphia, and associate director for clinical research at Montefiore Medical Center, Albert Einstein Cancer Center, New York.
“More importantly …”, Dr. Sparano continued, “…we also found that a positive test was associated with a 35 percent recurrence risk after two years, compared with only 2 percent for those with a negative CTC test.”
The concept is to explore the use of the CTC blood test in a new way. Currently, the test is FDA-approved for use by physicians to monitor response to treatment in patients with advanced breast, colon or prostate cancer, but not early stage cancer. A rise in the number of circulating tumour cells in the blood in patients with advanced disease may indicate trouble before it shows up on a scan. In this study, the research team evaluated this test in a different setting—individuals alive and cancer-free about five years after their diagnosis and potentially cured, but still at risk for having a recurrence of their disease.
”Our ultimate goal is to use blood tests like this to tailor treatment in a way that minimizes recurrence risk for those at high risk, and spare treatment for those at low risk who may be unlikely to benefit from it,” Dr. Sparano said. “The findings of this analysis provide strong evidence to further evaluate this new risk assessment approach using CTC and other blood-based tests in this setting”.
The test was done on a single blood sample provided by 547 breast cancer patients who had been diagnosed more than five years prior and treated as part of a large ECOG-ACRIN breast cancer treatment trial, E5103. This group of patients had stage two or three breast cancer, and the cells in their tumours were HER2-negative.
Many women in E5103 remain cancer free and are being followed for their breast cancer status as part of standard care. Dr. Sparano and colleagues set up a biobank and invited these patients to contribute additional specimens for future research into the reasons for late recurrence. The biobank was established by ECOG-ACRIN and the Coalition of Cancer Cooperative Groups with funding from the Breast Cancer Research Foundation, National Cancer Institute, and Susan G. Komen.
ECOG-ACRIN Cancer Research Grouphttps://tinyurl.com/ydgym4c3
Clearbridge BioMedics and Leica Biosystems to co-market automated solutions for circulating tumour cell (CTC) analysis
, /in E-News /by 3wmediaClearbridge BioMedics and Leica Biosystems have today announced a partnership, co-marketing each other’s products to support circulating tumour cell (CTC) research. This is specifically for the Clearbridge BioMedics ClearCell® FX CTC enrichment system and the Leica Biosystems’ BOND RX staining platform. This new partnership provides an integrated and automated workflow for CTC enrichment and immunostaining, improving on major challenges in CTC liquid biopsy testing, such as handling and standardization.
The ClearCell® FX System is an automated CTC enrichment system, powered by the patented CTChip® FR1 microfluidics biochip. Using a label-free approach, the ClearCell® FX System retrieves wholly-intact and viable CTCs from a standard blood draw. The gentle sorting principle retains high cell integrity and cell surface antigen expression. This coupled with single-step CTC retrieval, provides a seamless integration into pathology lab workflows.
Automated CTC staining on a glass slide is then performed on Leica Biosystems’ BOND RX. The BOND RX platform is an open and flexible system that efficiently automates staining for immunofluorescence (IF), immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) assays. It provides a high-throughput workflow with exceptional consistency and minimal hands-on time.
Linking these two advanced technologies will empower researchers and laboratories with an integrated solution for CTC enrichment and immunostaining, accelerating the development of clinical applications using CTCs.
“The global liquid biopsy market has been growing significantly and will continue to grow, due to trends such as rising prevalence of cancer, preference for personalized medicine and the move towards non-invasive procedures. Today’s partnership announcement between Leica Biosystems and Clearbridge BioMedics provides clinical research laboratories with a seamless end-to-end enrichment and immunostaining solution for CTCs. This will support the development of new therapies and diagnostics for cancer patients,” said Dr Michael Paumen, CEO of Clearbridge BioMedics. www.clearbridgebiomedics.comwww.leicabiosystems.com
Siemens Healthineers announces closing of Epocal acquisition
, /in E-News /by 3wmediaSiemens Healthineers has now confirmed that it has completed the acquisition of Epocal Inc. from Abbott to complete its blood gas portfolio. The closing of the deal occurred October 31, 2017. Financial details of the transaction were not disclosed.
In integrating Epocal Inc.’s offerings into its POC Ecosystem™ solution, Siemens Healthineers enables customized testing offerings based on individual facility needs – whether that is handheld testing, benchtop solutions or central lab applications – to help improve process efficiency. The epoc® product line will integrate seamlessly into the Siemens Healthineers POC Ecosystem solution for easy connection from many manufacturers’ point-of-care analysers to hospital information systems, providing a flexible, long-term solution.
“Health networks have varying needs for blood gas testing across physicians’ offices, clinics, emergency departments, laboratories and even in ambulances. Having any one solution is limiting and may not meet all patient needs, which is why customized testing solutions are so important for improving patient care,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “With a complete offering for blood gas diagnostics, we can help healthcare providers and point-of-care coordinators improve their workflows by offering the right test in the right setting at the right time.” www.siemens.com/epoc
EKF procalcitonin assay validated for Beckman AU chemistry analysers
, /in E-News /by 3wmediaEKF Diagnostics announces that its Stanbio Chemistry Procalcitonin (PCT) LiquiColor® assay has been FDA cleared and validated for use on Beckman AU 480, 680 and 5800 clinical chemistry analysers. EKF is pleased to confirm the immediate availability of a user-defined application (UDA) for running this 10-minute test for bacterial infection and sepsis on these Beckman AU analysers.
PCT is a widely accepted marker for use in conjunction with other tests to quickly identify sepsis and monitor progression/severity over time. EKF’s PCT test is designed to be used on an open channel of most main brand clinical chemistry analysers, including Roche Cobas, Abbott Architect and Hitachi systems. Therefore, the availability of the user-defined application (UDA) on Beckman AU analysers further increases the breadth of application of the LiquiColor PCT assay.
Trevor McCarthy, Sales Manager, EKF Central Laboratory Products, EMEA/APAC said, “The news regarding the FDA clearance and Beckman AU analyser validated application for the PCT LiquiColor assay will bolster trust in the quality and reliability of our product. Having EKF’s PCT assay validated on Beckman AU chemistry analysers allows us to provide a competitive alternative product for hospital labs and should open up new markets and opportunities for us to support improved and early detection of sepsis.”
The cost-effective, immunoturbidimetric assay, which features the use of monoclonal antibodies coated to latex particles, can determine PCT from just 20µL of serum and plasma specimens. Conveniently, the reagent set requires no reagent preparation and is designed to be used on open chemistry systems. It is available in a liquid-stable format, meaning that it can remain on-board a clinical chemistry analyser for up to four weeks.
PCT is a quick and effective adjunct marker in sepsis diagnosis which helps to differentiate between viral and bacterial infections, so enabling early administration of antimicrobial therapy. It is an important test, as the Surviving Sepsis Campaign (SSC) estimates that the incidence of sepsis is 3 per 1,000 worldwide. There has been a steady rise in the number of patients with sepsis; globally there are now over 18 million cases per year. Due to its high mortality, sepsis is a primary cause of death, accounting for over 60% of deaths per year in the developing world. It kills over 6 million new-borns and children each year and there are over 100,000 cases of maternal sepsis.
In addition to improving sepsis survival rates and improving antibiotic stewardship, studies have also shown that PCT testing reduces hospital costs and length of stay. For example, a recent large cohort study examined whether PCT testing helps to more effectively manage sepsis care. The study found that use of PCT testing on day one of admission into the ICU lead to an average of 1.2 fewer hospital days than patients who were not screened and saved an average of $2,759 (€2,337) on their total hospital costs. www.ekfdiagnostics.com
Landmark genetic study better predicts stomach cancer
, /in E-News /by 3wmediaA research team led by National University Health System (NUHS) and Duke-NUS Medical School has used genomic technologies to better understand intestinal metaplasia (IM), a known risk factor for gastric (stomach) cancer. Patients with IM are six times more likely to develop stomach cancer than those without. This study is an important part of an ambitious investigation to understand why some people develop stomach cancer, while others do not. The research could also help detect patients who are infected with the Helicobacter pylori bacteria, which is also linked to the disease.
Stomach cancer is the third deadliest cancer in the world according to World Health Organization (WHO) statistics, and claims more than 300 lives yearly in Singapore. The disease is believed to be caused by infection with Helicobacter pylori but is potentially treatable if detected early. Unfortunately, more than two-thirds of stomach cancer patients are only diagnosed at an advanced stage.
"Previous genetic studies on IM have mainly focused on patients who were already diagnosed with stomach cancer but these are limited in their ability to predict who are likely to develop the disease and how the disease will progress," said Professor Patrick Tan, co-lead investigator and Professor, Duke-NUS Medical School. Professor Tan is also Deputy Executive Director, Biomedical Research Council, Agency for Science, Technology, and Research, and a Senior Principal Investigator at the Cancer Science Institute of Singapore. "This new study is the first to comprehensively map out the genetic changes in IM in a cohort of stomach cancer-free subjects, which helps us better predict the possible occurrence and progression of the disease."
Dr Yeoh Khay Guan, co-lead investigator and Deputy Chief Executive, NUHS as well as Dean, NUS Yong Loo Lin School of Medicine added, "Our study is the largest series of IM to be studied in detail by genetic analysis. These new findings help us understand why some people have a higher risk of progression to stomach cancer, and identify those who may benefit from closer follow-up to prevent cancer or to detect it early so that it can be cured."
The researchers leveraged the near 3,000 participants-strong Gastric Cancer Epidemiology Programme (GCEP) cohort, recruited with the support of patients and doctors from four local public hospitals (National University Hospital, Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital), to show that a comprehensive analysis of the genetic patterns of IM can predict its subsequent progression towards stomach cancer. The genetic analysis of IM helps to identify those with a higher risk of progression to stomach cancer, adding further information to what is available by microscopic examination alone.
The research team is using this new information to identify biomarkers that can be applied in future in the clinic to identify people who have a high risk of progression to stomach cancer.
EurekAlertwww.eurekalert.org/pub_releases/2018-01/nuos-lgs010518.php
New brainstem changes identified in Parkinson’s disease
, /in E-News /by 3wmediaA pioneering study has found that patients with Parkinson’s disease have more errors in the mitochondrial DNA within the brainstem, leading to increased cell death in that area.
Experts at Newcastle and Sussex universities also revealed that surviving brain cells in the brainstem have more copies of mitochondrial DNA and this has not been identified before.
The study’s deeper understanding into Parkinson’s disease suggests a new target for therapies for patients with the debilitating condition.
Researchers say their findings are “surprising” as the results differ from what has been seen in studies of brain regions that harbour other brain cell-types.
Dr Joanna Elson, a mitochondrial geneticist at Newcastle University, said: “Our study is a major step forwards in gaining an enhanced insight into the serious condition.
Research shows that in Parkinson’s disease a brainstem region called the pedunculopontine nucleus (PPN) develops changes in DNA found in mitochondria – the batteries of the cell – as they produce and store energy that cells can use.
This study looked at cholinergic neurons that are responsible for producing the brain chemical acetylcholine, which is released by cholinergic nerve cells to send signals from one neuron to another.
Death of these cells in the PPN is believed to be the cause of some of the symptoms of Parkinson’s disease, such as problems with attention, walking and posture.
Identifying changes in the mitochondrial DNA in PPN cholinergic neurons has the potential to allow the development of more effective treatments targeted to specific cell-types.
The PPN is an understudied part of the brain and researchers used post-mortem tissue from the Newcastle Brain Tissue Resource, based at Newcastle University, to isolate single neurons for in-depth analysis.
Dr Ilse Pienaar, a neuroscientist at Sussex University, said: “At present, treatments are aimed at the whole brain of patient’s with Parkinson’s disease.
“Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments be produced.
“We believe that not only would cell-specific targeted treatments be more effective, but they would also be associated with fewer side-effects.”
The PPN was of interest because, in previous studies, patients with Parkinson’s disease displayed lower levels of mitochondrial DNA (mtDNA) in remaining dopaminergic neurons.
This study showed that mtDNA levels are higher in the surviving cholinergic neurons of the brainstem, but with both cell-types that undergo profound degeneration during Parkinson’s disease.
The finding identifies how vulnerable cell groups react and respond differently to the accumulation of mitochondrial DNA damage seen in the disease, highlighting the need for cell-specific treatments.
Newcastle Universitywww.ncl.ac.uk/press/articles/latest/2018/01/parkinsonsdiseaseresearch/
World-first array of multifunctional compounds for detection, imaging and treatment of Alzheimer’s Disease
, /in E-News /by 3wmediaHong Kong Baptist University (HKBU) Chemistry scholars have invented a new class of multifunctional cyanine compounds that can be used for detection, imaging and thus treatment of Alzheimer’s disease. The discovery has been granted four US patents and a patent by the Chinese government.
The research team was jointly led by Professor Ricky Wong Man-shing and Associate Professor Dr Li Hung-wing with members from the Department of Chemistry of HKBU. By making use of the proprietary compounds, the HKBU team, on one hand, has proved that the cyanine compounds applied onto a “nano”-detection platform can quantify trace amounts of Alzheimer’s disease related protein biomarkers present in human fluids such as cerebrospinal fluid, serum, saliva, and urine. It is a rapid, low-cost and ultrasensitive detection assay. On the other hand, the compounds also serve as an imaging agent for in vivo detection and monitoring of disease progression and understanding the disease pathogenesis as well as a drug candidate for treatment of the disease.
Alzheimer’s disease is the most common neurodegenerative disorder, it is incurable and the underlying cause is still not well understood. Alzheimer’s disease is characterized by the formation of amyloid plaque in human brains. Clinical evaluation, cognitive tests and neuroimaging (monitoring the brain’s structural changes) are commonly used to diagnose Alzheimer’s disease, but are only effective after symptoms appear. Moreover, neuroimaging, such as magnetic resonance imaging (MRI), requires injecting contrast agents into a person that may bring health risks.
The proteins of interest, namely beta amyloid peptide, tau, and p-tau, in human’s cerebrospinal fluid are linked to Alzheimer’s disease. The versatile detection assay using the compounds developed by the team requires only a minute amount of the sample fluids (a few microliters) to reliably quantify the target proteins. The detection assay developed by the team is fast, cheaper and more sensitive than traditional commercially available biological methods.
Detection is based on the specific immuno-interactions between the target antigen and detection antibody that is immobilised on the surface of magnetic nanoparticles. The sandwiched immuno-assembly is then labelled with a newly developed turn-on cyanine compound that enhances the fluorescence signal, which is quantified by an imaging system.
Dr Li said, “This newly developed assay will be particularly useful as a low-cost yet accurate diagnostic and prognostic tool for Alzheimer’s disease. It can also serve as a novel alternative non-invasive tool for population-wide screening for the disease. This scientific detection assay has a high potential to serve as a practical diagnosis tool.”
Dr Li said that the new approach is universal and general enough to be readily modified and elaborated further, such as replacing the antibodies with other disease-associated antibodies, nucleic acids, for a broad range of biomedical research and disease diagnostics.
Hong Kong Baptist Universityhkbuenews.hkbu.edu.hk/?t=press_release_details/2196
New acid-tolerant green fluorescent protein for bioimaging
, /in E-News /by 3wmediaVisualizing cellular components and processes at the molecular level is important for understanding the basis of any biological activity. Fluorescent proteins (FPs) are one of the most useful tools for investigating intracellular molecular dynamics.
However, FPs have usage limitations for imaging in low pH environments, such as in acidic organelles, including endosomes, lysosomes, and plant vacuoles. In environments of pH less than 6, most FPs lose their brightness and stability due to their neutral pKa. pKa is the measure of acid strength; the smaller the pKa is, the more acidic the substance is.
“Although there are reports of several acid-tolerant green FPs (GFPs), most have serious drawbacks. Furthermore, there is a lack of acid-tolerant GFPs that are practically applicable to bioimaging,” says Hajime Shinoda, lead author of an Osaka University study that aimed to design acid-tolerant monomeric GFP that is practically applicable to live-cell imaging in acidic organelles. “In the current study, we developed an acid-tolerant GFP. We called it Gamillus.”
Gamillus is a GFP cloned from Olindias formosa (flower hat jellyfish) and exhibits superior acid tolerance (pKa=3.4) and nearly twice as much brightness compared with the reported GFPs. The fluorescence spectrum is constant between pH4.5 and 9.0, which falls between the intracellular range in most cell types. X-ray crystallography (a technique used for determining the atomic and molecular structure of a crystal, in this case, a Gamillus crystal) and point mutagenesis suggest the acid tolerance of Gamillus is attributed to stabilization of deprotonation in its chemical structure.
“The applicability of Gamillus as a molecular tag was shown by the correct localization pattern of Gamillus fusions in a variety of cellular structures, including ones that are difficult to target,” corresponding author Takeharu Nagai says. “We believe Gamillus can be a powerful molecular tool for investigating unknown biological phenomena involving acidic organelles, such as autophagy.”
Osaka Universityresou.osaka-u.ac.jp/en/research/2017/20171229_1
Mechanism for resistance to immunotherapy treatment discovered
, /in E-News /by 3wmediaAn urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.
The scientists say the findings reveal potential new drug targets and might aid efforts to extend the benefits of immunotherapy treatment to more patients and additional types of cancer.
One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, led by Eliezer Van Allen, MD, of Dana-Farber and the Broad, and Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.
The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, MD, PhD, director of Dana-Farber’s Center for Cancer Immunotherapy Research, and Shirley Liu, PhD, of Dana-Farber.
The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodelling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit — sometimes durable — from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.
The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive "neoantigens" that help the patient’s immune system recognize and attack tumours, and make the cancer cells’ “microenvironment” hospitable to tumour-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.
To search for other characteristics of ccRCC tumours that influence immunotherapy response or resistance, the researchers used whole-exome DNA sequencing to analyse tumour samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analysed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.
When the data was sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumours lacked a functioning PRBM1 gene. (About 41 percent of patients with ccRCC kidney cancer have a non-functioning PRBM1 gene.) That gene encodes a protein called BAF 180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodelling complex.
Loss of the PRBM1 gene function caused the cancer cells to have increased expression of other genes, including a gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.
While the finding does not directly lead to a test for immunotherapy response yet, Choueiri said, "We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations."
In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 technique to sift the genomes of melanoma cells for changes that made tumours resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.
The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodelling complex — the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells — as being involved in resistance to immune T cells.
When the PRBM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex — ARID2 and BRD7 — are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors note, "represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack." Finding ways to alter those target molecules, they add, "will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy."
Dana-Farber Cancer Institutewww.dana-farber.org/newsroom/news-releases/2018/mechanism-for-resistance-to-immunotherapy-treatment-discovered/