On 14th November 2019 a “continuing medical education course” is organized at the Leiden University Medical Center (LUMC) entitled “Prime time for precision diagnostics driven by unmet clinical needs”. During this symposium (inter)national experts will discuss health and disease at a molecular level on the basis of Clinical Proteomics. Case studies are presented to exemplify the potential for precision diagnostics. Furthermore, it will be emphasized that clinical needs need to be defined to contribute to patient care in an efficient and effective way.
www.boerhaavecontinuingmedicaleducation.com
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Olympus’ Image of the Year Award recognizes the best in life science imaging worldwide. Participants can win a CX43 microscope with a DP27 digital camera, X Line objectives, or an OM-D E-M5 Mark II camera. Those interested in participating can enter until 31 January 2020 by uploading images at www.olympus-lifescience.com/ioty. Winners will be selected by a jury panel and announced in March 2020. The jury consists of global representatives from both science and the arts, including photo- grapher Ron Caplain; Geoff Williams, a bioimaging facility manager at Brown University; Urs Ziegler, the head of a microscopy imaging facility at the University of Zurich; Stefan Terjung, the operational manager of an advanced light microscopy facility at EMBL Heidelberg; Hiroaki Misono, a graduate school professor of brain science at Doshisha University; Zhu Xueliang, a professor at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; Yalin Wang, Director of Biomedical Research Core Facilities at Westlake University, Hangzhou, China; and Wendy Salmon, a light microscopy specialist of a bioimaging facility at MIT. All entries will be evaluated based on artistic and visual aspects, scientific impact, and microscope proficiency. Regional prizes in Asia, Europe, and the Americas will be awarded in addition to the global prize. The Image of the Year European Life Science Light Microscopy Award began in 2017 to celebrate both the artistic and scientific value of microscopy images. Now on a global scale, the competition aims to encourage people to look at scientific images in a new way, appreciate their beauty, and share images with others. Participants may upload up to three microscopy images when submitting the online form. Images, accompanied by a brief explanation that notes the equipment used, can be uploaded until 31 January 2020. The jury will select and notify the winners in March 2020.
www.olympus-lifescience.com/ioty
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AESKU.GROUP recently announced completed acquisition of immunofluorescence assay (IFA) specialist MBL BION from MBL Intl., securing their position as the leading provider of IFA solutions to clinical laboratories. The acquisition increases AESKU.GROUP’s addressable market and strengthens its market position. AESKU.GROUP has a track record of developing, producing, and marketing innovative diagnostic assays and automated systems, and has a global network of proven distribution partners. A significant factor in their success is complete solutions for clinical laboratories, including all-in-one testing and reading automation with the SQII for enzyme immunoassay (ELISA), HELIA® for line immunoassay (LIA), and HELIOS®, which was the first all-in-one system on the market for IFA. This innovation, along with the confirmation of IFA as the gold-standard for autoimmunity screening in clinical guidelines, has led to over 400 HELIOS placements worldwide and in-creased demand for AESKU IFA reagents. MBL Bion has over 40 years’ experience manufacturing IFA products of the highest quality and is a leading provider of autoimmunity and infectious disease testing slides. They have a strong market presence in the Americas, and a centre of manufacturing excellence in Des Plaines, IL, USA. Adding MBL Bion’s manufacturing capacity and broad range of reagents lets AESKU.GROUP help laboratories expand their IFA testing with the most extensive range of IFA products available on all-in-one automation combined with a unique quality control portfolio for the diagnosis of autoimmune and infectious diseases. AESKU.GROUP CEO Dr. Torsten Matthias was delighted with the acquisition, saying, “We have found true synergy. MBL BION’s operations and product portfolio fit perfectly with the AESKU.GROUP. Between the expansion of our IFA manufacturing in Buffalo, NY, and MBL BION’s Des Plaines operations, AESKU can speed order processing and delivery times. Furthermore, the high quality of their HEp-2 cells and extensive infectious disease testing slides add incredible value to our new HELIOS ‘HTC’ humidity and temperature control module. For the first time, clinical laboratories can access the highest level of automation and environmental control for both auto- immunity and infectious serology testing.”
www.aesku.com
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Genetic alterations in low-risk prostate cancer diagnosed by needle biopsy can identify men that harbour higher-risk cancer in their prostate glands, Mayo Clinic has discovered. The research found for the first time that genetic alterations associated with intermediate- and high-risk prostate cancer also may be present in some cases of low-risk prostate cancers.
The study found the needle biopsy procedure may miss higher-risk cancer that increases the risk of disease progression. Researchers say that men diagnosed with low-risk cancer may benefit from additional testing for these chromosomal alterations.
“We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care,” says George Vasmatzis, Ph.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and lead author on the study. “Overtreatment has been issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.”
Prostate cancer is assessed by Gleason patterns and score that indicate grade. The Gleason patterns are strongly associated with risk of disease progression. Gleason pattern 3 prostate cancer is considered to be low-risk. Gleason patterns 4 and 5 cancer carry a higher risk of aggressive behaviour.
Men whose tumour is composed entirely of Gleason pattern 3 may choose active surveillance. They are monitored closely with blood tests and needle biopsies, as necessary. Or they may be referred to treatment, such as surgery and radiation, particularly if they have Gleason pattern 4 or 5.
Men with a low-risk cancer sometimes choose surgery because they don’t want to risk disease progression. The study found that men who do not have these alterations in their cancers have a low risk of harbouring aggressive disease. These men may feel more comfortable choosing active surveillance. Alternatively, if a man’s low-risk tumour shows these alterations, they have a higher risk that their cancer may progress. They may consider treatment, including surgery.
Researchers performed DNA sequencing with a high-tech genomic tool known as mate-pair sequencing. This research was performed on specific Gleason patterns from frozen cancer specimens from 126 men who had their prostate glands removed. They found five genes are more frequently altered in Gleason patterns 4 and 5. These alterations were found more commonly in Gleason pattern 3 associated with higher Gleason patterns and not when Gleason pattern 3 was found alone.
“The needle biopsy procedure samples only a small portion of the tumour. It is not uncommon that a man with a Gleason pattern 3 on needle biopsy specimen harbours a higher-grade cancer next to the pattern 3 that was missed by the procedure,” says John Cheville, M.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and co-author of the study. “Therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason pattern 4 is nearby.”
Mayo Clinic
https://tinyurl.com/yxcg3wzk
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A chemical that highlights tumour cells has been used by surgeons to help spot and safely remove brain cancer in a trial presented at the 2018 NCRI Cancer Conference. The research was carried out with patients who had suspected glioma, the most common form of brain cancer. Treatment usually involves surgery to remove as much of the cancer as possible, but it can be challenging for surgeons to identify all of the cancer cells while avoiding healthy brain tissue.
Researchers say that using the fluorescent marker helps surgeons to distinguish the most aggressive cancer cells from other brain tissue and they hope this will ultimately improve patient survival. The research was presented by Dr Kathreena Kurian, a Reader/Associate Professor in brain tumour research at the University of Bristol and consultant neuropathologist at North Bristol NHS Trust, UK. The study was led by Colin Watts, Professor of Neurosurgery and chair of the Birmingham brain cancer programme at the University of Birmingham, UK. Dr Kurian explained: “Gliomas are difficult to treat with survival times often measured in months rather than years. Many patients are treated with surgery and the aim is to safely remove as much of the cancer as possible. Once a tumour is removed, it is passed on to a pathologist who examines the cells under a microscope to see if they are ‘high-grade’, fast growing cells, or ‘low-grade’ slower growing cells. And we can plan further treatment, such as radiotherapy or chemotherapy, based on that diagnosis. “We wanted to see if using a fluorescent marker could help surgeons objectively identify high-grade tumour cells during surgery, allowing them to remove as much cancer as possible while leaving normal brain tissue intact.”
The researchers used a compound called 5-aminolevulinic acid or 5-ALA, which glows pink when a light is shone on it. Previous research shows that, when consumed, 5-ALA accumulates in fast growing cancer cells and this means it can act as a fluorescent marker of high-grade cells.
The study involved patients with suspected high-grade gliomas treated at the Royal Liverpool Hospital, Kings College Hospital in London or Addenbrooke’s Hospital in Cambridge, UK. They were aged between 23 and 77 years, with an average (median) age of 59 years. Before surgery to remove their brain tumours, each patient was given a drink containing 5-ALA.
Surgeons then used operating microscopes to help them look for fluorescent tissue while removing tumours from the patients’ brains. The tissue they removed was sent to the pathology lab where scientists could confirm the accuracy of the surgeons’ work.
A total of 99 patients received the 5-ALA marker and could be assessed for signs of fluorescence. During their operations, surgeons re-ported seeing fluorescence in 85 patients and 81 of these were subsequently confirmed by pathologists to have high-grade disease, one was found to have low-grade disease and three could not be assessed.
In the 14 patients where surgeons did not see any fluorescence, only seven tumours could be subsequently evaluated by pathology but in all these cases, low-grade disease was confirmed. Professor Watts said: “Neurosurgeons need to be able to distinguish tumour tissue from other brain tissue, especially when the tumour contains fastgrowing, high-grade cancer cells. This is the first prospective trial to show the benefits of using 5-ALA to improve the accuracy of diagnosing high-grade glioma during surgery. These results show that the marker is very good at indicating the presence and location of high-grade cancer cells.
National Cancer Research Institute www.ncri.org.uk/wp-content/uploads/2018/11/Kurian-Glioma-for-online.pdf
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Pseudoachondroplasia (PSACH) is a severe inherited dwarfing condition characterised by disproportionate short stature, joint laxity, pain, and early onset osteoarthritis. In PSACH, a genetic mutation leads to abnormal retention of cartilage oligomeric matrix protein (COMP) within the endoplasmic reticulum (ER) of cartilage-producing cells (chondrocytes), which interferes with function and cell viability. In a report, investigators describe how this protein accumulation results in “ER stress” and initiates a host of pathologic changes. These findings may open up new ways to treat PSACH and other ER-stress-related conditions.
“This is the first study linking ER stress to midline 1 protein (MID1), a microtubule stabilizer that increases mammalian target of rapamycin complex 1 (mTORC1) signalling in chondrocytes and other cell types. This finding has significant implications for cellular functions including autophagy, protein synthesis, and potentially cellular viability. These results identify new therapeutic targets for this pathologic process in a wide spectrum of ER-stress disorders such as type 2 diabetes, Alzheimer disease, and tuberculosis,” explained Karen L. Posey, PhD, Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
PSACH symptoms generally are recognized beginning at two years of age. Patients with PSACH have normal intelligence and cranio-facial features. PSACH is caused by mutations in the gene encoding the cartilage oligomeric matrix protein (COMP). ER stress occurs when abnormal (unfolded or misfolded) COMP (MT-COMP) accumulates in the rough endoplasmic reticulum of chondrocytes. Rough ER, the portion of ER displaying ribosomes, is the network of membranous tubules within cells associated with protein and lipid synthesis and export.
In previous studies, Dr. Posey and her colleagues have investigated chondrocyte pathology in the growth plates of dwarf mice that express MT-COMP, in cultured rat chondrosarcoma (RCS) cells that express human MT-COMP, as well as in cultured cartilage nodules from PSACH patients. The mice replicate many of the clinical features and chondrocyte pathology reported in patients with PSACH.
In the current study, the researchers showed increased levels of MID1 protein in chondrocytes from the mutant dwarf mice as well as in cells from human PSACH patients. They also found that ER-stress-inducing drugs increased MID1 signalling, although oxidative stress did not.
The up-regulation of MID1 was associated with increased mTORC1 signalling in the growth plates of the dwarf mice. Rapamycin decreased intracellular retention of MT-COMP and decreased mTORC1 signaling. The mTOR pathway is activated during various cellular processes (eg, tumor formation and angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation) and is dysregulated in diseases such as cancer and type 2 diabetes.
The results of this work show that MID1, mTORC1 signalling, the microtubule network, protein synthesis, inflammation, and autophagy form a complex multifaceted response to protein accumulation in the ER when clearance efforts fail and MID1 may act as a pro-survival factor.
EurekAlertwww.eurekalert.org/pub_releases/2018-12/e-iuo121018.php
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In a new study, researchers at Uppsala University have identified a previously unknown mechanism that regulates release of insulin, a hormone that lowers blood glucose levels, from the β-cells (beta cells) of the pancreas. This mechanism is disrupted in type 2 diabetes. The scientists hope this finding will be used to develop new treatments against the disease.
Globally, more than 400 million people suffer from type 2 diabetes. One of the main problems is inadequate secretion, from the β-cells of the pancreas, of insulin hormone, which lowers blood sugar (blood glucose).
It has been known for some time that im-paired insulin secretion is due to an inability of the insulin-containing secretory granules to attach themselves (‘dock’) to, and then fuse with, the cell membrane. As a result, less insulin reaches the blood and, accordingly, the body becomes less able to reduce blood glucose levels sufficiently.
In the new study, the scientists identify a protein, Sac2, that is found at lower levels in patients with type 2 diabetes. In experiments, the researchers show that lowering the levels of this protein by experimental means leads to reduced insulin secretion from the β-cells. By using advanced microscopy techniques, the researchers were able to show that Sac2 is an important component on the surface of the insulin-containing secretory granules, where it modifies the fat composition of the membrane. In the absence of Sac2, a specific fat molecule accumulates on the surface of the secretory granules. This incapacitates them, so that they cannot dock to the cell membrane, which in turn causes insulin secretion to be reduced.
This study shows, first and foremost, that reduced levels of a single protein gives rise to β-cells that exhibit several defects associated with type 2 diabetes. But it also shows that the fat composition of the insulin-containing secretory granules is of importance for their ability to be released from the cells. The scientists now hope that it will be possible to use these findings to develop new ways of treating type 2 diabetes.
Uppsala Universitywww.uu.se/en/news-media/press-releases/press-release/?id=4814&area=3,8&typ=pm&lang=en
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Modern science and data sharing converged to underpin a study led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, that identified a gene associated with a rare condition that results in physical and intellectual disabilities of children.
The results suggest that rare variants in the gene DDX6 are associated with a significant disruption in the development of the central nervous system, governing such basic skills as the ability to walk and talk.
“One of the most powerful revelations of this study is the identification of pathogenic mutations in DDX6; a gene not previously linked to childhood disorders and one which appears to play a key role in early brain development,” said Chris Balak, a research associate in TGen’s Neurogenomics Division, and the study’s lead author.
Balak zeroed in on DDX6 by comparing the sequencing results from a 5-year-old Arizona girl who was seen at TGen’s Center for Rare Childhood Disorders (the Center) with those identified in large population databases and to the genomes of her parents, who are healthy. Following this revelation, and preliminary findings posted on a website shared by investigators worldwide, TGen identified four similar cases: two in the U.S., and one each in France and the Netherlands.
These children’s conditions were characterized by intellectual disability, developmental delay, speech and feeding difficulties, low muscle strength with difficulties walking, mild-to-moderate cardiac anomalies, and specific facial features.
“Something we are quite proud of with this work is our combined effort with other physi- cians and scientists in Europe to demonstrate that changes in this gene cause this rare syndrome in multiple patients,” said Dr. Matt Huentelman, TGen Professor of Neruogenomics, Scientific Director of the Center, and one of the study’s senior authors. “Collectively, our clinical and laboratory data describe a new brain development syndrome caused by genetic changes in DDX6.”
TGenwww.tgen.org/news/2019/august/15/tgen-identifies-ddx6-linked-to-disabilities/
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Liquid biopsy is likely to play an increasing role in identifying patients with colorectal cancer (CRC) who are likely to relapse after surgery, and has potential for optimising treatment for individual patients, according to new research.
Of 805 patients in the phase III IDEA-FRANCE trial who had liquid biopsy prior to adjuvant chemotherapy for stage III CRC, 109 (13.5%) had circulating tumour DNA (ctDNA) in their blood.
In this group, two-year disease-free survival (DFS) was 64%, compared to 82% in those who were ctDNA negative.
“In this large prospective trial, we confirmed that ctDNA is an independent prognostic factor in colorectal cancer and that approximately six out of 10 patients who are ctDNA positive will remain disease-free two years after standard adjuvant chemotherapy, compared to eight out of 10 of those who are ctDNA negative,” said study author Prof Julien Taieb, Hôpital European Georges Pompidou, Paris, France.
IDEA-FRANCE also showed that six months of adjuvant treatment was superior to three months in both ctDNA positive and negative patients, and that ctDNA positive patients treated for six months had a similar prognosis to ctDNA negative patients treated for three months.
Adjuvant therapy was FOLFOX (folinic acid, fluorouracil and oxaliplatin) in 90% of cases.
“ctDNA testing did not predict which patients should have three or six months of adjuvant chemotherapy and there is continuing debate over the optimal type and duration of treatment for patients who are ctDNA positive, but we do now know that ctDNA is a major prognostic factor which will be very useful in stratifying patients and driving future trials of colorectal cancer,” said Taieb.
“In all subgroups, ctDNA positive patients who only had three months of adjuvant therapy had the worst prognosis,” he added.
Thirty to 50% of patients with localised CRC relapse despite primary optimal therapy, and a second study reported at the ESMO Congress 2019 investigated whether ctDNA can be used to detect minimal residual disease and identify those at risk of recurrence.
The results showed that post-surgical plasma ctDNA predicted metastatic relapse a median of 10 months before recurrence was visible on radiological scans (hazard ratio 11.33; p=0.0001).
The researchers concluded that plasma ctDNA testing opens up an opportunity for precision treatment of patients with localised CRC.
Commenting on the results of the CRC presentations, Prof Alberto Bardelli, University of Turin, Italy, said: “When patients have surgery for early stage colorectal cancer, doubts remain as to whether the disease has been completely eradicated and, as a result, patients often receive adjuvant chemotherapy. However, the IDEA-FRANCE results have shown we can now use a blood test to say whether the patient is clear or not.”
ecancerecancer.org/en/news/16682-esmo-2019-liquid-biopsy-has-prognostic-role-in-colorectal-cancer-and-potential-for-guiding-therapy
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A new calculator developed by the University of Exeter will help clinicians classify whether a patient has type 1 or type 2 diabetes, ensuring they get the best treatment and reducing complications.
The calculator uses a model that takes into account available data about the patient, as well as blood test results. It can be used to identify if a person is likely to have type 1 diabetes, to reduce misdiagnosis. Former Prime Minister Theresa May was initially diagnosed with type 2 diabetes. Only when tablet treatment failed to work was she re-diagnosed with type 1.
It is often difficult for clinicians to diagnose which type of diabetes a patient has. While blood tests such as antibodies against the cells that make insulin, or a person’s genetic risk of type 1 diabetes may help diagnosis, these tests do not give a diagnosis on their own, and may be interpreted very differently depending on whether or not a person has other features of type 1 diabetes. The new calculator, currently available in beta format, combines available information from blood tests with a person’s age of diagnosis and BMI for a personalised medicine approach. The calculator was developed by researchers at the universities of Exeter, Oxford and Dundee.
The new calculator will build on the success of a similar calculator previously developed at Exeter, to help clinicians determine whether a patient has the diabetes subtype MODY, caused by a single gene. The online calculator has been used by more than 100,000 people, with more than 9,000 people downloading the calculator phone app Diabetes Diagnostics, which will be updated to include the new calculator. New research recently presented at the European Association for the Study of Diabetes conference in Barcelona has shown that almost half of all referrals sent to the UK diagnostic laboratory for MODY now report using the calculator, and those that report using the calculator have a higher detection rate compared with those that do not.
Dr Angus Jones, of the University of Exeter Medical School, who led the research, said: “The right diagnosis in diabetes is absolutely crucial to getting the best outcomes for patients, as treatment is very different in different types of diabetes. However in some people it can be very difficult to know what type of diabetes they have. Our new calculator can help clinicians by combining different features to give them the probability a person will have type 1 diabetes, and assess whether additional tests are likely to be helpful.” The new beta format calculator can be accessed here: www.diabetesgenes.org/t1dt2d-prediction-model/
University of Exeterwww.exeter.ac.uk/news/research/title_754422_en.html
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Continuing medical education course at the Leiden University Medical Center
, /in E-News /by 3wmediaOn 14th November 2019 a “continuing medical education course” is organized at the Leiden University Medical Center (LUMC) entitled “Prime time for precision diagnostics driven by unmet clinical needs”. During this symposium (inter)national experts will discuss health and disease at a molecular level on the basis of Clinical Proteomics. Case studies are presented to exemplify the potential for precision diagnostics. Furthermore, it will be emphasized that clinical needs need to be defined to contribute to patient care in an efficient and effective way. www.boerhaavecontinuingmedicaleducation.com
Olympus launches the first Global Image of the Year Award
, /in E-News /by 3wmediaOlympus’ Image of the Year Award recognizes the best in life science imaging worldwide. Participants can win a CX43 microscope with a DP27 digital camera, X Line objectives, or an OM-D E-M5 Mark II camera. Those interested in participating can enter until 31 January 2020 by uploading images at www.olympus-lifescience.com/ioty. Winners will be selected by a jury panel and announced in March 2020.
www.olympus-lifescience.com/iotyThe jury consists of global representatives from both science and the arts, including photo-
grapher Ron Caplain; Geoff Williams, a bioimaging facility manager at Brown University; Urs Ziegler, the head of a microscopy imaging facility at the University of Zurich; Stefan Terjung, the operational manager of an advanced light microscopy facility at EMBL Heidelberg; Hiroaki Misono, a graduate school professor of brain science at Doshisha University; Zhu Xueliang, a professor at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; Yalin Wang, Director of Biomedical Research Core Facilities at Westlake University, Hangzhou, China; and Wendy Salmon, a light microscopy specialist of a bioimaging facility at MIT.
All entries will be evaluated based on artistic and visual aspects, scientific impact, and microscope proficiency. Regional prizes in Asia, Europe, and the Americas will be awarded in addition to the global prize.
The Image of the Year European Life Science Light Microscopy Award began in 2017 to celebrate both the artistic and scientific value of microscopy images. Now on a global scale, the competition aims to encourage people to look at scientific images in a new way, appreciate their beauty, and share images with others.
Participants may upload up to three microscopy images when submitting the online form. Images, accompanied by a brief explanation that notes the equipment used, can be uploaded until 31 January 2020. The jury will select and notify the winners in March 2020.
Aesku has completed acquisition of MBL Bion
, /in E-News /by 3wmediaAESKU.GROUP recently announced completed acquisition of immunofluorescence assay (IFA) specialist MBL BION from MBL Intl., securing their position as the leading provider of IFA solutions to clinical laboratories. The acquisition increases AESKU.GROUP’s addressable market and strengthens its market position.
www.aesku.comAESKU.GROUP has a track record of developing, producing, and marketing innovative diagnostic assays and automated systems, and has a global network of proven distribution partners. A significant factor in their success is complete solutions for clinical laboratories, including all-in-one testing and reading automation with the SQII for enzyme immunoassay (ELISA), HELIA® for line immunoassay (LIA), and HELIOS®, which was the first all-in-one system on the market for IFA. This innovation, along with the confirmation of IFA as the gold-standard for autoimmunity screening in clinical guidelines, has led to over 400 HELIOS placements worldwide and in-creased demand for AESKU IFA reagents.
MBL Bion has over 40 years’ experience manufacturing IFA products of the highest quality and is a leading provider of autoimmunity and infectious disease testing slides. They have a strong market presence in the Americas, and a centre of manufacturing excellence in Des Plaines, IL, USA. Adding MBL Bion’s manufacturing capacity and broad range of reagents lets AESKU.GROUP help laboratories expand their IFA testing with the most extensive range of IFA products available on all-in-one automation combined with a unique quality control portfolio for the diagnosis of autoimmune and infectious diseases.
AESKU.GROUP CEO Dr. Torsten Matthias was delighted with the acquisition, saying, “We have found true synergy. MBL BION’s operations and product portfolio fit perfectly with the AESKU.GROUP. Between the expansion of our IFA manufacturing in Buffalo, NY, and MBL BION’s Des Plaines operations, AESKU can speed order processing and delivery times. Furthermore, the high quality of their HEp-2 cells and extensive infectious disease testing slides add incredible value to our new HELIOS ‘HTC’ humidity and temperature control module. For the first time, clinical laboratories can access the highest level of automation and environmental control for both auto-
immunity and infectious serology testing.”
Biological markers that could guide treatment for prostate cancer
, /in E-News /by 3wmediaGenetic alterations in low-risk prostate cancer diagnosed by needle biopsy can identify men that harbour higher-risk cancer in their prostate glands, Mayo Clinic has discovered. The research found for the first time that genetic alterations associated with intermediate- and high-risk prostate cancer also may be present in some cases of low-risk prostate cancers.
The study found the needle biopsy procedure may miss higher-risk cancer that increases the risk of disease progression. Researchers say that men diagnosed with low-risk cancer may benefit from additional testing for these chromosomal alterations.
“We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care,” says George Vasmatzis, Ph.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and lead author on the study. “Overtreatment has been issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.”
Prostate cancer is assessed by Gleason patterns and score that indicate grade. The Gleason patterns are strongly associated with risk of disease progression. Gleason pattern 3 prostate cancer is considered to be low-risk. Gleason patterns 4 and 5 cancer carry a higher risk of aggressive behaviour.
Men whose tumour is composed entirely of Gleason pattern 3 may choose active surveillance. They are monitored closely with blood tests and needle biopsies, as necessary. Or they may be referred to treatment, such as surgery and radiation, particularly if they have Gleason pattern 4 or 5.
Men with a low-risk cancer sometimes choose surgery because they don’t want to risk disease progression. The study found that men who do not have these alterations in their cancers have a low risk of harbouring aggressive disease. These men may feel more comfortable choosing active surveillance. Alternatively, if a man’s low-risk tumour shows these alterations, they have a higher risk that their cancer may progress. They may consider treatment, including surgery.
Researchers performed DNA sequencing with a high-tech genomic tool known as mate-pair sequencing. This research was performed on specific Gleason patterns from frozen cancer specimens from 126 men who had their prostate glands removed. They found five genes are more frequently altered in Gleason patterns 4 and 5. These alterations were found more commonly in Gleason pattern 3 associated with higher Gleason patterns and not when Gleason pattern 3 was found alone.
“The needle biopsy procedure samples only a small portion of the tumour. It is not uncommon that a man with a Gleason pattern 3 on needle biopsy specimen harbours a higher-grade cancer next to the pattern 3 that was missed by the procedure,” says John Cheville, M.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and co-author of the study. “Therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason pattern 4 is nearby.”
Mayo Clinic https://tinyurl.com/yxcg3wzk
Fluorescent marker can guide surgeons to remove dangerous brain tumour cells more accurately
, /in E-News /by 3wmediaA chemical that highlights tumour cells has been used by surgeons to help spot and safely remove brain cancer in a trial presented at the 2018 NCRI Cancer Conference. The research was carried out with patients who had suspected glioma, the most common form of brain cancer. Treatment usually involves surgery to remove as much of the cancer as possible, but it can be challenging for surgeons to identify all of the cancer cells while avoiding healthy brain tissue.
Researchers say that using the fluorescent marker helps surgeons to distinguish the most aggressive cancer cells from other brain tissue and they hope this will ultimately improve patient survival. The research was presented by Dr Kathreena Kurian, a Reader/Associate Professor in brain tumour research at the University of Bristol and consultant neuropathologist at North Bristol NHS Trust, UK. The study was led by Colin Watts, Professor of Neurosurgery and chair of the Birmingham brain cancer programme at the University of Birmingham, UK. Dr Kurian explained: “Gliomas are difficult to treat with survival times often measured in months rather than years. Many patients are treated with surgery and the aim is to safely remove as much of the cancer as possible. Once a tumour is removed, it is passed on to a pathologist who examines the cells under a microscope to see if they are ‘high-grade’, fast growing cells, or ‘low-grade’ slower growing cells. And we can plan further treatment, such as radiotherapy or chemotherapy, based on that diagnosis. “We wanted to see if using a fluorescent marker could help surgeons objectively identify high-grade tumour cells during surgery, allowing them to remove as much cancer as possible while leaving normal brain tissue intact.”
The researchers used a compound called 5-aminolevulinic acid or 5-ALA, which glows pink when a light is shone on it. Previous research shows that, when consumed, 5-ALA accumulates in fast growing cancer cells and this means it can act as a fluorescent marker of high-grade cells.
The study involved patients with suspected high-grade gliomas treated at the Royal Liverpool Hospital, Kings College Hospital in London or Addenbrooke’s Hospital in Cambridge, UK. They were aged between 23 and 77 years, with an average (median) age of 59 years. Before surgery to remove their brain tumours, each patient was given a drink containing 5-ALA.
Surgeons then used operating microscopes to help them look for fluorescent tissue while removing tumours from the patients’ brains. The tissue they removed was sent to the pathology lab where scientists could confirm the accuracy of the surgeons’ work.
A total of 99 patients received the 5-ALA marker and could be assessed for signs of fluorescence. During their operations, surgeons re-ported seeing fluorescence in 85 patients and 81 of these were subsequently confirmed by pathologists to have high-grade disease, one was found to have low-grade disease and three could not be assessed.
In the 14 patients where surgeons did not see any fluorescence, only seven tumours could be subsequently evaluated by pathology but in all these cases, low-grade disease was confirmed. Professor Watts said: “Neurosurgeons need to be able to distinguish tumour tissue from other brain tissue, especially when the tumour contains fastgrowing, high-grade cancer cells. This is the first prospective trial to show the benefits of using 5-ALA to improve the accuracy of diagnosing high-grade glioma during surgery. These results show that the marker is very good at indicating the presence and location of high-grade cancer cells.
National Cancer Research Institute www.ncri.org.uk/wp-content/uploads/2018/11/Kurian-Glioma-for-online.pdf
Improved understanding of the pathology of dwarfism may lead to new treatment targets
, /in E-News /by 3wmediaPseudoachondroplasia (PSACH) is a severe inherited dwarfing condition characterised by disproportionate short stature, joint laxity, pain, and early onset osteoarthritis. In PSACH, a genetic mutation leads to abnormal retention of cartilage oligomeric matrix protein (COMP) within the endoplasmic reticulum (ER) of cartilage-producing cells (chondrocytes), which interferes with function and cell viability. In a report, investigators describe how this protein accumulation results in “ER stress” and initiates a host of pathologic changes. These findings may open up new ways to treat PSACH and other ER-stress-related conditions.
“This is the first study linking ER stress to midline 1 protein (MID1), a microtubule stabilizer that increases mammalian target of rapamycin complex 1 (mTORC1) signalling in chondrocytes and other cell types. This finding has significant implications for cellular functions including autophagy, protein synthesis, and potentially cellular viability. These results identify new therapeutic targets for this pathologic process in a wide spectrum of ER-stress disorders such as type 2 diabetes, Alzheimer disease, and tuberculosis,” explained Karen L. Posey, PhD, Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
PSACH symptoms generally are recognized beginning at two years of age. Patients with PSACH have normal intelligence and cranio-facial features. PSACH is caused by mutations in the gene encoding the cartilage oligomeric matrix protein (COMP). ER stress occurs when abnormal (unfolded or misfolded) COMP (MT-COMP) accumulates in the rough endoplasmic reticulum of chondrocytes. Rough ER, the portion of ER displaying ribosomes, is the network of membranous tubules within cells associated with protein and lipid synthesis and export.
In previous studies, Dr. Posey and her colleagues have investigated chondrocyte pathology in the growth plates of dwarf mice that express MT-COMP, in cultured rat chondrosarcoma (RCS) cells that express human MT-COMP, as well as in cultured cartilage nodules from PSACH patients. The mice replicate many of the clinical features and chondrocyte pathology reported in patients with PSACH.
In the current study, the researchers showed increased levels of MID1 protein in chondrocytes from the mutant dwarf mice as well as in cells from human PSACH patients. They also found that ER-stress-inducing drugs increased MID1 signalling, although oxidative stress did not.
The up-regulation of MID1 was associated with increased mTORC1 signalling in the growth plates of the dwarf mice. Rapamycin decreased intracellular retention of MT-COMP and decreased mTORC1 signaling. The mTOR pathway is activated during various cellular processes (eg, tumor formation and angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation) and is dysregulated in diseases such as cancer and type 2 diabetes.
The results of this work show that MID1, mTORC1 signalling, the microtubule network, protein synthesis, inflammation, and autophagy form a complex multifaceted response to protein accumulation in the ER when clearance efforts fail and MID1 may act as a pro-survival factor.
EurekAlertwww.eurekalert.org/pub_releases/2018-12/e-iuo121018.php
New mechanism for dysfunctional insulin release identified
, /in E-News /by 3wmediaIn a new study, researchers at Uppsala University have identified a previously unknown mechanism that regulates release of insulin, a hormone that lowers blood glucose levels, from the β-cells (beta cells) of the pancreas. This mechanism is disrupted in type 2 diabetes. The scientists hope this finding will be used to develop new treatments against the disease.
Globally, more than 400 million people suffer from type 2 diabetes. One of the main problems is inadequate secretion, from the β-cells of the pancreas, of insulin hormone, which lowers blood sugar (blood glucose).
It has been known for some time that im-paired insulin secretion is due to an inability of the insulin-containing secretory granules to attach themselves (‘dock’) to, and then fuse with, the cell membrane. As a result, less insulin reaches the blood and, accordingly, the body becomes less able to reduce blood glucose levels sufficiently.
In the new study, the scientists identify a protein, Sac2, that is found at lower levels in patients with type 2 diabetes. In experiments, the researchers show that lowering the levels of this protein by experimental means leads to reduced insulin secretion from the β-cells. By using advanced microscopy techniques, the researchers were able to show that Sac2 is an important component on the surface of the insulin-containing secretory granules, where it modifies the fat composition of the membrane. In the absence of Sac2, a specific fat molecule accumulates on the surface of the secretory granules. This incapacitates them, so that they cannot dock to the cell membrane, which in turn causes insulin secretion to be reduced.
This study shows, first and foremost, that reduced levels of a single protein gives rise to β-cells that exhibit several defects associated with type 2 diabetes. But it also shows that the fat composition of the insulin-containing secretory granules is of importance for their ability to be released from the cells. The scientists now hope that it will be possible to use these findings to develop new ways of treating type 2 diabetes.
Uppsala Universitywww.uu.se/en/news-media/press-releases/press-release/?id=4814&area=3,8&typ=pm&lang=en
Gene links children with physical and intellectual disabilities
, /in E-News /by 3wmediaModern science and data sharing converged to underpin a study led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, that identified a gene associated with a rare condition that results in physical and intellectual disabilities of children.
The results suggest that rare variants in the gene DDX6 are associated with a significant disruption in the development of the central nervous system, governing such basic skills as the ability to walk and talk.
“One of the most powerful revelations of this study is the identification of pathogenic mutations in DDX6; a gene not previously linked to childhood disorders and one which appears to play a key role in early brain development,” said Chris Balak, a research associate in TGen’s Neurogenomics Division, and the study’s lead author.
Balak zeroed in on DDX6 by comparing the sequencing results from a 5-year-old Arizona girl who was seen at TGen’s Center for Rare Childhood Disorders (the Center) with those identified in large population databases and to the genomes of her parents, who are healthy. Following this revelation, and preliminary findings posted on a website shared by investigators worldwide, TGen identified four similar cases: two in the U.S., and one each in France and the Netherlands.
These children’s conditions were characterized by intellectual disability, developmental delay, speech and feeding difficulties, low muscle strength with difficulties walking, mild-to-moderate cardiac anomalies, and specific facial features.
“Something we are quite proud of with this work is our combined effort with other physi-
cians and scientists in Europe to demonstrate that changes in this gene cause this rare syndrome in multiple patients,” said Dr. Matt Huentelman, TGen Professor of Neruogenomics, Scientific Director of the Center, and one of the study’s senior authors. “Collectively, our clinical and laboratory data describe a new brain development syndrome caused by genetic changes in DDX6.”
TGenwww.tgen.org/news/2019/august/15/tgen-identifies-ddx6-linked-to-disabilities/
Liquid biopsy has prognostic role in colorectal cancer and potential for guiding therapy
, /in E-News /by 3wmediaLiquid biopsy is likely to play an increasing role in identifying patients with colorectal cancer (CRC) who are likely to relapse after surgery, and has potential for optimising treatment for individual patients, according to new research.
Of 805 patients in the phase III IDEA-FRANCE trial who had liquid biopsy prior to adjuvant chemotherapy for stage III CRC, 109 (13.5%) had circulating tumour DNA (ctDNA) in their blood.
In this group, two-year disease-free survival (DFS) was 64%, compared to 82% in those who were ctDNA negative.
“In this large prospective trial, we confirmed that ctDNA is an independent prognostic factor in colorectal cancer and that approximately six out of 10 patients who are ctDNA positive will remain disease-free two years after standard adjuvant chemotherapy, compared to eight out of 10 of those who are ctDNA negative,” said study author Prof Julien Taieb, Hôpital European Georges Pompidou, Paris, France.
IDEA-FRANCE also showed that six months of adjuvant treatment was superior to three months in both ctDNA positive and negative patients, and that ctDNA positive patients treated for six months had a similar prognosis to ctDNA negative patients treated for three months.
Adjuvant therapy was FOLFOX (folinic acid, fluorouracil and oxaliplatin) in 90% of cases.
“ctDNA testing did not predict which patients should have three or six months of adjuvant chemotherapy and there is continuing debate over the optimal type and duration of treatment for patients who are ctDNA positive, but we do now know that ctDNA is a major prognostic factor which will be very useful in stratifying patients and driving future trials of colorectal cancer,” said Taieb.
“In all subgroups, ctDNA positive patients who only had three months of adjuvant therapy had the worst prognosis,” he added.
Thirty to 50% of patients with localised CRC relapse despite primary optimal therapy, and a second study reported at the ESMO Congress 2019 investigated whether ctDNA can be used to detect minimal residual disease and identify those at risk of recurrence.
The results showed that post-surgical plasma ctDNA predicted metastatic relapse a median of 10 months before recurrence was visible on radiological scans (hazard ratio 11.33; p=0.0001).
The researchers concluded that plasma ctDNA testing opens up an opportunity for precision treatment of patients with localised CRC.
Commenting on the results of the CRC presentations, Prof Alberto Bardelli, University of Turin, Italy, said: “When patients have surgery for early stage colorectal cancer, doubts remain as to whether the disease has been completely eradicated and, as a result, patients often receive adjuvant chemotherapy. However, the IDEA-FRANCE results have shown we can now use a blood test to say whether the patient is clear or not.”
ecancerecancer.org/en/news/16682-esmo-2019-liquid-biopsy-has-prognostic-role-in-colorectal-cancer-and-potential-for-guiding-therapy
New calculator will help clinicians diagnose diabetes more accurately
, /in E-News /by 3wmediaA new calculator developed by the University of Exeter will help clinicians classify whether a patient has type 1 or type 2 diabetes, ensuring they get the best treatment and reducing complications.
The calculator uses a model that takes into account available data about the patient, as well as blood test results. It can be used to identify if a person is likely to have type 1 diabetes, to reduce misdiagnosis. Former Prime Minister Theresa May was initially diagnosed with type 2 diabetes. Only when tablet treatment failed to work was she re-diagnosed with type 1.
It is often difficult for clinicians to diagnose which type of diabetes a patient has. While blood tests such as antibodies against the cells that make insulin, or a person’s genetic risk of type 1 diabetes may help diagnosis, these tests do not give a diagnosis on their own, and may be interpreted very differently depending on whether or not a person has other features of type 1 diabetes. The new calculator, currently available in beta format, combines available information from blood tests with a person’s age of diagnosis and BMI for a personalised medicine approach. The calculator was developed by researchers at the universities of Exeter, Oxford and Dundee.
The new calculator will build on the success of a similar calculator previously developed at Exeter, to help clinicians determine whether a patient has the diabetes subtype MODY, caused by a single gene. The online calculator has been used by more than 100,000 people, with more than 9,000 people downloading the calculator phone app Diabetes Diagnostics, which will be updated to include the new calculator. New research recently presented at the European Association for the Study of Diabetes conference in Barcelona has shown that almost half of all referrals sent to the UK diagnostic laboratory for MODY now report using the calculator, and those that report using the calculator have a higher detection rate compared with those that do not.
Dr Angus Jones, of the University of Exeter Medical School, who led the research, said: “The right diagnosis in diabetes is absolutely crucial to getting the best outcomes for patients, as treatment is very different in different types of diabetes. However in some people it can be very difficult to know what type of diabetes they have. Our new calculator can help clinicians by combining different features to give them the probability a person will have type 1 diabetes, and assess whether additional tests are likely to be helpful.”
The new beta format calculator can be accessed here: www.diabetesgenes.org/t1dt2d-prediction-model/
University of Exeterwww.exeter.ac.uk/news/research/title_754422_en.html