Autophagy, the process by which cells that are starved for food resort to chewing up their own damaged proteins and membranes and recycling them into fuel, has emerged as a key pathway that cancer cells use to survive in the face of assault by chemotherapy and radiation. Using drugs to shut down that survival mechanism shows great promise, especially when combined with targeted agents and standard chemotherapies, but until recently, it has been unclear which patients’ cancers would respond to that combination therapy.
A team led by researchers from the Perelman School of Medicine at the University of Pennsylvania will present findings showing that colon cancer and lung cancer cell lines which expressed a gene known as helicase-like transcription factor (HLTF) tended to be impervious to the effects of the autophagy inhibition drug hydroxycholoroquine (HCQ). Cells where HLTF is silent, however, appeared to be sensitive to HCQ, which led the team to test HLTF expression in a group of colon cancer patients treated with two chemotherapies (the FOLFOX regimen plus bevacizumab) and HCQ. They found that low expression of HLTF predicted those who would respond to the combination therapy.
Since previous studies have shown that HLTF gene silencing is common in 20 to 40 percent of many epithelial cancers, the Penn team is hopeful their findings could lead to the development of a predictive biomarker to identify patients with other cancers who are most likely to respond to drug therapies involving autophagy inhibitors.
Penn Medicine
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Men who develop prostate cancer after inheriting a faulty gene need immediate surgery or radiotherapy rather than being placed under surveillance, as their disease is more aggressive than other types, a new study has found.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust found prostate cancers spread more quickly and were more often fatal in men who had inherited a faulty BRCA2 gene than in men without the faulty gene.
The research, funded by the Ronald and Rita McAulay Foundation and Cancer Research UK, could challenge current NHS guidelines for prostate cancer, under which BRCA2 mutation carriers are offered the same treatment options as non-carriers.
It is often difficult to tell at diagnosis whether prostate cancer will be life-threatening or not, and while treatment options for early-stage disease include surgery and radiotherapy, many men instead receive active surveillance to see if the disease starts to progress.
The new study is the largest to compare prostate cancer patients with and without BRCA mutations, in order to tell whether gene testing should help to direct management options.
Senior author Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Consultant in Clinical Oncology at The Royal Marsden, said: ‘It is clear from our study that prostate cancers linked to inheritance of the BRCA2 cancer gene are more deadly than other types. It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.’
The team from the ICR and The Royal Marsden, with collaborators across the UK, examined the medical records of 61 BRCA2-mutation carriers, 18 BRCA1-mutation carriers and 1,940 non-carriers.
They found BRCA1/2 mutation carriers were more likely to be diagnosed with advanced stage prostate cancers (37 per cent versus 28 per cent) or cancer that had already spread (18 per cent versus nine per cent) than non-carriers. Among those whose cancers had not spread out of the prostate at diagnosis, within five years more carriers than non-carriers had metastatic disease (23 per cent versus seven per cent).
Patients with BRCA2-mutations were also significantly less likely to survive the cancer, living an average of 6.5 years compared with 12.9 years for non-carriers. The team concluded that a BRCA2 test could be used in combination with other factors as a prognostic test. Men with a BRCA1 mutation also had a shorter average survival time of 10.5 years, but there was not a statistically significant difference with non-carriers.
ICR
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How do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?
Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.
‘Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,’ says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.
Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.
‘But when we tried to figure out what the modification was, we didn’t have the tools,’ he said.
Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. ‘It was like a detective story with many possibilities that had to be ruled out one by one,’ she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.
She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.
The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the ‘thorough and elegant work’ that Song brought to it, he said. ‘It’s such a radical finding that we needed to show all the key steps along the way.’
The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of ageing and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration.
University of Illinois at Chicago College of Medicine
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Montréal scientists identified the DOCK1 protein as a potential target to reduce the progression of metastases in patients suffering from breast cancer, the most common type of cancer in women.
Dr. Côté’s laboratory is interested in metastasis, which is the spread of cancer from an organ (or part of an organ) to another. Nearly 90 per cent of cancer patient deaths are attributable to metastasis, thus explaining the importance of understanding the underlying cellular and molecular mechanisms of this harmful process.
‘Despite important breakthroughs in breast cancer treatment, few mechanisms are known to explain the spread of metastases,’ says Dr. Côté, Director of the Cytoskeletal Organization and Cell Migration research unit at the IRCM. ‘We are looking to identify the proteins that regulate the metastatic process so that new agents can be developed and combined with current treatments.’
Two major breast cancer subtypes, HER2+ and Basal, have a tendency to be metastatic and recurrent, and are ultimately associated to a poor survival rate. Research at the IRCM was conducted on the HER2+ type (Human Epidermal growth factor Receptor 2), which represents approximately 25 per cent of breast cancer cases. HER2 positive tumours tend to develop and spread more quickly than other types of tumours.
‘By studying a genetic mouse model with HER2+ breast cancer, we identified the protein DOCK1 as an important regulator of metastasis,’ explains Mélanie Laurin, doctoral student in Dr. Côté’s laboratory and first author of the study. ‘When we eliminated this protein in mice, our results showed a significant decrease in lung metastases. We also discovered that the DOCK1 protein contributes to the growth of tumours.’
‘To show the correlation between the expression of DOCK1 and breast cancer prognosis, we performed an analysis of several databases of patient genic,’ adds Dr. Benjamin Haibe-Kains, researcher at the IRCM who collaborated with Dr. Côté’s team. ‘We did indeed discover that high levels of DOCK1 in HER2+ or Basal breast cancer patients are associated with a lower prognosis, or recurrence of the disease.’
‘Our work defined a new molecule required for the progression of breast cancer to the metastatic stage and allowed us to identify new markers that could become potential targets to stop the progression of metastases,’ concludes Dr. Côté. ‘We also showed that a chemical inhibitor of the DOCK1 protein, developed by Dr. Yoshinori Fukui, our collaborator in Japan, can stop the migration of cancerous cells. These results could eventually lead to the development of drugs that would limit the progression of metastatic breast cancer and could thereby improve patient prognosis.’
Institut de recherches cliniques de Montréal
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A team led by Massachusetts General Hospital (MGH) researchers has identified a genetic signature that appears to reflect the risk of tumour recurrence or spread in men surgically treated for prostate cancer. If confirmed in future studies, this finding not only may help determine which patients require additional treatment after the cancerous gland has been removed, it also may help address the most challenging problem in prostate cancer treatment – distinguishing tumours that require aggressive treatment from those that can safely be monitored.
‘Radical prostatectomy is the standard of care for men whose cancer is advanced but confined to the prostate gland, but we know that the factors we use to determine which patients need radiation therapy after surgery are inadequate,’ says W. Scott McDougal, MD, of the MGH Department of Urology, corresponding author of the report. ‘The treatments available to our patients can have significant impact on their quality of life, so a better way to know which patients with localised cancer need additional therapy after surgery and which require no additional treatment is a significant unmet need.’
Gene expression signatures indicating patient prognosis and sometimes the most appropriate treatment have been incorporated into care for breast cancer and other tumours. Studies looking for such markers in prostate cancer have had variable results, and their potential usefulness to guide treatment has not been determined. For the current study the research team – led by Chin-Lee Wu, MD, PhD, of the MGH Department of Pathology – examined samples of malignant tissue from around 200 prostate cancer patients who had radical prostatectomies at the MGH between 1993 and 1995, analyzing the expression patterns of more than 1,500 genes associated with prostate cancer in earlier studies. With the results of that analysis, they developed a 32-gene index to reflect the likelihood that a patient’s tumour would recur, signified by detectable levels of prostate-specific antigen (PSA) after the gland had been remove, or spread.
To validate the usefulness of the index, they used it to analyse tissue samples from a different group of almost 300 patients who had their prostates removed in 1996 and 1997, comparing the index with currently used prognostic factors – such as PSA levels, physical examination, and a tumour’s microscopic appearance – to see how accurately each predicted the actual incidence of tumour recurrence or metastasis during the 10 years after surgery. The expression-based index proved to be the most accurate method. Among those it designated as high-risk, the actual incidence of tumor recurrence was 47 percent and of metastasis, 14 percent. Among those classified as intermediate risk, actual recurrence was 22 percent, and metastasis occurred in 2 percent. No recurrence or metastasis were seen in patients classified as low-risk by the gene-expression index.
To get a sense of whether the index could help determine risk at the time of diagnosis, the researchers used it to assess pre-surgical needle biopsy samples from 79 patients in the validation group. The risk assignment based on biopsy results closely matched the assessment based on surgically removed tissue, and the prognostic ability of the index was better than that of other pathological information available at the time a biopsy was taken. Because the current report is based on study of patients treated at a single institution, the authors note, it requires confirmation in larger, multi-institutional studies.
‘A more accurate prognosis at the time of diagnosis could give patients and their physicians much more confidence in choosing a definitive therapy or pursuing active surveillance for those at low risk, which could reduce over-treatment, a critical issue in disease management,’ says lead author Wu, an associate professor of Pathology at Harvard Medical School. McDougal is the the Kerr Professor of Urology, at HMS.
Massachusetts General Hospital
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Researchers at the University of North Carolina have discovered that transcription factors regulating the levels of oxygen in the blood also play a role in the spread of the skin cancer melanoma.
A research team led by William Kim, MD, member of the UNC Lineberger Comprehensive Cancer Center, and graduate student and first author Sara Hanna, linked melanoma metastases to a pair of transcription factors known as HIF1 and HIF2.
Researchers found that HIF1 and HIF2 are over-expressed in melanoma tumours. In healthy cells, HIF1 and HIF2 assist in regulating hypoxia, the state caused by low levels of oxygen in the blood. Hypoxia has been linked to metastases in several solid tumours, and the UNC team has found that it promotes the spread of melanoma from the skin to other sites in the body through the lymphatic system.
Patients who are diagnosed with early stage melanomas have a high rate of survival, but the prognosis worsens significantly once the tumours spread to other sites throughout the body. Using in vitro systems and mouse models, researchers suppressed the expression of HIF1 and HIF2 in the melanoma tumours. While the inactivation of the transcription factors did not reduce the growth of the initial tumours, it did reduce the rate at which the melanoma spread to other sites in the body.
Both HIF1 and HIF2 independently activate the protein kinase SRC using different signalling pathways. The SRC protein has been linked to several different cancers, and the identification of its role in melanoma suggests that existing therapies targeting SRC may prove to be a viable target for therapies aimed at reducing the spread and ultimate lethality of the cancer.
‘What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,’ said Hanna.
University of North Carolina
For the first time, researchers have linked autism in a mouse model of the disease with abnormalities in specific regions of the animals’ chromosomes. The regions contain genes associated with aberrant brain development and activity.
‘These discoveries in mice may eventually pave the way towards understanding autism in human patients and devising new treatments,’ said co-senior author, Elliott H. Sherr, MD, PhD, a pediatric neurologist at UCSF Benioff Children’s Hospital and professor of neurology at UC San Francisco (UCSF).
The scientists bred a group of normal mice with a line of genetically modified mice that exhibit behaviours which are the mouse equivalent of autism. The 400 descendants of that crossbreeding, explained Sherr, ‘had a random assortment of genetics – some normal and healthy, some aberrant.’
The scientists exhaustively observed and recorded the behaviour of each descendant mouse. Since each animal’s genetic makeup was already known, the researchers were able to pinpoint associations between specific autistic behaviours and specific chromosomal regions.
‘This allowed us to say which regions we think contain the genes that contribute to which behaviour,’ said Sherr.
Sherr noted that those regions ‘contain genes that are already known to cause autism in humans, or are involved in brain development in such a way that makes it likely that they can cause autism.’
To test for autistic behaviour, the mice were put in the middle chamber of an enclosure with three chambers. In the chamber on one side was another mouse; in the other, an inanimate object. ‘Mice are social animals, so a normal mouse would spend much more time in the chamber with the other mouse,’ said Sherr. ‘An autistic mouse would spend more time with the object, or equal time with the object and the other mouse, because it didn’t care.’
The researchers also observed what the mice did when they were in a chamber together. ‘A healthy mouse will spend a lot of time sniffing or interacting with the other mouse, while an autistic mouse will roam around the chamber ignoring the other mouse as if it was inanimate,’ said Sherr.
The research will have a number of potential benefits, he said, particularly once researchers pinpoint the exact locations of the genes on the chromosomes. ‘Having the genes means that you can begin to pick apart the connection between the genes and the actual behaviour, and look at how the mutation on a gene might result in aberrant behaviour. Having an animal model means that you can look at the anatomy in a more careful way, study the cells in a tissue culture dish and manipulate them in other ways.’
Scientists will also be able to test the effects of exposure to toxins and other substances on the development of autism, he said.
Eventually, said Sherr, ‘Having an animal model will let us test potential drugs to treat autism.’
University of California – San Francisco
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The identification of potentially targetable kinase mutations has been an exciting advancement in lung cancer treatment. Although the mutations driving many lung carcinomas remain unknown, approximately 50 percent of lung adenocarcinoma cases harbour KRAS mutation, EGFR mutation, or ALK translocation, and an additional 5 percent or so have been shown to have mutations involving BRAF, PIK3CA, HER2, MET, MEK1, NRAS, and AKT. In the vast majority, these driver mutations are mutually exclusive. But in a recent study researchers have found that tumours with ALK rearrangements can harbour additional mutations.
Researchers looked at 25 cases of pulmonary adenocarcinoma surgically treated at Mayo Clinic between 1999 and 2007 with ALK gene rearrangement, confirmed by break-apart fluorescent in situ hybridisation (FISH) and immunohistochemistry (IHC). Using the DNA extracted from formalin-fixed paraffin-embedded tumour samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, with positive results confirmed by sequencing.
They found additional mutations in 5 of 25 (20 percent) of ALK positive cases. Four of these were point mutation in the MET gene that are of unknown clinical significance, since they may represent germline polymorphisms. However, one case had an EGFR mutation, further supporting that EGFR mutations can be present in ALK rearranged tumours, although it is rare.
‘Much is yet to be learned about treatment of patients with both ALK rearrangement and EGFR mutation,’ the authors report. ‘Although some of these patients have had a good response to the EGFR inhibitors erlotinib and gefitinib, one patient reportedly showed resistance to erlotinib. Further research is needed to determine if patients with coexisting EGFR mutation and ALK gene rearrangement may have altered response to EGFR or ALK inhibitors. This will be important to determine whether these drugs should be used in a synchronous or sequential fashion to achieve maximum benefit.’
EurekAlert
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Scientists from The University of Manchester have identified 14 new genes which could have important consequences for future treatments of childhood arthritis.
Scientists Dr Anne Hinks, Dr Joanna Cobb and Professor Wendy Thomson, from the University’s Arthritis Research UK Epidemiology Unit looked at DNA extracted from blood and saliva samples of 2,000 children with childhood arthritis and compared these to healthy people.
Principal Investigator Professor Thomson, who also leads the Inflammatory Arthritis in Children theme at the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, said: ‘This study brought together an international group of scientists from around the world and is the largest investigation into the genetics of childhood arthritis to date.’
Childhood arthritis affects one in 1,000 in the UK. It is caused by a combination of genetic and environmental risk factors, however until recently very little was known about the genes that are important in developing this disease – only three were previously known.
Dr Hinks, joint lead author of the study, said the findings were a significant breakthrough for understanding more about the biology of the disease and this might help identify novel therapies for the disease. ‘Childhood arthritis, also known as juvenile idiopathic arthritis (JIA), is a specific type of arthritis quite separate from types found in adults and there’s been only a limited amount of research into this area in the past,’ she said. ‘This study set out to look for specific risk factors. To identify these 14 genetic risk factors is quite a big breakthrough. It will help us to understand what’s causing the condition, how it progresses and then to potentially develop new therapies.’
The study may help to predict which children need specific treatment earlier and allow health workers to better control their pain management, quality of life and long-term outcome. Currently 30 per cent of children with the disease continue to suffer from arthritis in adulthood.
Dr Cobb, joint lead author, added: ‘There are lots of different forms of childhood arthritis so identifying the markers will help us understand a little bit more about the disease process. It will also help to categorise children with JIA into sub-types dependent on which genes they have and allow us to determine the best course of treatment.’
Manchester University
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Researchers from Huntsman Cancer Institute (HCI) at the University of Utah have developed a novel and powerful technique to identify the targets for a group of enzymes called RNA cytosine methyltransferases (RMTs) in human RNA. They applied their technique to a particular RMT, NSUN2, which has been implicated in mental retardation and cancers in humans, finding and validating many previously unknown RMT targets—an indication of the technique’s power.
‘Although RMTs have been known for many years, virtually nothing is known about the majority of these enzymes in humans,’ said Bradley R. Cairns, co-author of the study and Senior Director of Basic Science at HCI. ‘This new technique will now allow the very rapid identification of the direct target RNAs for each human RMT, and we are excited about conducting that work.’
Within all living cells, RNA acts as a critical intermediate in transmitting genetic information from DNA—RNA is made from DNA and then used to encode proteins called enzymes that control cell functions. A process called cytosine methylation attaches methyl molecules to cytosine bases in DNA and RNA molecules. RMTs act as catalysts to allow methylation at particular locations in RNA molecules. Methylation can regulate the flow of genetic information (from RNA to protein production) in cells, and it can change the way RNA interacts with proteins.
RNA methylation is currently poorly understood, partly because of limitations in the technique currently used to identify which RNA molecules and cytosine bases are RMT targets. As each cell contains thousands of different types of RNA molecules, often with only a small percentage being targets for a specific RMT, the first step in a study of RNA methylation is to sort out and concentrate the precise target RNA molecules for a particular RMT, in a process called enrichment.
The work involved a novel enrichment method, which applied a special ‘chemical cross-linker’ to physically join the RMT to an RNA that it is trying to methylate, said Vahid Khoddami, the study’s co-author and a member of the Cairns Lab. ‘Our new technique takes advantage of the mechanism of the enzyme. The drug/crosslinker we used looks like cytosine, so it is incorporated in place of the cytosine in the RNA. The RMT tries to methylate this drug— thinking it is a normal target cytosine—but instead becomes crosslinked to the RNA, defining the precise location of the intended methylation. As our reaction-based method requires that the enzyme both bind the RNA and commit to the act of methylation, it greatly increases our identification of true positives,’ said Khoddami.
‘This technique gives us 200-fold enrichment, when two-fold enrichment has been considered a great result in the past,’ said Khoddami. ‘In fact, for some RNA types, the enrichment is more than 700-fold.’
After the enrichment process, high-throughput gene sequencing is used to analyse the RNA samples obtained.
‘Our enrichment results were fantastic by themselves, but in the sequencing process we made another important discovery,’ Khoddami said. ‘We found that after sequencing, the target cytosine in the modified RNA instead appeared as an alternative molecule, guanosine, more than 50% of the time. After sequencing, you can look for these cytosine to guanosine transversions and know you have the precise target—in a single experiment.’
According to Khoddami, ten cytosine RMTs are known in humans, and only two of them have been partially characterised. ‘None of the other eight have been studied in the laboratory,’ he explained, ‘although some of them have been shown to have connections to cancer, infertility, and particular genetic disorders in humans.
‘These diseases have been puzzling because previously we did not have the tools to analyse the RNA. Now we have beautiful tools,’ said Khoddami.
Huntsman Cancer Institute
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Possible predictive biomarker for identifying patients who may respond to autophagy inhibitors
, /in E-News /by 3wmediaAutophagy, the process by which cells that are starved for food resort to chewing up their own damaged proteins and membranes and recycling them into fuel, has emerged as a key pathway that cancer cells use to survive in the face of assault by chemotherapy and radiation. Using drugs to shut down that survival mechanism shows great promise, especially when combined with targeted agents and standard chemotherapies, but until recently, it has been unclear which patients’ cancers would respond to that combination therapy.
A team led by researchers from the Perelman School of Medicine at the University of Pennsylvania will present findings showing that colon cancer and lung cancer cell lines which expressed a gene known as helicase-like transcription factor (HLTF) tended to be impervious to the effects of the autophagy inhibition drug hydroxycholoroquine (HCQ). Cells where HLTF is silent, however, appeared to be sensitive to HCQ, which led the team to test HLTF expression in a group of colon cancer patients treated with two chemotherapies (the FOLFOX regimen plus bevacizumab) and HCQ. They found that low expression of HLTF predicted those who would respond to the combination therapy.
Since previous studies have shown that HLTF gene silencing is common in 20 to 40 percent of many epithelial cancers, the Penn team is hopeful their findings could lead to the development of a predictive biomarker to identify patients with other cancers who are most likely to respond to drug therapies involving autophagy inhibitors. Penn Medicine
Scientists find that prostate cancer patients with BRCA2 mutations require urgent treatment
, /in E-News /by 3wmediaMen who develop prostate cancer after inheriting a faulty gene need immediate surgery or radiotherapy rather than being placed under surveillance, as their disease is more aggressive than other types, a new study has found.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust found prostate cancers spread more quickly and were more often fatal in men who had inherited a faulty BRCA2 gene than in men without the faulty gene.
The research, funded by the Ronald and Rita McAulay Foundation and Cancer Research UK, could challenge current NHS guidelines for prostate cancer, under which BRCA2 mutation carriers are offered the same treatment options as non-carriers.
It is often difficult to tell at diagnosis whether prostate cancer will be life-threatening or not, and while treatment options for early-stage disease include surgery and radiotherapy, many men instead receive active surveillance to see if the disease starts to progress.
The new study is the largest to compare prostate cancer patients with and without BRCA mutations, in order to tell whether gene testing should help to direct management options.
Senior author Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Consultant in Clinical Oncology at The Royal Marsden, said: ‘It is clear from our study that prostate cancers linked to inheritance of the BRCA2 cancer gene are more deadly than other types. It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.’
The team from the ICR and The Royal Marsden, with collaborators across the UK, examined the medical records of 61 BRCA2-mutation carriers, 18 BRCA1-mutation carriers and 1,940 non-carriers.
They found BRCA1/2 mutation carriers were more likely to be diagnosed with advanced stage prostate cancers (37 per cent versus 28 per cent) or cancer that had already spread (18 per cent versus nine per cent) than non-carriers. Among those whose cancers had not spread out of the prostate at diagnosis, within five years more carriers than non-carriers had metastatic disease (23 per cent versus seven per cent).
Patients with BRCA2-mutations were also significantly less likely to survive the cancer, living an average of 6.5 years compared with 12.9 years for non-carriers. The team concluded that a BRCA2 test could be used in combination with other factors as a prognostic test. Men with a BRCA1 mutation also had a shorter average survival time of 10.5 years, but there was not a statistically significant difference with non-carriers. ICR
Scientists learn what makes nerve cells so strong
, /in E-News /by 3wmediaHow do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?
Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.
‘Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,’ says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.
Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.
‘But when we tried to figure out what the modification was, we didn’t have the tools,’ he said.
Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. ‘It was like a detective story with many possibilities that had to be ruled out one by one,’ she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.
She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.
The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the ‘thorough and elegant work’ that Song brought to it, he said. ‘It’s such a radical finding that we needed to show all the key steps along the way.’
The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of ageing and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration. University of Illinois at Chicago College of Medicine
Scientists identify a potential target to reduce the progression of metastases, the main cause of death for breast cancer patients
, /in E-News /by 3wmediaMontréal scientists identified the DOCK1 protein as a potential target to reduce the progression of metastases in patients suffering from breast cancer, the most common type of cancer in women.
Dr. Côté’s laboratory is interested in metastasis, which is the spread of cancer from an organ (or part of an organ) to another. Nearly 90 per cent of cancer patient deaths are attributable to metastasis, thus explaining the importance of understanding the underlying cellular and molecular mechanisms of this harmful process.
‘Despite important breakthroughs in breast cancer treatment, few mechanisms are known to explain the spread of metastases,’ says Dr. Côté, Director of the Cytoskeletal Organization and Cell Migration research unit at the IRCM. ‘We are looking to identify the proteins that regulate the metastatic process so that new agents can be developed and combined with current treatments.’
Two major breast cancer subtypes, HER2+ and Basal, have a tendency to be metastatic and recurrent, and are ultimately associated to a poor survival rate. Research at the IRCM was conducted on the HER2+ type (Human Epidermal growth factor Receptor 2), which represents approximately 25 per cent of breast cancer cases. HER2 positive tumours tend to develop and spread more quickly than other types of tumours.
‘By studying a genetic mouse model with HER2+ breast cancer, we identified the protein DOCK1 as an important regulator of metastasis,’ explains Mélanie Laurin, doctoral student in Dr. Côté’s laboratory and first author of the study. ‘When we eliminated this protein in mice, our results showed a significant decrease in lung metastases. We also discovered that the DOCK1 protein contributes to the growth of tumours.’
‘To show the correlation between the expression of DOCK1 and breast cancer prognosis, we performed an analysis of several databases of patient genic,’ adds Dr. Benjamin Haibe-Kains, researcher at the IRCM who collaborated with Dr. Côté’s team. ‘We did indeed discover that high levels of DOCK1 in HER2+ or Basal breast cancer patients are associated with a lower prognosis, or recurrence of the disease.’
‘Our work defined a new molecule required for the progression of breast cancer to the metastatic stage and allowed us to identify new markers that could become potential targets to stop the progression of metastases,’ concludes Dr. Côté. ‘We also showed that a chemical inhibitor of the DOCK1 protein, developed by Dr. Yoshinori Fukui, our collaborator in Japan, can stop the migration of cancerous cells. These results could eventually lead to the development of drugs that would limit the progression of metastatic breast cancer and could thereby improve patient prognosis.’ Institut de recherches cliniques de Montréal
Gene-expression signature may signify risk for recurrence, metastasis in prostate cancer
, /in E-News /by 3wmediaA team led by Massachusetts General Hospital (MGH) researchers has identified a genetic signature that appears to reflect the risk of tumour recurrence or spread in men surgically treated for prostate cancer. If confirmed in future studies, this finding not only may help determine which patients require additional treatment after the cancerous gland has been removed, it also may help address the most challenging problem in prostate cancer treatment – distinguishing tumours that require aggressive treatment from those that can safely be monitored.
‘Radical prostatectomy is the standard of care for men whose cancer is advanced but confined to the prostate gland, but we know that the factors we use to determine which patients need radiation therapy after surgery are inadequate,’ says W. Scott McDougal, MD, of the MGH Department of Urology, corresponding author of the report. ‘The treatments available to our patients can have significant impact on their quality of life, so a better way to know which patients with localised cancer need additional therapy after surgery and which require no additional treatment is a significant unmet need.’
Gene expression signatures indicating patient prognosis and sometimes the most appropriate treatment have been incorporated into care for breast cancer and other tumours. Studies looking for such markers in prostate cancer have had variable results, and their potential usefulness to guide treatment has not been determined. For the current study the research team – led by Chin-Lee Wu, MD, PhD, of the MGH Department of Pathology – examined samples of malignant tissue from around 200 prostate cancer patients who had radical prostatectomies at the MGH between 1993 and 1995, analyzing the expression patterns of more than 1,500 genes associated with prostate cancer in earlier studies. With the results of that analysis, they developed a 32-gene index to reflect the likelihood that a patient’s tumour would recur, signified by detectable levels of prostate-specific antigen (PSA) after the gland had been remove, or spread.
To validate the usefulness of the index, they used it to analyse tissue samples from a different group of almost 300 patients who had their prostates removed in 1996 and 1997, comparing the index with currently used prognostic factors – such as PSA levels, physical examination, and a tumour’s microscopic appearance – to see how accurately each predicted the actual incidence of tumour recurrence or metastasis during the 10 years after surgery. The expression-based index proved to be the most accurate method. Among those it designated as high-risk, the actual incidence of tumor recurrence was 47 percent and of metastasis, 14 percent. Among those classified as intermediate risk, actual recurrence was 22 percent, and metastasis occurred in 2 percent. No recurrence or metastasis were seen in patients classified as low-risk by the gene-expression index.
To get a sense of whether the index could help determine risk at the time of diagnosis, the researchers used it to assess pre-surgical needle biopsy samples from 79 patients in the validation group. The risk assignment based on biopsy results closely matched the assessment based on surgically removed tissue, and the prognostic ability of the index was better than that of other pathological information available at the time a biopsy was taken. Because the current report is based on study of patients treated at a single institution, the authors note, it requires confirmation in larger, multi-institutional studies.
‘A more accurate prognosis at the time of diagnosis could give patients and their physicians much more confidence in choosing a definitive therapy or pursuing active surveillance for those at low risk, which could reduce over-treatment, a critical issue in disease management,’ says lead author Wu, an associate professor of Pathology at Harvard Medical School. McDougal is the the Kerr Professor of Urology, at HMS. Massachusetts General Hospital
Transcription factors regulating blood oxygen linked to melanoma metastases
, /in E-News /by 3wmediaResearchers at the University of North Carolina have discovered that transcription factors regulating the levels of oxygen in the blood also play a role in the spread of the skin cancer melanoma.
A research team led by William Kim, MD, member of the UNC Lineberger Comprehensive Cancer Center, and graduate student and first author Sara Hanna, linked melanoma metastases to a pair of transcription factors known as HIF1 and HIF2.
Researchers found that HIF1 and HIF2 are over-expressed in melanoma tumours. In healthy cells, HIF1 and HIF2 assist in regulating hypoxia, the state caused by low levels of oxygen in the blood. Hypoxia has been linked to metastases in several solid tumours, and the UNC team has found that it promotes the spread of melanoma from the skin to other sites in the body through the lymphatic system.
Patients who are diagnosed with early stage melanomas have a high rate of survival, but the prognosis worsens significantly once the tumours spread to other sites throughout the body. Using in vitro systems and mouse models, researchers suppressed the expression of HIF1 and HIF2 in the melanoma tumours. While the inactivation of the transcription factors did not reduce the growth of the initial tumours, it did reduce the rate at which the melanoma spread to other sites in the body.
Both HIF1 and HIF2 independently activate the protein kinase SRC using different signalling pathways. The SRC protein has been linked to several different cancers, and the identification of its role in melanoma suggests that existing therapies targeting SRC may prove to be a viable target for therapies aimed at reducing the spread and ultimate lethality of the cancer.
‘What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,’ said Hanna. University of North Carolina
Autism model in mice linked with genetics
, /in E-News /by 3wmediaFor the first time, researchers have linked autism in a mouse model of the disease with abnormalities in specific regions of the animals’ chromosomes. The regions contain genes associated with aberrant brain development and activity.
‘These discoveries in mice may eventually pave the way towards understanding autism in human patients and devising new treatments,’ said co-senior author, Elliott H. Sherr, MD, PhD, a pediatric neurologist at UCSF Benioff Children’s Hospital and professor of neurology at UC San Francisco (UCSF).
The scientists bred a group of normal mice with a line of genetically modified mice that exhibit behaviours which are the mouse equivalent of autism. The 400 descendants of that crossbreeding, explained Sherr, ‘had a random assortment of genetics – some normal and healthy, some aberrant.’
The scientists exhaustively observed and recorded the behaviour of each descendant mouse. Since each animal’s genetic makeup was already known, the researchers were able to pinpoint associations between specific autistic behaviours and specific chromosomal regions.
‘This allowed us to say which regions we think contain the genes that contribute to which behaviour,’ said Sherr.
Sherr noted that those regions ‘contain genes that are already known to cause autism in humans, or are involved in brain development in such a way that makes it likely that they can cause autism.’
To test for autistic behaviour, the mice were put in the middle chamber of an enclosure with three chambers. In the chamber on one side was another mouse; in the other, an inanimate object. ‘Mice are social animals, so a normal mouse would spend much more time in the chamber with the other mouse,’ said Sherr. ‘An autistic mouse would spend more time with the object, or equal time with the object and the other mouse, because it didn’t care.’
The researchers also observed what the mice did when they were in a chamber together. ‘A healthy mouse will spend a lot of time sniffing or interacting with the other mouse, while an autistic mouse will roam around the chamber ignoring the other mouse as if it was inanimate,’ said Sherr.
The research will have a number of potential benefits, he said, particularly once researchers pinpoint the exact locations of the genes on the chromosomes. ‘Having the genes means that you can begin to pick apart the connection between the genes and the actual behaviour, and look at how the mutation on a gene might result in aberrant behaviour. Having an animal model means that you can look at the anatomy in a more careful way, study the cells in a tissue culture dish and manipulate them in other ways.’
Scientists will also be able to test the effects of exposure to toxins and other substances on the development of autism, he said.
Eventually, said Sherr, ‘Having an animal model will let us test potential drugs to treat autism.’ University of California – San Francisco
Tumours with ALK rearrangements can harbour more mutations
, /in E-News /by 3wmediaThe identification of potentially targetable kinase mutations has been an exciting advancement in lung cancer treatment. Although the mutations driving many lung carcinomas remain unknown, approximately 50 percent of lung adenocarcinoma cases harbour KRAS mutation, EGFR mutation, or ALK translocation, and an additional 5 percent or so have been shown to have mutations involving BRAF, PIK3CA, HER2, MET, MEK1, NRAS, and AKT. In the vast majority, these driver mutations are mutually exclusive. But in a recent study researchers have found that tumours with ALK rearrangements can harbour additional mutations.
Researchers looked at 25 cases of pulmonary adenocarcinoma surgically treated at Mayo Clinic between 1999 and 2007 with ALK gene rearrangement, confirmed by break-apart fluorescent in situ hybridisation (FISH) and immunohistochemistry (IHC). Using the DNA extracted from formalin-fixed paraffin-embedded tumour samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, with positive results confirmed by sequencing.
They found additional mutations in 5 of 25 (20 percent) of ALK positive cases. Four of these were point mutation in the MET gene that are of unknown clinical significance, since they may represent germline polymorphisms. However, one case had an EGFR mutation, further supporting that EGFR mutations can be present in ALK rearranged tumours, although it is rare.
‘Much is yet to be learned about treatment of patients with both ALK rearrangement and EGFR mutation,’ the authors report. ‘Although some of these patients have had a good response to the EGFR inhibitors erlotinib and gefitinib, one patient reportedly showed resistance to erlotinib. Further research is needed to determine if patients with coexisting EGFR mutation and ALK gene rearrangement may have altered response to EGFR or ALK inhibitors. This will be important to determine whether these drugs should be used in a synchronous or sequential fashion to achieve maximum benefit.’ EurekAlert
Discovery of new genes will help childhood arthritis treatment
, /in E-News /by 3wmediaScientists from The University of Manchester have identified 14 new genes which could have important consequences for future treatments of childhood arthritis.
Scientists Dr Anne Hinks, Dr Joanna Cobb and Professor Wendy Thomson, from the University’s Arthritis Research UK Epidemiology Unit looked at DNA extracted from blood and saliva samples of 2,000 children with childhood arthritis and compared these to healthy people.
Principal Investigator Professor Thomson, who also leads the Inflammatory Arthritis in Children theme at the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, said: ‘This study brought together an international group of scientists from around the world and is the largest investigation into the genetics of childhood arthritis to date.’
Childhood arthritis affects one in 1,000 in the UK. It is caused by a combination of genetic and environmental risk factors, however until recently very little was known about the genes that are important in developing this disease – only three were previously known.
Dr Hinks, joint lead author of the study, said the findings were a significant breakthrough for understanding more about the biology of the disease and this might help identify novel therapies for the disease. ‘Childhood arthritis, also known as juvenile idiopathic arthritis (JIA), is a specific type of arthritis quite separate from types found in adults and there’s been only a limited amount of research into this area in the past,’ she said. ‘This study set out to look for specific risk factors. To identify these 14 genetic risk factors is quite a big breakthrough. It will help us to understand what’s causing the condition, how it progresses and then to potentially develop new therapies.’
The study may help to predict which children need specific treatment earlier and allow health workers to better control their pain management, quality of life and long-term outcome. Currently 30 per cent of children with the disease continue to suffer from arthritis in adulthood.
Dr Cobb, joint lead author, added: ‘There are lots of different forms of childhood arthritis so identifying the markers will help us understand a little bit more about the disease process. It will also help to categorise children with JIA into sub-types dependent on which genes they have and allow us to determine the best course of treatment.’ Manchester University
A powerful, more accurate, genetic analysis tool
, /in E-News /by 3wmediaResearchers from Huntsman Cancer Institute (HCI) at the University of Utah have developed a novel and powerful technique to identify the targets for a group of enzymes called RNA cytosine methyltransferases (RMTs) in human RNA. They applied their technique to a particular RMT, NSUN2, which has been implicated in mental retardation and cancers in humans, finding and validating many previously unknown RMT targets—an indication of the technique’s power.
‘Although RMTs have been known for many years, virtually nothing is known about the majority of these enzymes in humans,’ said Bradley R. Cairns, co-author of the study and Senior Director of Basic Science at HCI. ‘This new technique will now allow the very rapid identification of the direct target RNAs for each human RMT, and we are excited about conducting that work.’
Within all living cells, RNA acts as a critical intermediate in transmitting genetic information from DNA—RNA is made from DNA and then used to encode proteins called enzymes that control cell functions. A process called cytosine methylation attaches methyl molecules to cytosine bases in DNA and RNA molecules. RMTs act as catalysts to allow methylation at particular locations in RNA molecules. Methylation can regulate the flow of genetic information (from RNA to protein production) in cells, and it can change the way RNA interacts with proteins.
RNA methylation is currently poorly understood, partly because of limitations in the technique currently used to identify which RNA molecules and cytosine bases are RMT targets. As each cell contains thousands of different types of RNA molecules, often with only a small percentage being targets for a specific RMT, the first step in a study of RNA methylation is to sort out and concentrate the precise target RNA molecules for a particular RMT, in a process called enrichment.
The work involved a novel enrichment method, which applied a special ‘chemical cross-linker’ to physically join the RMT to an RNA that it is trying to methylate, said Vahid Khoddami, the study’s co-author and a member of the Cairns Lab. ‘Our new technique takes advantage of the mechanism of the enzyme. The drug/crosslinker we used looks like cytosine, so it is incorporated in place of the cytosine in the RNA. The RMT tries to methylate this drug— thinking it is a normal target cytosine—but instead becomes crosslinked to the RNA, defining the precise location of the intended methylation. As our reaction-based method requires that the enzyme both bind the RNA and commit to the act of methylation, it greatly increases our identification of true positives,’ said Khoddami.
‘This technique gives us 200-fold enrichment, when two-fold enrichment has been considered a great result in the past,’ said Khoddami. ‘In fact, for some RNA types, the enrichment is more than 700-fold.’
After the enrichment process, high-throughput gene sequencing is used to analyse the RNA samples obtained.
‘Our enrichment results were fantastic by themselves, but in the sequencing process we made another important discovery,’ Khoddami said. ‘We found that after sequencing, the target cytosine in the modified RNA instead appeared as an alternative molecule, guanosine, more than 50% of the time. After sequencing, you can look for these cytosine to guanosine transversions and know you have the precise target—in a single experiment.’
According to Khoddami, ten cytosine RMTs are known in humans, and only two of them have been partially characterised. ‘None of the other eight have been studied in the laboratory,’ he explained, ‘although some of them have been shown to have connections to cancer, infertility, and particular genetic disorders in humans.
‘These diseases have been puzzling because previously we did not have the tools to analyse the RNA. Now we have beautiful tools,’ said Khoddami. Huntsman Cancer Institute