As well as announcing the launch of a new global diagnostics business unit at Medica last month, Avantor Performance Materials also announced the creation of a new diagnostics product brand: BeneSpheradiagnostics solutions, which will include a broad and expanding range of reliable, affordable diagnostic technologies and easy-to-use products, focused on three segments: in vitro reagents and instruments for clinical chemistry, immunology, haematology, microbiology, histology and cytology and genetic testing; instruments for in vivo diagnostics, currently sold under the Diagnova name in India; and consumables and instruments for life sciences research in academia, government and pharmaceutical labs, also currently sold under the Diagnova name in India.
At the moment Avantor’s performance diagnostics solutions include J.T.Baker clinical reagents, which have provided world-class solutions for haematology and histology applications for over 30 years, and BeneSphera diagnostics solutions built on Diagnova, the company’s Indian-based diagnostics business with a 25-year legacy offering products, engineering and application support for immunology, clinical chemistry, haematology, microbiology, endoscopy and life science needs.
Avantor’s plans are to grow the new global diagnostics business through organic development and the strategic acquisition of R&D-backed manufacturing and distribution companies in targeted locations to support a strong global brand and supply chain.
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Hereditary hearing loss is the most common sensory disorder in humans. A German research team led by Ingo Kurth from the Institute of Human Genetics at the University Hospital Jena, Germany, used a number of different methods, including Roche’s NimbleGen Custom Sequence Capture 385K array to identify the gene mutated in the disease locus of the X-chromosome of a Spanish family with hereditary hearing loss [1].
Targeted enrichment was performed by the German Service Provider ATLAS Biolabs GmbH. In particular, the DNA of two affected males was subjected to target enrichment. Subsequent sequencing analysis at the Cologne Center for Genomics (CCG) resulted in the identification of a total of 3858 and 3443 X-chromosomal variants for each of these two individuals. Furthermore, a nonsense mutation in the small muscle protein, X-linked (SMPX) of the affected individuals had been detected. Nonsense mutations are significant, because they are point mutations in a sequence of DNA that cause a premature stop codon, or a nonsense codon in the transcribed mRNA, resulting in a truncated, incomplete, and usually nonfunctional protein. Based on their findings, the authors propose that long-term maintenance of mechanically stressed inner ear cells critically depends on SMPX function.
The NimbleGen Sequence Capture technology is a sophisticated process for the parallel enrichment of selected genomic regions from complex human genomic DNA. Sequence Capture allows enrichment of target regions in a single experiment, replacing the need to perform numerous PCR reactions. The efficiencies of parallel enrichment are an ideal complement for cost-effective, high throughput next-generation sequencing.
[1] Huebner et al. AmericanJournal of Human Genetics, Vol. 88: 621-627, May 13, 2011.
www.roche.com
For life science research only. Not for use in diagnostic procedures. NIMBLEGEN and SEQCAP are trademarks of Roche. Other brands or product names are trademarks of their respective holders.
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OHSU Knight Cancer Institute study results suggest that more patients than initially thought could potentially be treated with a new class of drugs, PARP inhibitors
A constellation of defective proteins suspected in causing a malfunction in the body’s ability to repair its own DNA could be the link scientists need to prove a new class of drugs will be effective in treating a broad range of ovarian cancer patients, an Oregon Health & Science University Knight Cancer Institute study found.
These research results have prompted additional exploration into whether the patient population included in clinical trials for drugs that target the enzyme poly ADP ribose polymerase (PARP) should be expanded. Several forms of cancer are more dependent on PARP for their growth than regular cells, which means that targeting these enzymes when they go haywire is a potentially effective way to treat ovarian cancer. Currently PARP inhibitors are being tested with patients who have two types of malfunctioning proteins, BRCA1 or BRCA2. But, the OHSU Knight Cancer Institute study of additional proteins, beyond BRCA proteins, suggests that they too are playing a role in driving ovarian cancer.
Tapping into the potential of PARP inhibitors could change the dynamics of ovarian cancer treatment. There has not been a substantial increase in treatment options for ovarian cancer in the past two decades, said Tanja Pejovic, M.D., Ph.D., gynaecologic oncologist at the OHSU Knight Cancer Institute. Pejovic, who led the study of these additional defective proteins, added that the results provide evidence that further research into the role of multiple proteins is warranted.
Only about 10 to 15 percent of women with ovarian cancer have BRCA 1 or BRCA 2 mutations. Pejovic’s study of 186 patients with nonhereditary cancer found that 41 percent who had an early recurrence of the disease also had abnormal levels of the other proteins tracked. In contrast, only 19.5 percent of patients who hadn’t yet had a recurrence of the disease in three years had abnormal levels of these proteins.
‘If we are able to identify the proteins that differentiate these patients at risk for early recurrence, this would open up a new direction in ovarian cancer treatment,’ Pejovic said.
The study — which was supported by the Sherie Hildreth Ovarian Cancer (SHOC) Foundation — focused on proteins that are supposed to assist cells in repairing harmful breaks in DNA strands, a process called homologous recombination (HR). The malfunctioning of HR is not well understood in ovarian cancers where there is no family history of the disease. However, there is evidence that these proteins influence a patient’s ability to respond to drugs and their survival rates after treatment.
Oregon Health & Science University
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The Center for Human Genetics and Laboratory Medicine Dr. Klein and Dr. Rost, and IMGM Laboratories, both located in Martinsried Germany, reported using the Roche GS Junior Benchtop System to sequence clinically relevant exons and identify genomic variations in solid tumors treated with an antibody-based medicine. This sequencing approach, easily expanded to complete coding regions, has great potential for personalized medicine, where individual treatment success is largely dependent on the mutation status of tumor genes. The high-quality long reads produced by the GS Junior System enable accurate and comprehensive analysis of the full range of genetic variations.
Personalized tumor treatments, such as monoclonal antibodies (mAb) that specifically target tumor-inducing proteins, require a precise and comprehensive assessment of an individual’s genetic profile for the targeted genes. Current therapies target only a limited region of the relevant tumor genes, whereas the next-generation GS Junior Sequencing System enables cost effective and comprehensive profiling of all the relevant genes. In contrast, conventional capillary sequencing techniques often lack the sensitivity and cost effectiveness to detect tumor mutations occurring at less than 20% frequency.
“The future of personalized tumor treatment lies in this sequencing approach,” said Dr. Hanns-Georg Klein, MD, CEO of both IMGM and the Center for Human Genetics. “Through our research, we’ve found that it’s critical to ensure a comprehensive analysis of a tumor variant population, including known and novel mutations.”
These findings underscore the utility of Roche’s GS Junior System for investigating complex tumor samples. The long, accurate sequencing reads are ideal for identifying multiple tumor mutations that can include structural variations and rare somatic mutations.
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‘The overactive bladder syndrome has become an accepted way to simplify a complex array of symptoms and leads people to believe that an overactive bladder is an independent disease in itself. However, the truth is not as simple as this, as there are usually several factors at work explaining the symptoms. This is also one of the reasons why so called overactive bladder medications often do not bring the hoped result,’ says Kari Tikkinen, MD, PhD, from the HUCS Department of Urology.
The article on overactive bladder syndrome, which was co-written by Tikkinen, who currently holds a senior researcher post at the McMaster University in Canada, and Anssi Auvinen, Professor of Epidemiology from the University of Tampere, was recently published. For the article, the researchers systematically reviewed the studies on overactive bladder and the channels through which these studies have been funded.
The authors argue that the symptoms of an ‘overactive bladder’ ought to be studied individually and not as an ambiguous constellation of symptoms. This way the underlying causes of the symptoms can be better understood and more effective treatments can be developed.
The expression ‘overactive bladder’ was coined at an industry-sponsored symposium held in 1997. The following year, the FDA approved the first drug for the treatment of ‘symptoms of overactive bladder’, after which the pharmaceutical industry launched high-profile, worldwide promotional campaigns for drugs aimed at treatment of the syndrome.
According to the current definition, overactive bladder (OAB) syndrome is defined as the presence of urinary urgency with or without urgency incontinence, usually with increased daytime frequency and nocturia in the absence of infection or other obvious pathology.
‘The definition is vague and ambiguous because it includes unspecific terms, such as ‘usually’ and ‘with or without’, and the unclear expression ‘other obvious pathology’,’ Tikkinen says and continues, ‘For the pharmaceutical industry this definition is probably quite useful, as it is partly the reason why one medicine can be prescribed to a large number of patients.’
Research into overactive bladder has increased significantly over the past ten years and the pharmaceutical industry has invested heavily in it. ‘It has previously been shown that research funded by commercial actors often ends up unpublished if the results don’t serve the interests of the company,’ Tikkinen points out.
Tikkinen and Auvinen also bring to the fore that in many studies on prevalence of overactive bladder, very mild symptoms have been classified as abnormal.
‘More independent, non-commercially funded research on the subject is needed. There are, in the end, a huge number of people who suffer from urinary urgency and increased urinary frequency, and current treatments are not bringing sufficient relief,’ Tikkinen says.
EurekAlert
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After a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease.
A report on the discovery was led by investigators at the University of Michigan Health System and Johns Hopkins University School of Medicine. The research team found that men who inherit this mutation have a 10 to 20 times higher risk of developing prostate cancer.
While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.
‘It’s what we’ve been looking for over the past 20 years,’ adds William B. Isaacs, Ph.D., professor of urology and oncology at the Johns Hopkins University School of Medicine, the study’s other senior author. ‘It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results.’
For this study, the researchers collaborated with John Carpten, Ph.D., at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, who used the latest technology to sequence the DNA of more than 200 genes in a human chromosome region known as 17q21-22. Cooney, working with Ethan Lange, Ph.D., of the University of North Carolina on the U-M Prostate Cancer Genetics Project, was the first to identify 17q21-22 as a region of interest.
Researchers started with samples from the youngest patients with prostate cancer in 94 families who had participated in studies at U-M and Johns Hopkins. Each of those families had multiple cases of the disease among close relatives, such as between fathers and sons or among brothers.
Members of four different families were found to have the same mutation in the HOXB13 gene, which plays an important role in the development of the prostate during the foetal stage and its function later in life. The mutation was carried by all 18 men with prostate cancer in these four families.
The researchers collaborated with Jianfeng Xu, Ph.D., and Lilly Zheng, Ph.D., at Wake Forest University to look for the same HOXB13 gene mutation among 5,100 men who had been treated for prostate cancer at either Johns Hopkins or U-M. The mutation was found in 1.4 percent—or 72 of the men. It turned out that those men were much more likely to have at least one first-degree relative, a father or brother, who also had been diagnosed. The researchers also looked for the mutation in a control group of 1,400 men without prostate cancer, and only one of those men carried the mutation. In addition, the researchers studied men who were specifically enrolled in studies of early-onset or familial prostate cancer.
‘We found that the mutation was significantly more common in men with a family history and early diagnosis compared with men diagnosed later, after age 55, without a family history. The difference was 3.1 percent versus 0.62 percent, Cooney says.
University of Michigan Health System
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Continuing a series of groundbreaking discoveries begun in 2010 about the genetic causes of the third most common form of inherited muscular dystrophy, an international team of researchers led by a scientist at Fred Hutchinson Cancer Research Center has identified the genes and proteins that damage muscle cells, as well as the mechanisms that can cause the disease.
The discovery could lead to a biomarker-based test for diagnosing facioscapulohumeral muscular dystrophy (FSHD), and the findings have implications for developing future treatments as well as for cancer immunotherapies in general.
The work establishes a viable roadmap for how the expression of the DUX4 gene can cause FSHD. Whether this is the sole cause of FSHD is not known; however, the latest findings ‘are about as strong of evidence as you can get’ of the genetic link, said corresponding author Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division.
Tapscott and colleagues sought answers to the questions about what the DUX4 protein does both normally in the body and in the FSHD disease process. In the latest study, they identified that the DUX4 protein regulates many genes that are normally expressed in the male germ line but are abnormally expressed in FSHD muscle. Germ line cells are inherited from parents and passed down to their offspring.
‘This study is a significant step forward by solidifying that the DUX4 transcription factor causes this disease, while offering a number of viable mechanisms for why the muscle is damaged,’ Tapscott said. Transcription factors are tools that cells use to control gene expression. Genes that are ‘turned on’ in the body are ‘transcribed,’ or translated, into proteins.
Now that scientists know that targets for DUX4 are expressed in skeletal muscle, an antibody- or RNA-based test could be developed to diagnose FSHD by examining muscle tissue from a biopsy, Tapscott said. Such biomarker-based tests also could be used to determine how well new treatments are working to suppress FSHD.
The study also discovered that DUX4 regulates cancer/testis antigens. Cancer/testis antigens are encoded by genes that are normally expressed only in the human germ line, but are also abnormally expressed in various tumour types, including melanoma and carcinomas of the bladder, lung and liver.
‘This knowledge now gives us a way to manipulate the expression of cancer/ testis antigens, potentially opening the opportunity to use these antigens in a cancer vaccine,’ Tapscott said.
Fred Hutchinson Cancer Research Center
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Using two cell surface markers found to be highly expressed in breast cancer lymph node metastases, researchers at Moffitt Cancer Center, working with colleagues at other institutions, have developed targeted, fluorescent molecular imaging probes that can non-invasively detect breast cancer lymph node metastases. The new procedure could spare breast cancer patients invasive and unreliable sentinel lymph node (SLN) biopsies and surgery-associated negative side effects.
‘The majority of breast cancer patients, up to 74 percent, who undergo SLN biopsy are found to be negative for axillary nodal, or ALN, metastases,’ said corresponding author David L. Morse, Ph.D., an associate member at Moffitt whose research areas include experimental therapeutics and diagnostic imaging. ‘Determining the presence or absence of ALN metastasis is critical to breast cancer staging and prognosis. Because of the unreliability of the SLN biopsy and its potential for adverse effects, a non-invasive, more accurate method to assess lymph node involvement is needed.’
The authors note that the postoperative complications to the SLN biopsy can include lymphedema, seroma formation, sensory nerve injury and limitations in patient range of motion. In addition, biopsies fail to identify disease in axillary lymph nodes in five to 10 percent of patients.
In developing targeted molecular probes to identify breast cancer in axillary lymph nodes, the research team from Moffitt, the University of Arizona and University of Florida used two surface cell markers – CAIX and CAXII. CAIX is a cell surface marker known to be ‘highly and broadly expressed in breast cancer lymph node metastases’ and absent in normal tissues.
CAIX and CAXII are both integral plasma membrane proteins with large extracellular components that are accessible for binding of targeted imaging probes, explained Morse. In addition, several studies have shown that CAIX expression is associated with negative prognosis and resistance to chemo and radiation therapy for breast cancer. CAXII is a protein expressed in over 75 percent of axillary lymph node metastases.
The researchers subsequently developed their targeting agents by using monoclonal antibodies specific for binding CAIX and CAXII, both of which are known to promote tumour growth.
According to the researchers, a number of non-invasive optical imaging procedures for SLN evaluation have been investigated, but the approaches have lacked the ability to target tumour metastasis biomarkers.
‘These methods provide only anatomic maps and do not detect tumour cells present in lymph nodes,’ explained Morse. ‘Using mouse models of breast cancer metastasis and a novel, monoclonal anti-body-based molecular imaging agents, we developed a targeted, non-invasive method to detect ALN metastasis using fluorescence imaging.’
In addition to the imaging study with mice, the researchers also reported that the combination of CAIX and CAXII covered 100 percent of patient-donated samples used in their tissue microarray (TMA) study.
Moffitt Cancer Center
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Tilting the scales in an ongoing debate, University of Wisconsin-Madison researchers have found new evidence that human cytomegalovirus (HCMV) is associated with glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy.
The findings confirm what only a handful of scientists have found, but in a manner that University of Wisconsin School of Medicine and Public Health researchers believe enhances the scientific rigor of earlier studies.
The study hints for the first time that HCMV may work differently than other cancer-related viruses – possibly by affecting only tumour stem cells, self-renewing cells that keep the tumour growing. The new research may place HCMV in an expanding group of viruses associated with cancer.
‘As many as 15 to 20 percent of all human cancers are caused by viruses, and the number is growing,’ says HCMV expert Dr. Robert Kalejta, associate professor of oncology at the UW School of Medicine and Public Health (SMPH). ‘The viruses may not cause cancer on their own, but they play a critical role in the process.’
Among others, human papilloma virus (HPV) causes cervical cancer, Epstein-Barr virus (EBV) causes lymphoma and hepatitis C virus (HCV) causes liver cancer.
HCMV’s role in GBM has been debated, with many scientists and clinicians remaining skeptical. Oncologist Dr. Charles Cobbs of California Pacific Medical Center has been the main proponent of the theory that HCMV contributes to GBM.
Dr. John Kuo, assistant professor of neurological surgery and human oncology and a cancer stem cell scientist at the School of Medicine and Public Health, was one of the skeptical ones, but he says he’s now convinced that HCMV is associated with human GBM specimens.
Still, the association does not prove a causal relationship between HCMV and the development of GBM, he says.
‘This study may open up a new unexplored area of research for this incurable disease,’ says Kuo, who is director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics. He also co-ordinates clinical trials as chair of the brain tumour group at the Carbone Cancer Center.
Two years ago, Kalejta’s team added support to Cobb’s position when it showed that two HCMV proteins shut down a key protein that restricts tumour growth in general.
‘HCMV can also do every one of the things that are generally considered the 10 hallmarks of cancer,’ says Kalejta, a member of the McArdle Laboratory for Cancer Research, Carbone Cancer Center, Stem Cell and Regenerative Medicine Center and Institute for Molecular Virology at UW-Madison.
The problem with studying HCMV is that the virus is present in a harmless way in almost everyone, so scientists can’t ask if HCMV-positive people are more likely to get cancer than people without HCMV.
Kalejta’s postdoctoral fellow Dr. Padhma Ranganatan used a standard laboratory test, rather than the ultra-sensitive test Cobb has used, to see if HCMV was present in 75 GBM samples. The UW-Madison researchers also looked to see if the entire virus genome – all of its DNA – rather than just a portion of it was present in the tissues. Finally, they wanted to learn if all cells within the tumour or just some of them were infected.
The analysis showed that HCMV is statistically more likely to be present in GBM sample tissues than in other brain tumour and epileptic brain tissues. The whole virus genome, not a portion of it, was present in GBM samples. And the data suggested that a minority of GBM cells were infected with HCMV.
‘We hypothesize that HCMV may be infecting only tumour stem cells, unlike other viruses, which infect every single tumour cell,’ says Kalejta. ‘This leads us to predict that HCMV functions by a unique mechanism that no other virus uses.’
University of Wisconsin-Madison
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Roche sets up co –marketing agreement with private laboratory to support greater access to HPV testing
In an innovative commercial agreement, leading healthcare company Roche and foremost private cellular pathology laboratory Unilabs-IHS, are collaborating to help make state-of-the art testing for signs of cervical cancer more accessible to thousands of women in London and throughout the UK.
Roche’s leading-edge and fully automated cobas® HPV test which runs on the acclaimed cobas 4800 system, will provide a fast turn-around of cervical smear samples from potentially thousands of women per year, sent to the London based laboratory from clinicians from all over the country. The testing at Unilabs-IHS, will not only be conducted as a follow up to the traditional “Pap” cervical smear method to check ambiguous results, it will also be used upon request in primary screening for cervical pre cancer, giving a greater chance to avoid disease progression.
The ultra-high reliability of the cobas HPV test will be of huge benefit for clinicians and patients alike, due to the test’s unique genotyping that individually identifies genotypes 16 and 18, the highest risk types associated with the development of cervical cancer and its precursor lesions, while simultaneously identifying 12 other high risk HPV types. Such technology provides better risk stratification of patients enabling a more sensitive and efficient approach to cervical screening.
Dr Glen Dixon, Medical Director of Cytopathology at Unilabs-IHS from Unilabs-IHS said “We are delighted to have come to this agreement with Roche. Using the cobas HPV test on the cobas 4800 platform for our HPV testing work load, means that clinicians will not only have the fastest ever turnaround times, but will also have enhanced and incontrovertible HPV results, with no need to re-test – and all at no extra cost.”
Paul Eros, Director of Molecular Diagnostics at Roche said: “HPV testing provides earlier identification of those women at risk of developing cervical cancer. The agreement that we have struck with Unilabs-IHS for cervical screening with the cobas HPV test, is a significant step forward towards spreading access to HPV testing at the primary screening stage. Given the clear benefits of this technology to patients as well as the NHS, we look forward to seeing the technology’s timely introduction at the primary screening stage, across the country via the national cervical screening programme – promising a better deal for women and a more efficient approach to cervical screening.”
www.roche.com
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Avantor launches new global diagnostics business unit and a new brand of diagnostic products
, /in E-News /by 3wmediaAs well as announcing the launch of a new global diagnostics business unit at Medica last month, Avantor Performance Materials also announced the creation of a new diagnostics product brand: BeneSpheradiagnostics solutions, which will include a broad and expanding range of reliable, affordable diagnostic technologies and easy-to-use products, focused on three segments: in vitro reagents and instruments for clinical chemistry, immunology, haematology, microbiology, histology and cytology and genetic testing; instruments for in vivo diagnostics, currently sold under the Diagnova name in India; and consumables and instruments for life sciences research in academia, government and pharmaceutical labs, also currently sold under the Diagnova name in India.
At the moment Avantor’s performance diagnostics solutions include J.T.Baker clinical reagents, which have provided world-class solutions for haematology and histology applications for over 30 years, and BeneSphera diagnostics solutions built on Diagnova, the company’s Indian-based diagnostics business with a 25-year legacy offering products, engineering and application support for immunology, clinical chemistry, haematology, microbiology, endoscopy and life science needs.
Avantor’s plans are to grow the new global diagnostics business through organic development and the strategic acquisition of R&D-backed manufacturing and distribution companies in targeted locations to support a strong global brand and supply chain.
Identifying SMPX mutations underlying human hereditary hearing loss
, /in E-News /by 3wmediaHereditary hearing loss is the most common sensory disorder in humans. A German research team led by Ingo Kurth from the Institute of Human Genetics at the University Hospital Jena, Germany, used a number of different methods, including Roche’s NimbleGen Custom Sequence Capture 385K array to identify the gene mutated in the disease locus of the X-chromosome of a Spanish family with hereditary hearing loss [1].
Targeted enrichment was performed by the German Service Provider ATLAS Biolabs GmbH. In particular, the DNA of two affected males was subjected to target enrichment. Subsequent sequencing analysis at the Cologne Center for Genomics (CCG) resulted in the identification of a total of 3858 and 3443 X-chromosomal variants for each of these two individuals. Furthermore, a nonsense mutation in the small muscle protein, X-linked (SMPX) of the affected individuals had been detected. Nonsense mutations are significant, because they are point mutations in a sequence of DNA that cause a premature stop codon, or a nonsense codon in the transcribed mRNA, resulting in a truncated, incomplete, and usually nonfunctional protein. Based on their findings, the authors propose that long-term maintenance of mechanically stressed inner ear cells critically depends on SMPX function.
The NimbleGen Sequence Capture technology is a sophisticated process for the parallel enrichment of selected genomic regions from complex human genomic DNA. Sequence Capture allows enrichment of target regions in a single experiment, replacing the need to perform numerous PCR reactions. The efficiencies of parallel enrichment are an ideal complement for cost-effective, high throughput next-generation sequencing.
[1] Huebner et al. American Journal of Human Genetics, Vol. 88: 621-627, May 13, 2011.
www.roche.com
For life science research only. Not for use in diagnostic procedures.
NIMBLEGEN and SEQCAP are trademarks of Roche.
Other brands or product names are trademarks of their respective holders.
Faulty proteins may prove significant in identifying new treatments for ovarian cancer
, /in E-News /by 3wmediaOHSU Knight Cancer Institute study results suggest that more patients than initially thought could potentially be treated with a new class of drugs, PARP inhibitors
A constellation of defective proteins suspected in causing a malfunction in the body’s ability to repair its own DNA could be the link scientists need to prove a new class of drugs will be effective in treating a broad range of ovarian cancer patients, an Oregon Health & Science University Knight Cancer Institute study found.
These research results have prompted additional exploration into whether the patient population included in clinical trials for drugs that target the enzyme poly ADP ribose polymerase (PARP) should be expanded. Several forms of cancer are more dependent on PARP for their growth than regular cells, which means that targeting these enzymes when they go haywire is a potentially effective way to treat ovarian cancer. Currently PARP inhibitors are being tested with patients who have two types of malfunctioning proteins, BRCA1 or BRCA2. But, the OHSU Knight Cancer Institute study of additional proteins, beyond BRCA proteins, suggests that they too are playing a role in driving ovarian cancer.
Tapping into the potential of PARP inhibitors could change the dynamics of ovarian cancer treatment. There has not been a substantial increase in treatment options for ovarian cancer in the past two decades, said Tanja Pejovic, M.D., Ph.D., gynaecologic oncologist at the OHSU Knight Cancer Institute. Pejovic, who led the study of these additional defective proteins, added that the results provide evidence that further research into the role of multiple proteins is warranted.
Only about 10 to 15 percent of women with ovarian cancer have BRCA 1 or BRCA 2 mutations. Pejovic’s study of 186 patients with nonhereditary cancer found that 41 percent who had an early recurrence of the disease also had abnormal levels of the other proteins tracked. In contrast, only 19.5 percent of patients who hadn’t yet had a recurrence of the disease in three years had abnormal levels of these proteins.
‘If we are able to identify the proteins that differentiate these patients at risk for early recurrence, this would open up a new direction in ovarian cancer treatment,’ Pejovic said.
The study — which was supported by the Sherie Hildreth Ovarian Cancer (SHOC) Foundation — focused on proteins that are supposed to assist cells in repairing harmful breaks in DNA strands, a process called homologous recombination (HR). The malfunctioning of HR is not well understood in ovarian cancers where there is no family history of the disease. However, there is evidence that these proteins influence a patient’s ability to respond to drugs and their survival rates after treatment. Oregon Health & Science University
Research on personalized tumor treatment using Roche´s GS Junior Sequencing System
, /in E-News /by 3wmediaThe Center for Human Genetics and Laboratory Medicine Dr. Klein and Dr. Rost, and IMGM Laboratories, both located in Martinsried Germany, reported using the Roche GS Junior Benchtop System to sequence clinically relevant exons and identify genomic variations in solid tumors treated with an antibody-based medicine. This sequencing approach, easily expanded to complete coding regions, has great potential for personalized medicine, where individual treatment success is largely dependent on the mutation status of tumor genes. The high-quality long reads produced by the GS Junior System enable accurate and comprehensive analysis of the full range of genetic variations.
Personalized tumor treatments, such as monoclonal antibodies (mAb) that specifically target tumor-inducing proteins, require a precise and comprehensive assessment of an individual’s genetic profile for the targeted genes. Current therapies target only a limited region of the relevant tumor genes, whereas the next-generation GS Junior Sequencing System enables cost effective and comprehensive profiling of all the relevant genes. In contrast, conventional capillary sequencing techniques often lack the sensitivity and cost effectiveness to detect tumor mutations occurring at less than 20% frequency.
“The future of personalized tumor treatment lies in this sequencing approach,” said Dr. Hanns-Georg Klein, MD, CEO of both IMGM and the Center for Human Genetics. “Through our research, we’ve found that it’s critical to ensure a comprehensive analysis of a tumor variant population, including known and novel mutations.”
These findings underscore the utility of Roche’s GS Junior System for investigating complex tumor samples. The long, accurate sequencing reads are ideal for identifying multiple tumor mutations that can include structural variations and rare somatic mutations.
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The concept of ‘overactive bladder’ serves better commercial rather than patient interests
, /in E-News /by 3wmedia‘The overactive bladder syndrome has become an accepted way to simplify a complex array of symptoms and leads people to believe that an overactive bladder is an independent disease in itself. However, the truth is not as simple as this, as there are usually several factors at work explaining the symptoms. This is also one of the reasons why so called overactive bladder medications often do not bring the hoped result,’ says Kari Tikkinen, MD, PhD, from the HUCS Department of Urology.
The article on overactive bladder syndrome, which was co-written by Tikkinen, who currently holds a senior researcher post at the McMaster University in Canada, and Anssi Auvinen, Professor of Epidemiology from the University of Tampere, was recently published. For the article, the researchers systematically reviewed the studies on overactive bladder and the channels through which these studies have been funded.
The authors argue that the symptoms of an ‘overactive bladder’ ought to be studied individually and not as an ambiguous constellation of symptoms. This way the underlying causes of the symptoms can be better understood and more effective treatments can be developed.
The expression ‘overactive bladder’ was coined at an industry-sponsored symposium held in 1997. The following year, the FDA approved the first drug for the treatment of ‘symptoms of overactive bladder’, after which the pharmaceutical industry launched high-profile, worldwide promotional campaigns for drugs aimed at treatment of the syndrome.
According to the current definition, overactive bladder (OAB) syndrome is defined as the presence of urinary urgency with or without urgency incontinence, usually with increased daytime frequency and nocturia in the absence of infection or other obvious pathology.
‘The definition is vague and ambiguous because it includes unspecific terms, such as ‘usually’ and ‘with or without’, and the unclear expression ‘other obvious pathology’,’ Tikkinen says and continues, ‘For the pharmaceutical industry this definition is probably quite useful, as it is partly the reason why one medicine can be prescribed to a large number of patients.’
Research into overactive bladder has increased significantly over the past ten years and the pharmaceutical industry has invested heavily in it. ‘It has previously been shown that research funded by commercial actors often ends up unpublished if the results don’t serve the interests of the company,’ Tikkinen points out.
Tikkinen and Auvinen also bring to the fore that in many studies on prevalence of overactive bladder, very mild symptoms have been classified as abnormal.
‘More independent, non-commercially funded research on the subject is needed. There are, in the end, a huge number of people who suffer from urinary urgency and increased urinary frequency, and current treatments are not bringing sufficient relief,’ Tikkinen says. EurekAlert
Researchers find first major gene mutation associated with hereditary prostate cancer risk
, /in E-News /by 3wmediaAfter a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease.
A report on the discovery was led by investigators at the University of Michigan Health System and Johns Hopkins University School of Medicine. The research team found that men who inherit this mutation have a 10 to 20 times higher risk of developing prostate cancer.
While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.
‘It’s what we’ve been looking for over the past 20 years,’ adds William B. Isaacs, Ph.D., professor of urology and oncology at the Johns Hopkins University School of Medicine, the study’s other senior author. ‘It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results.’
For this study, the researchers collaborated with John Carpten, Ph.D., at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, who used the latest technology to sequence the DNA of more than 200 genes in a human chromosome region known as 17q21-22. Cooney, working with Ethan Lange, Ph.D., of the University of North Carolina on the U-M Prostate Cancer Genetics Project, was the first to identify 17q21-22 as a region of interest.
Researchers started with samples from the youngest patients with prostate cancer in 94 families who had participated in studies at U-M and Johns Hopkins. Each of those families had multiple cases of the disease among close relatives, such as between fathers and sons or among brothers.
Members of four different families were found to have the same mutation in the HOXB13 gene, which plays an important role in the development of the prostate during the foetal stage and its function later in life. The mutation was carried by all 18 men with prostate cancer in these four families.
The researchers collaborated with Jianfeng Xu, Ph.D., and Lilly Zheng, Ph.D., at Wake Forest University to look for the same HOXB13 gene mutation among 5,100 men who had been treated for prostate cancer at either Johns Hopkins or U-M. The mutation was found in 1.4 percent—or 72 of the men. It turned out that those men were much more likely to have at least one first-degree relative, a father or brother, who also had been diagnosed. The researchers also looked for the mutation in a control group of 1,400 men without prostate cancer, and only one of those men carried the mutation. In addition, the researchers studied men who were specifically enrolled in studies of early-onset or familial prostate cancer.
‘We found that the mutation was significantly more common in men with a family history and early diagnosis compared with men diagnosed later, after age 55, without a family history. The difference was 3.1 percent versus 0.62 percent, Cooney says. University of Michigan Health System
Genes and disease mechanisms behind a common form of muscular dystrophy
, /in E-News /by 3wmediaContinuing a series of groundbreaking discoveries begun in 2010 about the genetic causes of the third most common form of inherited muscular dystrophy, an international team of researchers led by a scientist at Fred Hutchinson Cancer Research Center has identified the genes and proteins that damage muscle cells, as well as the mechanisms that can cause the disease.
The discovery could lead to a biomarker-based test for diagnosing facioscapulohumeral muscular dystrophy (FSHD), and the findings have implications for developing future treatments as well as for cancer immunotherapies in general.
The work establishes a viable roadmap for how the expression of the DUX4 gene can cause FSHD. Whether this is the sole cause of FSHD is not known; however, the latest findings ‘are about as strong of evidence as you can get’ of the genetic link, said corresponding author Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division.
Tapscott and colleagues sought answers to the questions about what the DUX4 protein does both normally in the body and in the FSHD disease process. In the latest study, they identified that the DUX4 protein regulates many genes that are normally expressed in the male germ line but are abnormally expressed in FSHD muscle. Germ line cells are inherited from parents and passed down to their offspring.
‘This study is a significant step forward by solidifying that the DUX4 transcription factor causes this disease, while offering a number of viable mechanisms for why the muscle is damaged,’ Tapscott said. Transcription factors are tools that cells use to control gene expression. Genes that are ‘turned on’ in the body are ‘transcribed,’ or translated, into proteins.
Now that scientists know that targets for DUX4 are expressed in skeletal muscle, an antibody- or RNA-based test could be developed to diagnose FSHD by examining muscle tissue from a biopsy, Tapscott said. Such biomarker-based tests also could be used to determine how well new treatments are working to suppress FSHD.
The study also discovered that DUX4 regulates cancer/testis antigens. Cancer/testis antigens are encoded by genes that are normally expressed only in the human germ line, but are also abnormally expressed in various tumour types, including melanoma and carcinomas of the bladder, lung and liver.
‘This knowledge now gives us a way to manipulate the expression of cancer/ testis antigens, potentially opening the opportunity to use these antigens in a cancer vaccine,’ Tapscott said. Fred Hutchinson Cancer Research Center
Researchers find new, non-invasive way to identify lymph node metastasis
, /in E-News /by 3wmediaUsing two cell surface markers found to be highly expressed in breast cancer lymph node metastases, researchers at Moffitt Cancer Center, working with colleagues at other institutions, have developed targeted, fluorescent molecular imaging probes that can non-invasively detect breast cancer lymph node metastases. The new procedure could spare breast cancer patients invasive and unreliable sentinel lymph node (SLN) biopsies and surgery-associated negative side effects.
‘The majority of breast cancer patients, up to 74 percent, who undergo SLN biopsy are found to be negative for axillary nodal, or ALN, metastases,’ said corresponding author David L. Morse, Ph.D., an associate member at Moffitt whose research areas include experimental therapeutics and diagnostic imaging. ‘Determining the presence or absence of ALN metastasis is critical to breast cancer staging and prognosis. Because of the unreliability of the SLN biopsy and its potential for adverse effects, a non-invasive, more accurate method to assess lymph node involvement is needed.’
The authors note that the postoperative complications to the SLN biopsy can include lymphedema, seroma formation, sensory nerve injury and limitations in patient range of motion. In addition, biopsies fail to identify disease in axillary lymph nodes in five to 10 percent of patients.
In developing targeted molecular probes to identify breast cancer in axillary lymph nodes, the research team from Moffitt, the University of Arizona and University of Florida used two surface cell markers – CAIX and CAXII. CAIX is a cell surface marker known to be ‘highly and broadly expressed in breast cancer lymph node metastases’ and absent in normal tissues.
CAIX and CAXII are both integral plasma membrane proteins with large extracellular components that are accessible for binding of targeted imaging probes, explained Morse. In addition, several studies have shown that CAIX expression is associated with negative prognosis and resistance to chemo and radiation therapy for breast cancer. CAXII is a protein expressed in over 75 percent of axillary lymph node metastases.
The researchers subsequently developed their targeting agents by using monoclonal antibodies specific for binding CAIX and CAXII, both of which are known to promote tumour growth.
According to the researchers, a number of non-invasive optical imaging procedures for SLN evaluation have been investigated, but the approaches have lacked the ability to target tumour metastasis biomarkers.
‘These methods provide only anatomic maps and do not detect tumour cells present in lymph nodes,’ explained Morse. ‘Using mouse models of breast cancer metastasis and a novel, monoclonal anti-body-based molecular imaging agents, we developed a targeted, non-invasive method to detect ALN metastasis using fluorescence imaging.’
In addition to the imaging study with mice, the researchers also reported that the combination of CAIX and CAXII covered 100 percent of patient-donated samples used in their tissue microarray (TMA) study. Moffitt Cancer Center
New evidence links virus to brain cancer
, /in E-News /by 3wmediaTilting the scales in an ongoing debate, University of Wisconsin-Madison researchers have found new evidence that human cytomegalovirus (HCMV) is associated with glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy.
The findings confirm what only a handful of scientists have found, but in a manner that University of Wisconsin School of Medicine and Public Health researchers believe enhances the scientific rigor of earlier studies.
The study hints for the first time that HCMV may work differently than other cancer-related viruses – possibly by affecting only tumour stem cells, self-renewing cells that keep the tumour growing. The new research may place HCMV in an expanding group of viruses associated with cancer.
‘As many as 15 to 20 percent of all human cancers are caused by viruses, and the number is growing,’ says HCMV expert Dr. Robert Kalejta, associate professor of oncology at the UW School of Medicine and Public Health (SMPH). ‘The viruses may not cause cancer on their own, but they play a critical role in the process.’
Among others, human papilloma virus (HPV) causes cervical cancer, Epstein-Barr virus (EBV) causes lymphoma and hepatitis C virus (HCV) causes liver cancer.
HCMV’s role in GBM has been debated, with many scientists and clinicians remaining skeptical. Oncologist Dr. Charles Cobbs of California Pacific Medical Center has been the main proponent of the theory that HCMV contributes to GBM.
Dr. John Kuo, assistant professor of neurological surgery and human oncology and a cancer stem cell scientist at the School of Medicine and Public Health, was one of the skeptical ones, but he says he’s now convinced that HCMV is associated with human GBM specimens.
Still, the association does not prove a causal relationship between HCMV and the development of GBM, he says.
‘This study may open up a new unexplored area of research for this incurable disease,’ says Kuo, who is director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics. He also co-ordinates clinical trials as chair of the brain tumour group at the Carbone Cancer Center.
Two years ago, Kalejta’s team added support to Cobb’s position when it showed that two HCMV proteins shut down a key protein that restricts tumour growth in general.
‘HCMV can also do every one of the things that are generally considered the 10 hallmarks of cancer,’ says Kalejta, a member of the McArdle Laboratory for Cancer Research, Carbone Cancer Center, Stem Cell and Regenerative Medicine Center and Institute for Molecular Virology at UW-Madison.
The problem with studying HCMV is that the virus is present in a harmless way in almost everyone, so scientists can’t ask if HCMV-positive people are more likely to get cancer than people without HCMV.
Kalejta’s postdoctoral fellow Dr. Padhma Ranganatan used a standard laboratory test, rather than the ultra-sensitive test Cobb has used, to see if HCMV was present in 75 GBM samples. The UW-Madison researchers also looked to see if the entire virus genome – all of its DNA – rather than just a portion of it was present in the tissues. Finally, they wanted to learn if all cells within the tumour or just some of them were infected.
The analysis showed that HCMV is statistically more likely to be present in GBM sample tissues than in other brain tumour and epileptic brain tissues. The whole virus genome, not a portion of it, was present in GBM samples. And the data suggested that a minority of GBM cells were infected with HCMV.
‘We hypothesize that HCMV may be infecting only tumour stem cells, unlike other viruses, which infect every single tumour cell,’ says Kalejta. ‘This leads us to predict that HCMV functions by a unique mechanism that no other virus uses.’ University of Wisconsin-Madison
HPV testing for cervical cancer risk patients set to increase
, /in E-News /by 3wmediaRoche sets up co –marketing agreement with private laboratory to support greater access to HPV testing
In an innovative commercial agreement, leading healthcare company Roche and foremost private cellular pathology laboratory Unilabs-IHS, are collaborating to help make state-of-the art testing for signs of cervical cancer more accessible to thousands of women in London and throughout the UK.
Roche’s leading-edge and fully automated cobas® HPV test which runs on the acclaimed cobas 4800 system, will provide a fast turn-around of cervical smear samples from potentially thousands of women per year, sent to the London based laboratory from clinicians from all over the country. The testing at Unilabs-IHS, will not only be conducted as a follow up to the traditional “Pap” cervical smear method to check ambiguous results, it will also be used upon request in primary screening for cervical pre cancer, giving a greater chance to avoid disease progression.
The ultra-high reliability of the cobas HPV test will be of huge benefit for clinicians and patients alike, due to the test’s unique genotyping that individually identifies genotypes 16 and 18, the highest risk types associated with the development of cervical cancer and its precursor lesions, while simultaneously identifying 12 other high risk HPV types. Such technology provides better risk stratification of patients enabling a more sensitive and efficient approach to cervical screening.
Dr Glen Dixon, Medical Director of Cytopathology at Unilabs-IHS from Unilabs-IHS said “We are delighted to have come to this agreement with Roche. Using the cobas HPV test on the cobas 4800 platform for our HPV testing work load, means that clinicians will not only have the fastest ever turnaround times, but will also have enhanced and incontrovertible HPV results, with no need to re-test – and all at no extra cost.”
Paul Eros, Director of Molecular Diagnostics at Roche said: “HPV testing provides earlier identification of those women at risk of developing cervical cancer. The agreement that we have struck with Unilabs-IHS for cervical screening with the cobas HPV test, is a significant step forward towards spreading access to HPV testing at the primary screening stage. Given the clear benefits of this technology to patients as well as the NHS, we look forward to seeing the technology’s timely introduction at the primary screening stage, across the country via the national cervical screening programme – promising a better deal for women and a more efficient approach to cervical screening.”
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