Sickle cell disease is a group of inherited blood disorders caused by genetic mutations in the beta-globin gene, resulting in abnormal haemoglobin. Red blood cells become hard, sticky and sickle-shaped, with reduced ability to carry oxygen. Symptoms of sickle cell disease include swelling of the hands and feet, pain due to clogging of blood vessels, anaemia and stroke. The disease can be cured with stem cell or bone marrow transplants, but there is a high risk that recipients of transplants will reject the donated marrow or cells, which can result in serious side effects and even death.
Researchers at the Salk Institute for Biological Studies in the US have now developed a way to use patients’ own cells to potentially cure sickle cell disease and many other disorders caused by mutations affecting haemoglobin. To do that, they used a two-step approach. First, they took adult skin cells from a patient with a beta-globin mutation that causes sickle cell disease. They used six genes to coax these cells to revert to iPSCs, which could then be developed into blood cells. The genes were introduced into the cells using a technique that avoids the use of viruses and insertion of transgenes into the cells’ genome. Their next step was to repair the beta-globin gene mutation in the stem cells. To swap the defective gene with a normal copy in the iPSCs, the investigators used a modified adenovirus that, unlike viruses used in other methods, does not replicate itself in the body and does not alter the host cells’ DNA. The viral genes were deleted and replaced with a DNA sequence that contained a normal beta-globin gene. The modified virus then delivered the new genetic material inside the iPSCs, where the DNA region containing the broken gene was replaced with the sequence containing the normal gene. By replacing a relatively large region of DNA, the technique allows many gene mutations to be repaired at once.
http://tinyurl.com/d2tuptg
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A recent analysis of clinical trial results performed by the Radiation Therapy Oncology Group (RTOG) demonstrate that a chromosomal abnormality—specifically, the absence (co-deletion) of chromosomes 1p and 19q—have definitive prognostic and predictive value for managing the treatment of adult patients with pure and mixed anaplastic oligodendrogliomas. The presence of the chromosomal abnormality was associated with a substantially better prognosis and near-doubling of median survival time when treatment with combined chemotherapy and radiation therapy was compared to treatment with radiation therapy alone.
Oligodendrogliomas are uncommon tumours that represent approximately 4.0% of all brain tumours. Mixed oliogdendrogliomas (those also containing astrocytic elements) account for 1.0% of all brain tumours. Pure and mixed oligodendrogliomas that contain anaplastic (malignant) cells typically grow more rapidly than non-anaplastic tumours.
The RTOG 9402 trial A Phase III Intergroup Randomized Comparison of Radiation Alone vs. Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas was conducted with four other National Cancer Institute (NCI)-supported co-operative groups. Trial participants had a pathologically confirmed pure or mixed anaplastic oligodendroglioma and were randomly assigned into one of two treatment arms. The 148 participants randomised to Arm 1 were treated with PCV (procarbazine, CCNU [lomustine] and vincristine) chemotherapy and radiation therapy (RT), and the 143 participants randomised to Arm 2 were treated with RT alone.
RTOG 9402 study results showed no survival benefit for patients treated with early PVC chemotherapy plus RT over RT alone. Although a significant impact on median progression-free survival time was realised (2.6 years versus 1.7 years for RT alone), the regimen was associated with significantly more adverse side effects. The study authors also reported that study participants in both arms whose tumour lacked chromosomes 1p and 19q had longer median survival times as compared with participants without these deletions (> 7 vs. 2.8 years, respectively). This led the study authors to conclude that ‘tumours with 1p and 19q co-deletion are less aggressive or more responsive to PCV chemotherapy or both.’
A recent analysis undertaken of the RTOG 9402 data (at a median study participant follow-up time of 11 years) is planned for submission to the 2012 American Society of Clinical Oncology Annual Meeting. However, due to the finding’s significance for patient care, results are reported here in advance of submission.
Radiation Therapy Oncology Group
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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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Scientists based at the Cancer Research UK Cambridge Research Institute have discovered how receptors for the female sex hormone oestrogen attach to a different part of the DNA in breast cancer patients who are more likely to relapse, according to a study.
Crucially, they also found that within these more aggressive breast cancers, the oestrogen receptor (ER) was being ‘redirected’ to a different part of the genome by a protein called FOXA1. So drugs that specifically block FOXA1 could help treat patients who do not respond to conventional hormone treatments, such as tamoxifen.
The researchers used state of the art technology, called ChIP sequencing, to analyse ER-genome interactions in frozen breast tumour samples and create a map of all of the sites in the human genome where ER attaches itself to the DNA and switches on particular genes.
This map was used to compare where in the genome ER attached in tumours from people that responded well to treatment, versus those that went on to relapse or were resistant to treatment from the start.
This revealed almost 500 contact points that were common across all the samples analysed, but also a distinct set of contact points specific to patients with different clinical outcomes – of which 599 were associated with good response to treatment and 1,192 with poor response.
Studying patterns of gene activity in these two areas of the genome allowed the researchers to identify a subset of genes that are more active in tumours that return and spread.
Carlos Caldas, Professor of Cancer Medicine at the Department of Oncology at the University of Cambridge and the Cancer Research UK Cambridge Research Institute said: ‘Some breast cancers are treated with hormone treatments, such as tamoxifen, which work by blocking oestrogen receptors. But we know that about a third of patients either fail to respond to this type of treatment or go on to relapse at a later date.
‘Understanding the genetic differences that determine who will or won’t respond to a given treatment is a vital step in being able to choose the right drugs for individual patients. The next step will be to see if these findings can be repeated in larger groups of patients.’
Cancer Research UK’s Dr Jason Carroll, who jointly led the study with Professor Caldas, said: ‘These findings suggest that ER binds to different regions of the genome DNA in breast cancer patients that respond to treatment, compared to those that relapse and whose cancer spreads.
‘We know from previous studies involving breast cancer cells growing in the lab that a protein called FOXA1 is needed for oestrogen receptors to interact with the DNA and switch on genes that fuel cancer growth. But this is the first time we’ve examined frozen tumour samples and shown that FOXA1 redirects ER to different locations within the DNA in patients with different outcomes. This switches on different sets of genes, which in turn affect the outcome of the patient. We now hope to develop ways of blocking FOXA1 to help treat patients who no longer respond to standard treatments.’
University of Cambridge
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New research indicates that targeted drugs such as gefitinib might more effectively treat non-small cell lung cancer if they could be combined with agents that block certain microRNAs.
The study was led by investigators with the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). It shows that overexpression of two genes, called MET and EGFR, causes the deregulation of six microRNAs, and that this deregulation leads to gefitinib resistance.
The findings support the development of agents that restore the levels of these microRNAs. It also offers a new strategy for treating non-small cell lung cancer (NSCLC), which is responsible for about 85 percent of the 221,000 lung-cancer cases and 157,000 deaths that occur annually in the United States.
Finally, it suggests that measuring the expression levels of certain microRNAs – those controlled by the MET gene – might predict which lung-cancer cases are likely to be resistant to gefitinib.
EGFR (which stands for ‘epidermal growth factor receptor’) is frequently over-expressed in non-small cell lung cancer (NSCLC), and this leads to uncontrolled cell proliferation. Gefitinib selectively inhibits EGFR activation and triggers cancer cells to self-destruct by apoptosis. NSCLC cells inevitably develop resistance to the drug, however. This study reveals how this resistance occurs.
‘Our findings suggest that gefitinib resistance that is caused by MET overexpression is at least partly due to miRNA deregulation,’ says principal investigator Dr. Carlo M. Croce, director of Ohio State’s Human Cancer Genetics program and a member of the OSUCCC – James Molecular Biology and Cancer Genetics program.
First author Michela Garofalo notes that stratifying NSCLC patients based on MET expression or the expression of miRNAs regulated by MET might allow for individualisation of treatment.
‘Such a strategy could improve treatment efficacy and patient quality of life by sparing patients from the side effects of treatments that are likely to fail,’ says Garofalo, who is a research scientist in Croce’s laboratory at the OSUCCC – James.
For this study, Croce, Garofalo and their colleagues used lung cancer cell lines, animal models and analysis of human NSCLC tissue. Key technical findings include the following:
•Both EGFR and MET control miR-30b, miR30c, miR-221, and miR-222. These miRNAs are oncogenic; they inhibit pro-apoptotic genes.
•Overexpression of the four oncogenic miRNAs rendered gefitinib-sensitive cells resistant to treatment; inhibiting the four enhanced gefitinib sensitivity and blocked NSCLC tumor growth in an animal model.
•MET alone controls levels of miR-103 and miR-203, which have a tumor-suppressor function. Forcing their expression enhanced gefitinib sensitivity and blocked NSCLC tumor growth in an animal model.
Funding from the National Cancer Institute and a Kimmel Scholar Award supported this research.
Ohio State University
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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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Researchers have identified a genetic signature for a severe, often painful food allergy – eosinophilic esophagitis – that could lead to improved diagnosis and treatment for children unable to eat a wide variety of foods.
The scientists, from Cincinnati Children’s Hospital Medical Center that they have pinpointed a dysregulated microRNA signature for eosinophilic esophagitis (EoE), a disease that also may cause weight loss, vomiting, heartburn and swallowing difficulties.
Interestingly, the dysregulated microRNA was reversible with steroid treatment, according to the study’s senior investigator, Marc E. Rothenberg, MD, PhD, director of Allergy and Immunology and the Center for Eosinophilic Disorders at Cincinnati Children’s. MicroRNAs are short segments of RNA that can regulate whether genetic messengers (mRNAs) are degraded or translated into protein.
‘The identification of biomarkers specific to EoE is a significant advancement for both the diagnosis and treatment of the disease,’ explains Rothenberg. ‘The microRNA signature provides an opportunity for more precise analysis of oesophageal biopsies.’
Rothenberg said children with EoE now undergo anaesthesia and invasive endoscopy to diagnose and monitor the allergy. The ability to determine the presence and status of EoE with a non-invasive method, such as blood test that measures microRNAs, would have a positive impact on individuals and families.
In the current study, investigators analyzed esophageal microRNA expression of patients with active EoE, steroid-induced EoE remission, patients with chronic (non-eosinophilic) esophagitis and of healthy individuals. Additionally, they assessed plasma microRNA expression of patients with active EoE, remission of EoE remission and of healthy individuals.
The researchers found that EoE was associated with 32 differentially regulated microRNAs and distinguishable from the non-eosinophilic forms of esophagitis (such as reflux disease). Esophageal eosinophil levels correlated significantly with expression of the most increased microRNAs, miR-21 and miR-223, and most decreased, miR-375. MiR-223 was also one of the most increased microRNAs in the plasma, along with miR-146a and miR-146b.
Notably, the expression of microRNAs dysregulated in patients with active EoE was normalised in patients with EoE who responded to steroid treatment. This suggests a significantly specific microRNA signature for disease activity points to its promise for use as a biomarker for EoE.
EurekAlert
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Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.
A team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.
De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.
Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analysing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.
‘Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,’ said Gleeson. Realising they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.
The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.
‘We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly,’ said Gleeson. ‘These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.’
The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.
‘Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere,’ said Mathern. ‘Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere.’
But a less-invasive drug therapy would still be more appealing.
‘We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly,’ said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. ‘We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?’
EurekAlert
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Tufts Medical Center researchers have shown that presence of a gene strongly linked to appetite regulation is highly predictive of a premature infant’s readiness to feed orally. An analysis of just a drop of an infant’s saliva could be the key to preventing many feeding problems and the expensive medical complications that can occur when infants are fed by mouth too early.
In a study Maron and colleagues have identified a biomarker in saliva that predicts a baby is not yet ready to feed 95 percent of the time. The biomarker, a gene for the neuropeptide Y2 receptor, NPY2R, is a known regulator of feeding behaviour. In their study, the researchers demonstrated that levels of NPY2R in saliva decline as a newborn matures enough to feed orally.
‘There’s a really important need for a better understanding and a more accurate assessment of infants’ feeding skills, ” said Jill L. Maron, MD, MPH, a researcher at the Mother Infant Research Institute at Tufts Medical Center. ‘Nearly every baby born early is at risk for feeding associated morbidities, which often lead to prolonged hospitalisations, short and long term health complications, and significant parental anxiety. This is a way of monitoring the most vulnerable babies very non-invasively. We can help guide clinical care without ever hurting them.”
Currently, caregivers use a variety of subjective measurements, such as evaluating a baby’s sucking and swallowing skills, to determine when it’s safe to feed a baby by mouth. But these methods are imprecise and often lead to feeding a baby too early, which can cause the child to choke, accidentally inhale breast milk or formula into their lungs leading to pneumonia, or other problems. Babies who suffer these early feeding difficulties can also go on to develop long-term feeding problems and are at risk of developmental delays. Research indicates that more than 40 percent of children in feeding disorder clinics were premature babies.
The NPY2R gene has been studied extensively because it helps regulate appetite and plays a role in both obesity and eating disorders. But no one had examined its role in prompting premature babies to eat, because most researchers were not focusing on appetite’s role in newborn feeding problems.
Tufts Medical Center
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Virginia Commonwealth University School of Medicine researchers have discovered that changes in the gene expression of a key enzyme may contribute to high blood pressure and increase susceptibility to forming blood clots in pregnant women with preeclampsia.
These findings could provide clues to the best treatment approaches for high blood pressure and the formation of blood clots that can block blood flow to a pregnant woman’s internal organs and lead to organ failure.
Researchers have been working to determine the root cause of preeclampsia on the molecular level and have now identified that epigenetic mechanisms may be at play. Epigenetics refers to changes in gene expression that are mediated through mechanisms other than changes in the DNA sequence.
In a study published, the VCU team reported that thromboxane synthase – an important inflammatory enzyme – is increased in the blood vessels of expectant mothers with preeclampsia. The thromboxane synthase gene codes for this enzyme, which is involved in several processes including cardiovascular disease and stroke. This enzyme results in the synthesis of thromboxane, which increases blood pressure and causes blood clots.
‘The present work is unique because it opens up a new concept as to the cause and subsequent consequences of preeclampsia relating to epigenetics,’ said corresponding author Scott W. Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology. ‘It is the first study to show that epigenetic alterations in the blood vessels of the mother are related to preeclampsia.’
According to Walsh, one of the main epigenetic mechanisms is methylation of the DNA, which controls the expression of genes. The increase of this enzyme in the blood vessels is related to reduced DNA methylation and the infiltration of neutrophils into the blood vessels. Neutrophils are white blood cells that normally help fight infection.
In the future, Walsh said some potential treatments for preeclampsia may include inhibition of thromboxane synthase, blockade of thromboxane receptors or dietary supplementation with folate. He said that folate supplementation could increase methylation donors to protect against adverse changes in DNA methylation that affect expression of the thromboxane synthase enzyme.
Virginia Commonwealth University
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