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Imaging: seeing or imagining? (Part 2)

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical Devices R&D Investment, tagged , , , , , , , , , , , , , , , , , , , , on September 29, 2012| 7 Comments »

Imaging: seeing or imagining? (Part 2)

Author and Curator: Dror Nir, PhD

Article 11.3.2 Imaging seeing or imagining Part 2

This post is a continuation of

Imaging: seeing or imagining? (Part 1)

http://pharmaceuticalintelligence.com/2012/09/10/imaging-seeing-or-imagining-part-1/

That is the question…

Anyone who follows healthcare news, as I do , cannot help being impressed with the number of scientific and non-scientific items that mention the applicability of Magnetic Resonance Imaging (‘MRI’) to medical procedures.

A very important aspect that is worthwhile noting is that the promise MRI bears to improve patients’ screening – pre-clinical diagnosis, better treatment choice, treatment guidance and outcome follow-up – is based on new techniques that enables MRI-based tissue characterisation.

Magnetic resonance imaging (MRI) is an imaging device that relies on the well-known physical phenomena named “Nuclear Magnetic Resonance”. It so happens that, due to its short relaxation time, the 1H isotope (spin ½ nucleus) has a very distinctive response to changes in the surrounding magnetic field. This serves MRI imaging of the human body well as, basically, we are 90% water. The MRI device makes use of strong magnetic fields changing at radio frequency to produce cross-sectional images of organs and internal structures in the body. Because the signal detected by an MRI machine varies depending on the water content and local magnetic properties of a particular area of the body, different tissues or substances can be distinguished from one another in the scan’s resulting image.

MRI scan of a breast lesion (Source Radiology.com)

The main advantages of MRI in comparison to X-ray-based devices such as CT scanners and mammography systems are that the energy it uses is non-ionizing and it can differentiate soft tissues very well based on differences in their water content.

In the last decade, the basic imaging capabilities of MRI have been augmented for the purpose of cancer patient management, by using magnetically active materials (called contrast agents) and adding functional measurements such as tissue temperature to show internal structures or abnormalities more clearly.

In order to increase the specificity and sensitivity of MRI imaging in cancer detection, various imaging strategies have been developed. The most discussed in MRI related literature are:

  • T2 weighted imaging: The measured response of the 1H isotope in a resolution cell of a T2-weighted image is related to the extent of random tumbling and the rotational motion of the water molecules within that resolution cell. The faster the rotation of the water molecule, the higher the measured value of the T2 weighted response in that resolution cell. For example, prostate cancer is characterized by a low T2 response relative to the values typical to normal prostatic tissue [5].

T2 MRI pelvis with Endo Rectal Coil ( DATA of Dr. Lance Mynders, MAYO Clinic)

  • Dynamic Contrast Enhanced (DCE) MRI involves a series of rapid MRI scans in the presence of a contrast agent. In the case of scanning the prostate, the most commonly used material is gadolinium [4].

Axial MRI Lava DCE with Endo Rectal ( DATA of Dr. Lance Mynders, MAYO Clinic)

  • Diffusion weighted (DW) imaging: Provides an image intensity that is related to the microscopic motion of water molecules [5].

DW image of the left parietal glioblastoma multiforme (WHO grade IV) in a 59-year-old woman, Al-Okaili R N et al. Radiographics 2006;26:S173-S189

  • Multifunctional MRI: MRI image overlaid with combined information from T2-weighted scans, dynamic contrast-enhancement (DCE), and diffusion weighting (DW) [5].
  • Blood oxygen level-dependent (BOLD) MRI: Assessing tissue oxygenation. Tumors are characterized by a higher density of micro blood vessels. The images that are acquired follow changes in the concentration of paramagnetic deoxyhaemoglobin [5].

In the last couple of years, medical opinion leaders are offering to use MRI to solve almost every weakness of the cancer patients’ pathway. Such proposals are not always supported by any evidence of feasibility. For example, a couple of weeks ago, the British Medical Journal published a study [1] concluding that women carrying a mutation in the BRCA1 or BRCA2 genes who have undergone a mammogram or chest x-ray before the age of 30 are more likely to develop breast cancer than those who carry the gene mutation but who have not been exposed to mammography. What is published over the internet and media to patients and lay medical practitioners is: “The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.”.

Why is ultrasound not mentioned as a potential “non-ionising radiation imaging technique”?

Another illustration is the following advert:

Advert in favour of MRI termal imaging of breast

An MRI scan takes between 30 to 45 minutes to perform (not including the time of waiting for the interpretation by the radiologist). It requires the support of around 4 well-trained team members. It costs between $400 and $3500 (depending on the scan).

The important question, therefore, is: Are there, in the USA, enough MRI  systems to meet the demand of 40 million scans a year addressing women with radiographically dense  breasts? Toda there are approximately 10,000 MRI systems in the USA. Only a small percentage (~2%) of the examinations are related to breast cancer. A

A rough calculation reveals that around 10,000 additional MRI centers would need to be financed and operated to meet that demand alone.

References

  1. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK), BMJ 2012; 345 doi: 10.1136/bmj.e5660 (Published 6 September 2012), Cite this as: BMJ 2012;345:e5660 – http://www.bmj.com/content/345/bmj.e5660
  1. http://www.auntminnieeurope.com/index.aspx?sec=sup&sub=wom&pag=dis&itemId=607075
  1. Ahmed HU, Kirkham A, Arya M, Illing R, Freeman A, Allen C, Emberton M. Is it time to consider a role for MRI before prostate biopsy? Nat Rev Clin Oncol. 2009;6(4):197-206.
  1. Puech P, Potiron E, Lemaitre L, Leroy X, Haber GP, Crouzet S, Kamoi K, Villers A. Dynamic contrast-enhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. Urology. 2009;74(5):1094-9.
  1. Advanced MR Imaging Techniques in the Diagnosis of Intraaxial Brain Tumors in Adults, Al-Okaili R N et al. Radiographics 2006;26:S173-S189 ,

http://radiographics.rsna.org/content/26/suppl_1/S173.full

  1. Ahmed HU. The Index Lesion and the Origin of Prostate Cancer. N Engl J Med. 2009 Oct; 361(17): 1704-6

Writer: Dror Nir, PhD.

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Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, International Global Work in Pharmaceutical, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged , , , on September 20, 2012| 5 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Negative selection was examined using two measures that highlight different periods of selection in the human genome. The first measure, inter-species, pan-mammalian constraint (GERP-based scores; 24 mammals) addresses selection during mammalian evolution. The second measure is intra-species constraint estimated from the numbers of variants discovered in human populations using data from the 1000 Genomes project and covers selection over human evolution.

For DNaseI elements and bound motifs most sets of elements show enrichment in pan mammalian constraint and decreased human population diversity, though for some cell types the DNaseI sites do not appear overall to be subject to pan-mammalian constraint. Bound TF motifs have a natural control from the set of TF motif with equal sequence potential for binding but without binding evidence from ChIP-seq experiments; in all cases, the bound motifs showed both more mammalian constraint and higher suppression of human diversity.

Consistent with previous findings, genome-wide evidence was not observed for pan-mammalian selection of novel RNA sequences. There are also a large number of elements without mammalian constraint, between 17-90% for TF-binding regions as well as DHSs and FAIRE regions. Previous studies could not determine whether these sequences are either biochemically active, but with little overall impact on the organism, or are under lineage specific selection. By isolating sequences preferentially inserted into the primate lineage, which is only feasible given the genome-wide scale of this data, this issue was specifically examined. The majority of primate-specific sequence is due to retrotransposon activity, but an appreciable proportion is non-repetitive primate-specific sequence. Of 104,343,413 primate-specific bases (excluding repetitive elements), 67,769,372 (65%) are found within ENCODE-identified elements. Examination of 227,688 variants segregating in these primate specific regions revealed that all classes of elements (RNA and regulatory) show depressed derived allele frequencies, consistent with recent negative selection occurring in at least some of these regions. This suggests that an appreciable proportion of the unconstrained elements are lineage specific elements required for organismal function, consistent with long standing views of recent evolution, and the remainder are likely to be “neutral” elements which are not currently under selection, but may still affect cellular or larger scale phenotypes without an effect on fitness.

The binding patterns of TFs are not uniform, and can be correlated both inter-and intra-species measures of negative selection with the overall information content of motif positions. The selection on some motif positions is as high as protein coding exons. These aggregate measures across motifs show that the binding preferences found in the population of sites are also relevant to the per-site behavior. By developing a per-site metric of population effect on bound motifs, it was found that highly constrained bound instances across mammals are able to buffer the impact of individual variation.

It was proposed to express the deleterious effect of TFBS mutations in terms of mutational load, a known population genetics metric that combines the frequency of mutation with predicted phenotypic consequences that it causes. This metric was adapted to use the reduction in PWM score associated with a mutation as a crude but computable measure of such phenotypic consequences. It was not assumed that TFBS load at a given site reduces an individual’s biological fitness. Rather, it was argued that binding sites that tolerate a higher load are less functionally constrained. This approach, although undoubtedly a crude one, makes it possible to consistently estimate TFBS constraints for different TFs and even different organisms and ask why TFBS mutations are tolerated differently in different contexts.

It was first asked whether motif load would be able to detect the expected link between evolutionary and individual variation. A published metric was used, Branch Length Score (BLS), to characterise the evolutionary conservation of a motif instance. This metric utilises both a PWM based model of the conservation of bases and allows for motif movement. Reassuringly, mutational load correlated with BLS in both species, with evolutionary non-conserved motifs (BLS=0) showing by far the highest degree of variation in the population. At the same time, ∼40% of human and fly TFBSs with an appreciable load (L>5e-3) still mapped to reasonably conserved sites (BLS>0.2, ∼50% percentile in both organisms), demonstrating that score-reducing mutations at evolutionary preserved sequences can be tolerated in these populations.

Using this metric, the original findings were confirmed, suggesting that TFBSs with higher PWM scores are generally more functionally constrained compared to ‘weaker’ sites. The fraction of detected sites mapping to bound regions remained similar across the whole analysed score range, suggesting that this relationship is unlikely to be an artefact of higher false-positive rates at ‘weaker’ sites. This global observation, however, does not rule out the possibility that a weaker match at some sites is specifically preserved to ensure dose-specific TF binding. This may be the case, for example, for Drosophila Bric-à-brac motifs, which exhibited no correlation between motif load and PWM score, consistent with the known dosage-dependent function of Bric-à-brac in embryo patterning.

Motif load was used to address whether TFBSs proximal to transcription start sites (TSS) are more constrained compared to more distant regulatory regions. This was found to be the case in the human, but not in Drosophila. CTCF binding sites in both species were a notable exception, tolerating the lowest mutational load at locations 500bp-1kb from TSS, but not closer to the TSS, suggesting that the putative role of CTCF in establishing chromatin domains is particularly important in proximity of gene promoters.

To gain further insight into the functional effects of TFBS mutations, a dataset was used that mapped human CTCF binding sites across four individuals. TFBS mutations detected in this dataset often did not result in a significant loss of binding, with ∼75% mutated sites retaining at least two thirds of the binding signal. This was particularly prominent at conserved sites (BLS>0.5), 90% of which showed this ‘buffering’ effect. To address whether buffering could be explained solely by the flexibility of CTCF sequence preferences, it was analysed between-allele differences in the PWM score at polymorphic binding sites. As expected, globally CTCF binding signal correlated with the PWM score of the underlying motifs. Consistent with this, alleles with minor differences in PWM match generally had little effect on the binding signal compared to sites with larger PWM score changes, suggesting that the PWM model adequately describes the functional constraints of CTCF binding sites. At the same time, it was found that CTCF binding signals could be maintained even in those cases, where mutations resulted in significant changes of PWM score, particularly at evolutionary conserved sites. A linear interaction model confirmed that the effect of motif mutations on CTCF binding was significantly reduced with increasing conservation. These effects were not due to the presence of additional CTCF motifs (as 96% of bound regions only contained a single motif), while differences between more and less conserved sites could not be explained away by differences in the PWM scores of their major alleles. A CTCF dataset from three additional individuals generated by a different laboratory yielded consistent conclusions, suggesting that our observations were not due to over-fitting.

Taken together, CTCF binding data for multiple individuals show that mutations can be buffered to maintain the levels of binding signal, particularly at highly conserved sites, and this effect cannot be explained solely by the flexibility of CTCF’s sequence consensus. It was asked whether mechanisms potentially accountable for such buffering would also affect the relationship between sequence and binding in the absence of mutations. Training an interaction linear model across the whole set of mapped CTCF binding sites revealed that conservation consistently weakens the relationship between PWM score and the binding intensity. Thus, CTCF binding to evolutionary conserved sites may generally have a reduced dependence on sequence.

Source References:

http://www.nature.com/encode/threads/impact-of-evolutionary-selection-on-functional-regions

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Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , on September 10, 2012| 1 Comment »

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Reporter: Aviva Lev-Ari, PhD, RN

Article-7.4.2. Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Nature (2012) doi:10.1038/nature11404

Received 09 March 2012 
Accepted 09 July 2012 
Published online 09 September 2012
Correspondence to: 

The primary and processed data used to generate the analyses presented here can be downloaded by registered users fromThe Cancer Genome Atlas (https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp,https://cghub.ucsc.edu/ and https://tcga-data.nci.nih.gov/docs/publications/lusc_2012/).

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 andKEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.

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Mitochondria and Cancer: An overview of mechanisms

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Genome Biology, tagged , , , , , , , , , , , , on September 1, 2012| 11 Comments »

Author and Curator: Ritu Saxena, Ph.D.

Screen Shot 2021-07-19 at 7.07.57 PM

Word Cloud By Danielle Smolyar

Role of mitochondria in cancer has long been speculated. Infact, Warburg in his 1956 publication talked about  how cancer cells exhibit a different mechanism of mitochondrial respiration than normal cells and how this basic difference in glucose metabolism could be utilized to develop targeted therapies against cancer cells. Several decades later, mitochondrial defects, both genetic and functional have been detected and associated with cancer. Here is a brief overview of the mechanisms by which mitochondrial defects could be associated with cancer:

1. Alteration in energy metabolism- well documented function of mitochondria is ATP production through oxidative phosphorylation that involved both mitochondrial and nuclear proteins. Various complexes are involved in the process of electron transport through the respiratory chain. Some electrons might leak, leading to formation of ROS. Further, certain mutations in the ETC could tamper with the mechanism of electron transfer resulting in increased leakage of electrons finally leading to an increase in ROS production. ROS has been associated with cancer, however, the exact mechanism is not known.

2. Alteration of apoptotic machinery- Mitochondrial houses several pro-apoptotic proteins including cytochrome c, apoptosis induced factor (AIF), endonuclease G, and smac/DIABLO. However, when these are released into from mitochondrial, apoptotic signaling is triggered and the cell goes through programmed death. For example, release of cytochrome c into the cytosol triggers a set of proteins referred to as caspases leading to apoptosis of the cell. The exact role of mtDNA mutations in the cellular response to anticancer agents that target apoptotic machinery has not been defined and a lot of research is being done in this area.

3. Somatic mutations- While germline mutations of the mtDNA have implicated in several diseases such as Pearson Marrow syndrome Kearns-Sayre-CPEO, Leber’s hereditary optic neuropathy, Leigh’s syndrome and several others, somatic mutations have also been a associated with several diseases, especially cancer. High rate of mutations in the mtDNA, much more than that of the nuclear genome is the result of several factors – the absence of histone proteins, close proximity to the electron transport chain, reduced repair machinery, lack of introns. The mtDNA mutations could be induced by endogenous or exogenous agents such as ROS, chemical agents, and/or radiation. The mutations could either be detrimental to its survival in which case it would vanish eventually. In case it confers growth advantage to the cell, the mutation would eventually develop into a homoplasmic state where all the alleles of the different copies of the mtDNA harbor it. It may cause a functional change of the protein derived from the mutated gene resulting in the alterations of mitochondrial function. It might be speculated that the mutated mtDNA results in increase in endogenous ROS production further leading to DNA damage, genetic instability and cancer development.

Sources:

Warburg publication: http://www.ncbi.nlm.nih.gov/sites/entrez/13298683?dopt=Abstract&holding=f1000,f1000m,isrctn

Mitochondrial ROS bifurcation: http://informahealthcare.com/doi/abs/10.1080/10715760290021225

Mitochondria and apoptosis: http://www.ncbi.nlm.nih.gov/sites/entrez/11711427?dopt=Abstract&holding=f1000,f1000m,isrctn

Mitochondria and Cancer: http://www.molecular-cancer.com/content/1/1/9/#B7

Related posts:

http://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

http://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/

http://pharmaceuticalintelligence.com/2012/08/14/detecting-potential-toxicity-in-mitochondria/

http://pharmaceuticalintelligence.com/2012/08/01/mitochondrial-mechanisms-of-disease-in-diabetes-mellitus/

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

http://pharmaceuticalintelligence.com/2012/07/08/the-mechanism-of-action-of-the-drug-acthar-for-systemic-lupus-erythematosus-sle/

http://pharmaceuticalintelligence.com/2012/07/05/stem-cells-for-the-rescue-of-mitochondrial-dysfunction-in-parkinsons-disease-7/

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Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm

Posted in Genome Biology, Molecular Genetics & Pharmaceutical, Population Health Management, Genetics & Pharmaceutical, tagged , , , , on August 7, 2012| 2 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Gametogenesis is a biological process by which precursor cells undergo cell division and differentiation to form mature haploid gametes. Human gametogenesis occurs by mitotic division of gametogonia, followed by meiotic division of gametocytes into various gametes. During this process, the gamete genome experiences both programmed and spontaneous changes, among which meiotic recombination shuffles the two haploid somatic genomes to create a unique hybrid haploid genome for each gamete cell, while accumulated replication errors contribute point mutations that may affect the gametes’ functionality. This results in an enormous variety of new genomes being created in the gametes, thereby enabling one’s children to add to the genetic diversity of the human race in a more complex manner than by simply mixing and matching entire parental chromosomes. The genome-wide recombination activity and de novo mutation rate have been directly characterized in many model organisms. However, it has been unclear how an individual human’s genome is edited during gametogenesis. Despite the advances in personal genomics, gamete genome variation within individuals, especially fine-scale personal recombination activity and germline mutation rates, has been as yet generally inaccessible.

An important feature of single molecule multiple displacement amplification (MDA) is its repetitive usage of the originating genuine template molecule. Even if an amplification error happens in the initial stage, there will still be a large fraction of products preserving the correct base information from the original template, and the power of statistics from multiple coverage discriminates these errors from true genomic variation. Using this microfluidic MDA approach, for the first genome-wide single-cell analysis of human sperm was reported. A personal recombination map was created for an individual to measure the rate of de novo mutations in this individual’s germline. The advantage of sampling a large set of meioses from a single individual for fine-scale analysis allowed to uncover individual specific features potentially buried under population data. It was proposed that this partially overlapping feature is also the general pattern in individuals. While some hot spots are dying in some people, new recombination activities evolve to refill the hot spot pool. Support for this theory comes from single-cell analysis. Recombination data from 91 single sperm cells presented a comprehensive landscape of personal recombination activity. Genome-wide meiotic drive and gene conversion were also directly tested. Single-cell whole-genome sequencing further revealed primary information about human sperm genome instability and mutation rate. In this study, microfluidics to single-cell whole genome amplification was applied. This technique not only enabled great parallelization, but also improved amplification performance. MDA is sensitive to environmental contamination, and extensive sample purification is required for traditional bench-top whole genome amplifications.

The data from this study suggested that the germline mutation rate can vary greatly among different individuals, but not among different cells from the same individual. This may explain why the male mutation rate is not always higher than the female. DNA methylation also affects genome instability and C/T point mutation levels but in opposite ways. A fine tuned methylation level is therefore required for high-quality sperm genome. The ability to study a large number of single sperm cells has offered several new insights in meiosis. Studying the germline genome is but one application of single-cell genomics, and it is expected that the method will find applications in many other fields, including cancer, aging, immunology, and developmental biology.

Source References:

Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm.

(http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide%20Single-Cell%20Analysis%20of%20Recombination%20Activity%20and%20De%20Novo%20Mutation%20Rates%20in%20Human%20Sperm)

Personal Recombination Map from Individual’s Sperm Cell and its Importance

(http://pharmaceuticalintelligence.com/2012/07/23/personal-recombination-map-from-individuals-sperm-cell-and-its-importance/).

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Scientists Make Groundbreaking Discovery Of Mutation Causing Genetic Disorder In Humans

Posted in Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, Cardiovascular Pharmacogenomics, Medical and Population Genetics, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , on May 28, 2012| Leave a Comment »

Reporter: Ritu Saxena, Ph.D.

Singapore, May 14, 2012 (ACN Newswire via COMTEX) — Scientists at A*STAR’s Institute of Medical Biology (IMB), in collaboration with doctors and scientists in Jordan, Turkey, Switzerland and USA, have identified the genetic cause of a birth defect known as Hamamy syndrome[1]. Their groundbreaking findings were published on May 13th in the prestigious journal Nature Genetics. The work lends new insights into common ailments such as heart disease, osteoporosis, blood disorders and possibly sterility.

Hamamy syndrome is a rare genetic disorder which is marked by abnormal facial features and defects in the heart, bone, blood and reproductive cells. Its exact cause was unknown until now. The international team, led by scientists at IMB, have pinpointed the genetic mistake to be a mutation in a single gene called IRX5.

This is the first time that a mutation in IRX5 (and the family of IRX genes) has ever been discovered in man. IRX5 is part of a family of transcription factors that is highly conserved in all animals, meaning that this gene is present not only in humans but also in mice, fish, frogs, flies and even worms. Using a frog model, the scientists demonstrated that Irx5 orchestrates cell movements in the developing foetus which underlie head and gonad formation.

Carine Bonnard, a final-year PhD student at IMB and the first author of the paper, said, “Because Hamamy syndrome causes a wide range of symptoms, not just in newborn babies but also in the adult, this implies that IRX5 is critical for development in the womb as well as for the function of many organs in our adult body. For example, patients with this disease cannot evacuate tears from their eyes, and they will also go on to experience repetitive bone fractures (Annex A) or progressive myopia as they age. This discovery of the causative gene is a significant finding that will catalyze research efforts into the role of the Irx gene family and greatly increase our understanding of human health, such as bone homeostasis, or gamete formation for instance.”

“We believe that this discovery could open up new therapeutic solutions to common diseases like osteoporosis, heart disease, anaemia which affect millions of people worldwide,” said Dr Bruno Reversade, Senior Principle Investigator at IMB. “The findings also provide a framework for understanding fascinating evolutionary questions, such as why humans of different ethnicities have distinct facial features and how these are embedded in our genome. IRX genes have been repeatedly co-opted during evolution, and small variation in their activity could underlie fine alterations in the way we look, or perhaps even drastic ones such as the traits seen in an elephant, whale, turtle or frog body pattern.”

Only a handful of people in the world have been identified with Hamamy Syndrome making it a very rare genetic disorder. Rare genetic diseases, usually caused by mutations in a single gene, provide a unique opportunity to better understand more common disease processes. These “natural” experiments are similar to carefully controlled knockout animal experiments in which the function of single genes are analyzed and often give major insights into general health issues.[2]

Prof Birgitte Lane, Executive Director of IMB, said, “Understanding how various pathways in the human body function is the foundation for developing new therapeutic targets. This is an important piece of research that I believe will be of great interest to many scientists and clinicians around the world because of the clinical and genetic insights it brings to a large range of diseases.”

Notes for editor:

The research findings described in this news release can be found on Nature Genetics’s website under the title “Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1” by Carine Bonnard[1], Anna C Strobl[2], Mohammad Shboul1, Hane Lee[3], Barry Merriman[3], Stanley F Nelson[3], Osama H Ababneh[4], Elif Uz[5],[6], Tulay Guran[7], Hulya Kayserili[8], Hanan Hamamy[9],[10] & Bruno Reversade[1],[11].

[1] Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

[2] Division of Systems Biology, Medical Research Council National Institute for Medical Research, London, UK

[3] Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA

[4] Department of Opthalmology, Faculty of Medicine, University of Jordan, Amman, Jordan

[5] Department of Biology, Faculty of Arts and Sciences, Duzce University, Duzce, Turkey

[6] Gene Mapping Laboratory, Department of Medical Genetics, Hacettepe University Medical Faculty, Ankara, Turkey

[7] Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul, Turkey

[8] Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

[9] Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland

[11] Department of Pediatrics, National University of Singapore, Singapore

Correspondence should be addressed to B.R. (Bruno@reversade.com)

The article can be accessed fromhttp://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2259.html .

About the Institute of Medical Biology (IMB)

IMB is one of the Biomedical Sciences Institutes of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, the 7th and youngest of the BMRC Research Institutes, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life. From 2011, IMB also hosts the inter-research institute Skin Biology Cluster platform.

IMB has 20 research teams of international excellence in stem cells, genetic diseases, cancer and skin and epithelial biology, and works closely with clinical collaborators to target the challenging interface between basic science and clinical medicine. Its growing portfolio of strategic research topics is targeted at translational research on the mechanisms of human diseases, with a cell-to-tissue emphasis that can help identify new therapeutic strategies for disease amelioration, cure and eradication. For more information about IMB, please visit www.imb.a-star.edu.sg .

About the Reversade Laboratory

Dr. Reversade, a human geneticist and embryologist holds a Senior Principal Investigator position at IMB and an adjunct faculty position at the Department of Paediatrics in the National University of Singapore. He is a Fellow of the Branco Weiss Foundation based at ETH in Switzerland and also the first recipient of an A*STAR Investigatorship, a programme which provides competitive and prestigious fellowships to support the next generation of international scientific leaders, offering funding and access to state-of-the-art scientific equipment and facilities at A*STAR. For more information about Dr. Reversade’s laboratory, please visit www.reversade.com .

About A*STAR

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity. A*STAR supports Singapore’s key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, and with other local and international partners. For more information about A*STAR, please visit www.a-star.edu.sg .

Source: http://www.marketwatch.com/story/scientists-make-groundbreaking-discovery-of-mutation-causing-genetic-disorder-in-humans-2012-05-14?pagenumber=1

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Mystery unveiled about Missing breast cancer genes

Posted in Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, International Global Work in Pharmaceutical, tagged , , , , , on May 11, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Researchers from the University of Adelaide are hoping to better understand why the mutated genes for breast and ovarian cancer are not passed on more frequently from one generation of women to the next.

That’s despite a documented link between breast cancer genes and increased fertility in women.

Dr Jack da Silva from the University’s School of Molecular & Biomedical Science says that because women who carry breast cancer genes are more fertile, in theory they have a greater chance of passing these genes on to future generations.

“A recent study in the United States found that mutations in the breast cancer genes BRCA1 and BRCA2 were directly linked with a 50% increase in the fertility of women, which is a huge number,” Dr da Silva says.

“With such an increased fertility rate, you would expect to see a high frequency of these cancer-causing genes in modern populations, but in fact that is not the case — the frequencies are relatively low.”

In a paper being published May 9 in the Proceedings of the Royal Society B, he argues that the so-called “grandmother effect” may in part be the reason behind this phenomenon.

“In an earlier study, researchers found that post-menopausal women create a ‘grandmother effect’ — that is, the longer they live, the more they are able to support their daughters and their grandchildren, thereby creating an environment in which more grandchildren are born.

“The reverse of this is that women who die earlier — such as from breast or ovarian cancer, which are usually post-menopausal — will no longer be able to support their daughters and grandchildren. This has the effect of limiting the number of grandchildren born, and therefore the chances of passing on the mutated genes from one generation to the next is also limited,” Dr da Silva says.

However, the “grandmother effect” does not entirely negate the increased fertility caused by breast cancer genes, he says.

“Our change to today’s industrial and technological age has been relatively rapid in human history. For most of our existence, we have been hunter-gatherers. During this time, female fertility was limited, and this may have reduced the increase in fertility caused by mutations of these genes.”

Dr da Silva says further studies examining modern-day hunter-gatherer societies might shed more light on how and why the spread of these genetic mutations occurs across generations.

http://www.sciencedaily.com/releases/2012/05/120508220004.htm

 

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