The Economic and Social Research Council (ESRC) announced on 23 Oct continued funding, from 2007 to 2012, for its three research centres, CESAGen, EGENIS and INNOGEN, that, along with the ESRC Genomics Policy and Research Forum, make up the ESRC Genomics Network. As part of the 2000 and 2002 Spending Review, the ESRC received 10 million pounds to fund initiatives looking at the social and economic context of genomics.
The Centre for Economic and Social Aspects of Genomics (CESAGen), which will receive around 8 million pounds of funding over five years, is a Cardiff-Lancaster collaboration led by Professor Ruth Chadwick, in which researchers from the social sciences and the humanities work closely with those in the natural and medical sciences to address the social, economic and policy aspects of development in genomics. Key challenges in the next few years will include addressing the social dimensions of the applications of genomics in health service delivery, with reference to both common and rare diseases; and in areas such as food and nutrition, behaviour and criminal responsibility, and human enhancement.
EGENIS, the ESRC Centre for Genomics in Society, based at Exeter will receive almost 4 million pounds over the five years. EGENIS, headed by Professor John Dupre, is an interdisciplinary research centre looking at the social implications of contemporary genetic science especially in areas such as nutrigenomics, systems biology and gene therapy which have the potential to become highly contentious in society.
Innogen, a collaboration between Edinburgh University and the Open University, is the ESRC Centre for Social and Economic Research on Innovation in Genomics and will receive further funding of around 5 million pounds over five years. Innogen's research programme brings together social, medical and natural scientists to work on evolution of the new life science economy and the governance of innovation in the life sciences, in partnership with industry and private interest groups; policy makers and regulators; citizens and public interest groups, in genomics innovation. Taking over from Professor Joyce Tait, Innogen will also welcome a new Centre Director, Professor David Wield, from October 2007.
Commenting on the announcements, Adrian Alsop, Director for Research, Training and Development for the ESRC, said, "We are delighted to announce this second phase of funding for our genomics research centres. The unique ESRC Genomics Network allows us to work in collaboration with medical and natural scientists in order to build understanding in this area. The Network has quickly established a world leading presence for the UK in this important area. Insights from social science explain how genomic technologies can benefit our health service and realise the potential benefits that they bring to developing countries."
FOR FURTHER INFORMATION, CONTACT: Alexandra Saxon at ESRC
1. The ESRC is the UK's largest funding agency for research and postgraduate training relating to social and economic issues. It provides independent, high quality, relevant research to business, the public sector and Government. The ESRC's planned total expenditure in 2006-07 is ?169 million. At any one time the ESRC supports over 4,000 researchers and postgraduate students in academic institutions and research policy institutes. More at esrcsocietytoday.ac/
2. ESRC Society Today offers free access to a broad range of social science research and presents it in a way that makes it easy to navigate and saves users valuable time. As well as bringing together all ESRC-funded research (formerly accessible via the Regard website) and key online resources such as the Social Science Information Gateway and the UK Data Archive, non-ESRC resources are included, for example the Office for National Statistics. The portal provides access to early findings and research summaries, as well as full texts and original datasets through integrated search facilities. More at esrcsocietytoday.ac/
3. CESAGen works with natural scientists while conducting multidisciplinary research into the economic and social factors that shape genomic science, as applied not only to humans but also to plants and animals. In the light of considerable national and international attention to these issues, and increased public debate, CESAGen aims to undertake a programme of public engagement as well as feeding its research into policy circles. For more information visit: cesagen.lancs.ac/
4. Egenis is the ESRC Centre for Genomics in Society charged with researching the impact of genetic technologies in society. Egenis is part of the University of Exeter. For more information visit: ex.ac/egenis
5. Innogen is the ESRC Centre for Social and Economic Research on Innovation in Genomics. Formed in October 2002, it is part of the ESRC Genomics Network and studies the evolution of genomics and life sciences and their far-reaching social and economic implications. Innogen's research provides a sound base for decision-making in science, industry, policy and public arenas and improves our understanding of each of these groups and their interactions. Innogen is based at the University of Edinburgh in collaboration with The Open University. Staff working at Innogen include interdisciplinary researchers, social scientists, economists, and lawyers. Innogen also engages with a wide range of stakeholders, nationally and internationally. For more information visit: innogen.ac/
Contact: Annika Howard
Economic & Social Research Council
вторник, 30 августа 2011 г.
суббота, 27 августа 2011 г.
Screening Embryos Before IVF Implantation Leads To Fewer Babies For Older Women, New Study
Preimplantation genetic screening (PGS) fails to improve IVF outcomes in older women; it leads to fewer pregnancies and live births, an embryologist from
The Netherlands announced at the 23rd annual conference of the European Society of Human Reproduction and Embryology (ESHRE) in Lyon, France,
yesterday.
The findings of the study are also published in the New England Journal of Medicine (NEJM).
Pregnancy rates of older women having IVF tend to be disappointingly low, wrote the researchers, and there is a view that screening embryos
before implantation for problems such as aneuploidies (too few or too many chromosomes) is a way to improve the effectiveness of IVF for these women.
Sebastiaan Mastenbroek,from the Centre for Reproductive Medicine of the Academic Medical Centre of the University of Amsterdam, and his team tested this
hypothesis and concluded that PGS should not be carried out routinely on embryos that are to be implanted in women over 35.
Mastenbroek and colleagues conducted a multi-centre, randomized, double-blind, controlled trial where they compared three cycles of IVF with and without PGS
in 408 women aged between 35 and 41.
206 of the women were assigned to PGS, while the rest were not (non-PGS, or control group).
The ongoing pregnancy rate was considerably lower in the PGS group compared to the non-PGS group.
Mastenbroek said:
"We found that, at 12 weeks, 52 of the women in the PGS group were pregnant (25 per cent), whereas 74 of the control group (37 per cent) had an ongoing
pregnancy."
"And the women in the PGS group also had a significantly lower live birth rate: 49 or 24 per cent, as opposed to 71 or 35 per cent, of the controls," he
added.
The researchers concluded that:
"Preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of
advanced maternal age."
Speculating on their findings, the researchers said there could be several explanations for the failure of PGS to improve IVF in older women.
Perhaps it's the biposy of a cell from an early embryo (this is taken on day 3 after conception) that hampers successful implantation, said Mastenbroek,
although the effect of biopsy alone has not yet been studied.
Also, there is a limit to the number of chromosomes that can be tested by PGS and that could lead to implantation of embryos that appear normal but are not.
For instance IVF often produces mosaic embryos (more than one genetic individual), so testing a single cell does not analyse chromosomes representative of
all the cells of the embryo.
Many IVF centres worldwide are using PGS more and more. In 2003 the ESHRE preimplantation genetic diagnosis (ESHRE-PGD) consortium received reports of more
than 1,700 IVF cycles for which PGS were used. Since only 50 per cent of the IVF centres in the world report their data to the consortium, this figure is
likely to be an under-estimate, said the researchers.
Talking about figures for the US, Mastenbroek said that:
"In a recent survey of 415 assisted reproductive technology clinics in the US, 186 respondents (45 per cent) reported that they had performed a total of
2,197 cycles of PGS in 2005."
Mastenbroek and colleagues are going on to study why PGS does not work. Even though there is no scientific evidence to support the effectiveness or otherwise of PGS
apart from this study, patients and doctors are inclined to use it.
"The idea of screening embryos for chromosomal abnormalities to increase live birth rates in IVF is very plausible, and women of advanced maternal age are
willing to undergo any technique that may provide them with a baby," Mastenbroek explained.
He also said that more studies are needed since their research only covered older women who have PGS:
"We believe our findings imply that the efficacy of the technique also needs to be investigated in other groups of women who are offered PGS, such as those
who suffer recurrent miscarriage or repeated failure of IVF, since evidence for a benefit of PGS in these groups of women is currently still
lacking."
"In Vitro Fertilization with Preimplantation Genetic Screening."
Mastenbroek, Sebastiaan, Twisk, Moniek, van Echten-Arends, Jannie, Sikkema-Raddatz, Birgit, Korevaar, Johanna C., Verhoeve, Harold R., Vogel, Niels E.A.,
Arts, Eus G.J.M., de Vries, Jan W.A., Bossuyt, Patrick M., Buys, Charles H.C.M., Heineman, Maas Jan, Repping, Sjoerd, van der Veen, Fulco.
N Engl J Med 2007 357: 9-17
Volume 357:9-17, July 5, 2007, Number 1
Click here for Abstract.
Click here for more information on Assisted Reproductive Technology (from the
CDC).
: Catharine Paddock
Writer: blog
The Netherlands announced at the 23rd annual conference of the European Society of Human Reproduction and Embryology (ESHRE) in Lyon, France,
yesterday.
The findings of the study are also published in the New England Journal of Medicine (NEJM).
Pregnancy rates of older women having IVF tend to be disappointingly low, wrote the researchers, and there is a view that screening embryos
before implantation for problems such as aneuploidies (too few or too many chromosomes) is a way to improve the effectiveness of IVF for these women.
Sebastiaan Mastenbroek,from the Centre for Reproductive Medicine of the Academic Medical Centre of the University of Amsterdam, and his team tested this
hypothesis and concluded that PGS should not be carried out routinely on embryos that are to be implanted in women over 35.
Mastenbroek and colleagues conducted a multi-centre, randomized, double-blind, controlled trial where they compared three cycles of IVF with and without PGS
in 408 women aged between 35 and 41.
206 of the women were assigned to PGS, while the rest were not (non-PGS, or control group).
The ongoing pregnancy rate was considerably lower in the PGS group compared to the non-PGS group.
Mastenbroek said:
"We found that, at 12 weeks, 52 of the women in the PGS group were pregnant (25 per cent), whereas 74 of the control group (37 per cent) had an ongoing
pregnancy."
"And the women in the PGS group also had a significantly lower live birth rate: 49 or 24 per cent, as opposed to 71 or 35 per cent, of the controls," he
added.
The researchers concluded that:
"Preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of
advanced maternal age."
Speculating on their findings, the researchers said there could be several explanations for the failure of PGS to improve IVF in older women.
Perhaps it's the biposy of a cell from an early embryo (this is taken on day 3 after conception) that hampers successful implantation, said Mastenbroek,
although the effect of biopsy alone has not yet been studied.
Also, there is a limit to the number of chromosomes that can be tested by PGS and that could lead to implantation of embryos that appear normal but are not.
For instance IVF often produces mosaic embryos (more than one genetic individual), so testing a single cell does not analyse chromosomes representative of
all the cells of the embryo.
Many IVF centres worldwide are using PGS more and more. In 2003 the ESHRE preimplantation genetic diagnosis (ESHRE-PGD) consortium received reports of more
than 1,700 IVF cycles for which PGS were used. Since only 50 per cent of the IVF centres in the world report their data to the consortium, this figure is
likely to be an under-estimate, said the researchers.
Talking about figures for the US, Mastenbroek said that:
"In a recent survey of 415 assisted reproductive technology clinics in the US, 186 respondents (45 per cent) reported that they had performed a total of
2,197 cycles of PGS in 2005."
Mastenbroek and colleagues are going on to study why PGS does not work. Even though there is no scientific evidence to support the effectiveness or otherwise of PGS
apart from this study, patients and doctors are inclined to use it.
"The idea of screening embryos for chromosomal abnormalities to increase live birth rates in IVF is very plausible, and women of advanced maternal age are
willing to undergo any technique that may provide them with a baby," Mastenbroek explained.
He also said that more studies are needed since their research only covered older women who have PGS:
"We believe our findings imply that the efficacy of the technique also needs to be investigated in other groups of women who are offered PGS, such as those
who suffer recurrent miscarriage or repeated failure of IVF, since evidence for a benefit of PGS in these groups of women is currently still
lacking."
"In Vitro Fertilization with Preimplantation Genetic Screening."
Mastenbroek, Sebastiaan, Twisk, Moniek, van Echten-Arends, Jannie, Sikkema-Raddatz, Birgit, Korevaar, Johanna C., Verhoeve, Harold R., Vogel, Niels E.A.,
Arts, Eus G.J.M., de Vries, Jan W.A., Bossuyt, Patrick M., Buys, Charles H.C.M., Heineman, Maas Jan, Repping, Sjoerd, van der Veen, Fulco.
N Engl J Med 2007 357: 9-17
Volume 357:9-17, July 5, 2007, Number 1
Click here for Abstract.
Click here for more information on Assisted Reproductive Technology (from the
CDC).
: Catharine Paddock
Writer: blog
среда, 24 августа 2011 г.
Genetic Link To Age-Related Macular Degeneration Reported In The Lancet
A new genetic association with the condition age-related macular degeneration (AMD) is reported in an Article published early Online and in an upcoming edition of The Lancet, Dr Sarah Ennis and Professor Andrew Lotery, University of Southampton, UK, and colleagues.
AMD is the most prevalent form of visual impairment and blindness in developed countries. The recent Rotterdam study showed 64% of people aged 80 years or over have signs of the disease, and around 12% of this age group have AMD so severe it causes them to go blind. In the UK, the yearly economic burden of AMD is estimated to be some ??80 million. And the total yearly costs of health-care usage are seven times higher for patients with AMD than for controls, largely attributable to the decreased independence of affected individuals and increased need for assistance with daily living.
The researchers looked at a UK sample of patients with AMD (479) and controls (479) and screened 32 genes potentially involved in the condition. They found an association with the SERPING1 gene, which is involved in production of proteins for the 'complement' system within the eye that helps clear foreign material and infection. By analysing single base pair mutations, the group initially identified a single variant within the SERPING1 gene in which frequencies of the variant forms were significantly distorted in patients with AMD compared to controls. The researchers then replicated their findings in a separate US cohort of patients, and further verified their finding by conducting a secondary high-density analysis that revealed an additional five variants in the SERPING1 gene, all of which were associated with AMD.
The authors conclude: "Our study shows a strong association between age-related macular degeneration and SERPING1, with supporting evidence from an independent replication and a secondary high-density scan of the gene...genetic variation in SERPING1 may implicate the classic pathway of complement activation in AMD...Our findings add to the growing understanding of the genetics of age-related macular degeneration, which should ultimately lead to novel treatments for this common and devastating disease."
In an accompanying Comment (login required) Dr Caroline Klaver, Erasmus Medical Centre, Netherlands, and Professor Arthur Bergen, Netherlands Institute for Neurosciences, Netherlands, say that the next steps in the research should include replication of the study's findings in large independent cohorts as well as functional studies.
Article
"Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study"
Sarah Ennis, Catherine Jomary, Robert Mullins, Angela Cree, Xiaoli Chen, Alex MacLeod, Stephen Jones, Andrew Collins, Edwin Stone, Andrew Lotery
The Lancet - DOI:10.1016/S0140-6736(08)61348-3
Click here to read the Summary of the Article online.
The Lancet
AMD is the most prevalent form of visual impairment and blindness in developed countries. The recent Rotterdam study showed 64% of people aged 80 years or over have signs of the disease, and around 12% of this age group have AMD so severe it causes them to go blind. In the UK, the yearly economic burden of AMD is estimated to be some ??80 million. And the total yearly costs of health-care usage are seven times higher for patients with AMD than for controls, largely attributable to the decreased independence of affected individuals and increased need for assistance with daily living.
The researchers looked at a UK sample of patients with AMD (479) and controls (479) and screened 32 genes potentially involved in the condition. They found an association with the SERPING1 gene, which is involved in production of proteins for the 'complement' system within the eye that helps clear foreign material and infection. By analysing single base pair mutations, the group initially identified a single variant within the SERPING1 gene in which frequencies of the variant forms were significantly distorted in patients with AMD compared to controls. The researchers then replicated their findings in a separate US cohort of patients, and further verified their finding by conducting a secondary high-density analysis that revealed an additional five variants in the SERPING1 gene, all of which were associated with AMD.
The authors conclude: "Our study shows a strong association between age-related macular degeneration and SERPING1, with supporting evidence from an independent replication and a secondary high-density scan of the gene...genetic variation in SERPING1 may implicate the classic pathway of complement activation in AMD...Our findings add to the growing understanding of the genetics of age-related macular degeneration, which should ultimately lead to novel treatments for this common and devastating disease."
In an accompanying Comment (login required) Dr Caroline Klaver, Erasmus Medical Centre, Netherlands, and Professor Arthur Bergen, Netherlands Institute for Neurosciences, Netherlands, say that the next steps in the research should include replication of the study's findings in large independent cohorts as well as functional studies.
Article
"Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study"
Sarah Ennis, Catherine Jomary, Robert Mullins, Angela Cree, Xiaoli Chen, Alex MacLeod, Stephen Jones, Andrew Collins, Edwin Stone, Andrew Lotery
The Lancet - DOI:10.1016/S0140-6736(08)61348-3
Click here to read the Summary of the Article online.
The Lancet
воскресенье, 21 августа 2011 г.
Why Tumor Cells Become Resistant
Cells with irreparable DNA damage normally induce programmed cell death, or apoptosis. However, this mechanism often fails in tumor cells so that transformed cells are able to multiply and spread throughout the body. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered a possible cause of this failure. Tumor cells simply degrade a protein that triggers apoptosis in the case of DNA damage. Blocking this protein degradation might set apoptosis back in operation and, thus, increase the effectiveness of radiotherapy or chemotherapy. The researchers have now published their results in Nature Cell Biology.
Proteins that trigger programmed cell death, or apoptosis, must be kept under careful control. After all, a cell should induce its own death only if its genetic material is damaged so severely that there is a danger of its transformation into a malignantly growing tumor cell. However, minor damages in the DNA can be corrected by the cell's special repair mechanisms - hence, no reason to commit suicide!
Among the proteins that trigger apoptosis after severe DNA damage is the HIPK2 molecule. Scientists in Dr. Thomas Hofmann's research group at the German Cancer Research Center (DKFZ) have now shown that although HIPK2 is continuously produced in healthy cells, it is instantly degraded again. An enzyme called Siah-1 attaches labels to HIPK2 marking it as "garbage". Thus, the cell prevents that apoptosis is induced "accidentally".
Slightly damaged cells enter a kind of alarm status: They block degradation of HIPK2 by Siah-1 for a short time. But as soon as the damage is repaired, the cell immediately resumes labeling HIPK2 as garbage and degrades the molecule. Only in severely damaged cells, such as by a broken DNA double strand, degradation of HIPK2 by the Siah-1 enzyme is blocked permanently. As a result, HIPK2 accumulates, apoptosis is triggered, and the cell commits suicide.
Researchers assume that this could be one of the reasons why radiation therapy or chemotherapy is sometimes ineffective. Both treatment methods cause severe damage to tumor cells, which eventually leads to programmed cell death. "If resistances occur, this is often caused by tumor cells 'refusing' to take the order to commit suicide," Thomas Hofmann explains.
To prevent HIPK2 degradation, Hoffmann and his colleagues conducted experiments in which they blocked the Siah-1 enzyme. As a result, HIPK2 was able to accumulate even in cells that were only slightly damaged, and apoptosis was induced. "Cancer medicine might be able to make use of our discovery," speculates Hofmann. "For example, we could use a Siah-1 blocker simultaneously with chemotherapy or radiotherapy to get the cells back into the apoptosis program."
Melanie Winter, Dirk Sombroek, Ilka Dauth, Jutta Moehlenbrink, Karin Scheuermann, Johanna Crone and Thomas G. Hofmann: Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology, 2008; DOI 10.1038/ncb1743.
The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V.).
Source: Dr. Stefanie Seltmann
Helmholtz Association of German Research Centres
Proteins that trigger programmed cell death, or apoptosis, must be kept under careful control. After all, a cell should induce its own death only if its genetic material is damaged so severely that there is a danger of its transformation into a malignantly growing tumor cell. However, minor damages in the DNA can be corrected by the cell's special repair mechanisms - hence, no reason to commit suicide!
Among the proteins that trigger apoptosis after severe DNA damage is the HIPK2 molecule. Scientists in Dr. Thomas Hofmann's research group at the German Cancer Research Center (DKFZ) have now shown that although HIPK2 is continuously produced in healthy cells, it is instantly degraded again. An enzyme called Siah-1 attaches labels to HIPK2 marking it as "garbage". Thus, the cell prevents that apoptosis is induced "accidentally".
Slightly damaged cells enter a kind of alarm status: They block degradation of HIPK2 by Siah-1 for a short time. But as soon as the damage is repaired, the cell immediately resumes labeling HIPK2 as garbage and degrades the molecule. Only in severely damaged cells, such as by a broken DNA double strand, degradation of HIPK2 by the Siah-1 enzyme is blocked permanently. As a result, HIPK2 accumulates, apoptosis is triggered, and the cell commits suicide.
Researchers assume that this could be one of the reasons why radiation therapy or chemotherapy is sometimes ineffective. Both treatment methods cause severe damage to tumor cells, which eventually leads to programmed cell death. "If resistances occur, this is often caused by tumor cells 'refusing' to take the order to commit suicide," Thomas Hofmann explains.
To prevent HIPK2 degradation, Hoffmann and his colleagues conducted experiments in which they blocked the Siah-1 enzyme. As a result, HIPK2 was able to accumulate even in cells that were only slightly damaged, and apoptosis was induced. "Cancer medicine might be able to make use of our discovery," speculates Hofmann. "For example, we could use a Siah-1 blocker simultaneously with chemotherapy or radiotherapy to get the cells back into the apoptosis program."
Melanie Winter, Dirk Sombroek, Ilka Dauth, Jutta Moehlenbrink, Karin Scheuermann, Johanna Crone and Thomas G. Hofmann: Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology, 2008; DOI 10.1038/ncb1743.
The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V.).
Source: Dr. Stefanie Seltmann
Helmholtz Association of German Research Centres
четверг, 18 августа 2011 г.
Molecular DNA Switch Found To Be The Same For All Life
The molecular machinery that starts the process by which a biological cell divides into two identical daughter cells apparently worked so well early on that evolution has conserved it across the eons in all forms of life on Earth. Researchers with the U.S. Department of Energy's Lawrence Berkeley National Laboratory and the University of California at Berkeley have shown that the core machinery for initiating DNA replication is the same for all three domains of life - Archaea, Bacteria and Eukarya.
In two papers that will be concurrently published in the August edition of the journal Nature Structural and Molecular Biology (now available on-line), the researchers report the identification of a helical substructure within a superfamily of proteins, called AAA+, as the molecular "initiator" of DNA replication in a bacteria, Escherichia coli (E. coli), and in a eukaryote, Drosophila melanogaster, the fruit fly. Taken with earlier research that identified AAA+ proteins at the heart of the DNA replication initiator in archaea organisms, these new findings indicate that DNA replication is an ancient event that evolved millions of years ago, prior to when Archaea, Bacteria and Eukarya split into separate domains of life.
"The ability of a cell to replicate its DNA in a timely and faithful manner is fundamental for survival, but, despite decades of study, the structural and molecular basis for initiating DNA replication, and the degree to which these mechanisms have been conserved by evolution have been ill defined and hotly debated," said biophysicist Eva Nogales, a collaborator on the Drosophila study.
Said biochemist Michael Botchan, also a collaborator on the Drosophila study, "Our two papers fuse together a number of biophysical research techniques to take our understanding of the mechanics of DNA opening and replisome construction to a new level."
Biochemist and structural biologist James Berger, a participant in both studies added, "Our findings of evolutionary kinship between the DNA initiators in all three domains make sense because, to paraphrase Francois Jacob, the one thing a cell wants to do is to become two cells. A cell can't do this if it doesn't replicate its DNA in the right place, at the right time, and in the right manner, while simultaneously avoiding over-replication."
The Drosophila results were reported in a paper entitled: Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex. This study was led by Botchan and Nogales, and included Megan Clarey, Jan Erzberger, Patricia Grob, Andres Leschziner and Berger. Nogales and Berger hold appointments with Berkeley Lab's Life Science and Physical Biosciences Divisions, respectively, and with UC Berkeley's Molecular and Cell Biology Department, in which Botchan is a professor. Nogales is also an investigator with the Howard Hughes Medical Institute.
The Eli results were presented in a paper entitled:Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling. Berger led this study and his collaborators included Erzberger and Melissa Mott.
While the research studies behind these two papers were not coordinated, they did benefit from "a convenient congruence of timely results," as Berger explained.
"We had solved our initiator structures in the Eli study just as results were being generated from the Botchan and Nogales groups on the Drosophila study. Once we compared notes, we immediately pooled forces. When we subsequently were able to dock our bacterial model into a region of their eukaryotic structure, it solidified the evolutionary and functional similarities between the two mechanisms."
For the Eli study, Berger and his team utilized the exceptionally bright and intense x-rays of Beamline 8.3.1 at Berkeley Lab's Advanced Light Source synchrotron. With the data gathered at this protein crystallography facility,
Berger and his team assembled a high-resolution model of the molecular structure of a protein known as DnaA, which is a member of the AAA+ family. While it has long been known that DnaA controls the process of initiating DNA replication in bacteria, the molecular details of its myriad activities have until now been a mystery.
Berger's team found that when the DnaA protein binds with adenosine triphosphate or ATP, the nucleotide molecule that supplies energy to all components of a cell, the ring-shaped AAA+ proteins assemble into a right-handed spiraling superstructure. This arrangement was unexpected, because in other functional AAA+ complexes, the ring assemblies are closed. In addition, the architecture indicated that the AAA+ superhelix will wrap coils of the DNA double-helix around its exterior, causing the familiar "spiral staircase" of the DNA to deform as a first step in the separation and unwinding of its two gene-carrying strands.
"It is likely that the AAA+ rings of the replication initiators are open to allow others proteins to dock onto the initiator complex," said Berger. "These other proteins can help add layers of complexity, such as assisting with helicase loading or inactivating the initiator after replication has begun. The open rings also probably allow DNA to interact with the interior of the initiator assembly."
Bacterial cells, like the cells of Achaeans, are prokaryotes, meaning their DNA is not contained within a defined nucleus. Eukaryotes consist of plants and animals and all other organisms whose DNA is contained within a membrane-bound nucleus. Whereas DNA replication in bacteria is typically initiated at a single sites, DNA replication in eukaryotes can be an immensely complicated multi-event affair, involving the coordinated initiation and regulation of hundreds and even thousands of protein machines at different sites throughout the genome. Furthermore, the highly packaged nature of eukaryotic genomes makes it difficult for these protein machines to access the DNA. Because of this complexity, the mechanism for initiating DNA replication in eukaryotes was presumed to be much different than the prokaryote initiator.
Studies over the past decade have demonstrated that all of the multiple events that initiate DNA replication in a eukaryote are directed by a single complex of proteins called the origin recognition complex (ORC). However, until now, models of the ORC proteins have lacked sufficient detail to identify the structure of the initiator. In their Drosophila study, Nogales and Botchan and their collaborators studied fruit fly ORC using single-particle electron microscopy. Their images revealed for the first time how the ORC when bound to ATP forms a AAA+ helical structure much like the DnaA superhelix found by Berger and his team in their Eli study.
"This work provides the first view of the mechanical transitions in ORC driven by ATP in a higher organism," said Nogales. "While our studies have not yet shown the initiator wrapped around the DNA, the structural similarity to the DnaA initiator found in the Eli study suggests that there are likely to be strong mechanistic commonalities in the ways that initiators engage and remodel replication origins, as well as in how they facilitate replisome assembly."
The idea that all three domains of life share the same DNA replication initiator is new and will require some re-thinking on the part of biologists who study eukaryotes. Re-thinking will also be required for models of DNA replication that predicted initiators would have similar structures to the protein "clamps" and "clamp loaders" already identified as key mechanisms in the DNA replication process.
Said Berger, "Our work shows that there are major structural distinctions between assembled initiator and clamp loader complexes. This not only has important implications for the respective functions of these different mechanisms, it also calls into question some cherished models in the field."
The two studies by Nogales, Berger, Botchan and their colleagues also show how when nature finds a mechanism that works well, such a mechanism is conserved through evolution.
Said Nogales, "The specialization of DNA replication initiators took place a long time ago, separating them from other members of the AAA+ superfamily of proteins while maintaining an identity among themselves that reflects the importance of the replication process. Through the millions of years, evolution has added bells and whistles around this highly conserved central engine."
The Eli study was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and the National Institutes of Health (NIH). The Drosophila study was also supported by NIH, plus the U.S. Department of Energy's Office of Biological and Environmental Research and HHMI.
Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our Website at lbl/
Copies of the two scientific papers discussed in this press release can be viewed on-line at nature/nsmb/index.html
Eva Nogales can be reached by e-mail at
ENogaleslbl
James Berger can be reached by e-mail at
jmbergercalmail.berkeley.edu
Michael Botchan can be reached by e-mail at
mbotchanberkeley.edu
Contact: Lynn Yarris
DOE/Lawrence Berkeley National Laboratory/
In two papers that will be concurrently published in the August edition of the journal Nature Structural and Molecular Biology (now available on-line), the researchers report the identification of a helical substructure within a superfamily of proteins, called AAA+, as the molecular "initiator" of DNA replication in a bacteria, Escherichia coli (E. coli), and in a eukaryote, Drosophila melanogaster, the fruit fly. Taken with earlier research that identified AAA+ proteins at the heart of the DNA replication initiator in archaea organisms, these new findings indicate that DNA replication is an ancient event that evolved millions of years ago, prior to when Archaea, Bacteria and Eukarya split into separate domains of life.
"The ability of a cell to replicate its DNA in a timely and faithful manner is fundamental for survival, but, despite decades of study, the structural and molecular basis for initiating DNA replication, and the degree to which these mechanisms have been conserved by evolution have been ill defined and hotly debated," said biophysicist Eva Nogales, a collaborator on the Drosophila study.
Said biochemist Michael Botchan, also a collaborator on the Drosophila study, "Our two papers fuse together a number of biophysical research techniques to take our understanding of the mechanics of DNA opening and replisome construction to a new level."
Biochemist and structural biologist James Berger, a participant in both studies added, "Our findings of evolutionary kinship between the DNA initiators in all three domains make sense because, to paraphrase Francois Jacob, the one thing a cell wants to do is to become two cells. A cell can't do this if it doesn't replicate its DNA in the right place, at the right time, and in the right manner, while simultaneously avoiding over-replication."
The Drosophila results were reported in a paper entitled: Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex. This study was led by Botchan and Nogales, and included Megan Clarey, Jan Erzberger, Patricia Grob, Andres Leschziner and Berger. Nogales and Berger hold appointments with Berkeley Lab's Life Science and Physical Biosciences Divisions, respectively, and with UC Berkeley's Molecular and Cell Biology Department, in which Botchan is a professor. Nogales is also an investigator with the Howard Hughes Medical Institute.
The Eli results were presented in a paper entitled:Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling. Berger led this study and his collaborators included Erzberger and Melissa Mott.
While the research studies behind these two papers were not coordinated, they did benefit from "a convenient congruence of timely results," as Berger explained.
"We had solved our initiator structures in the Eli study just as results were being generated from the Botchan and Nogales groups on the Drosophila study. Once we compared notes, we immediately pooled forces. When we subsequently were able to dock our bacterial model into a region of their eukaryotic structure, it solidified the evolutionary and functional similarities between the two mechanisms."
For the Eli study, Berger and his team utilized the exceptionally bright and intense x-rays of Beamline 8.3.1 at Berkeley Lab's Advanced Light Source synchrotron. With the data gathered at this protein crystallography facility,
Berger and his team assembled a high-resolution model of the molecular structure of a protein known as DnaA, which is a member of the AAA+ family. While it has long been known that DnaA controls the process of initiating DNA replication in bacteria, the molecular details of its myriad activities have until now been a mystery.
Berger's team found that when the DnaA protein binds with adenosine triphosphate or ATP, the nucleotide molecule that supplies energy to all components of a cell, the ring-shaped AAA+ proteins assemble into a right-handed spiraling superstructure. This arrangement was unexpected, because in other functional AAA+ complexes, the ring assemblies are closed. In addition, the architecture indicated that the AAA+ superhelix will wrap coils of the DNA double-helix around its exterior, causing the familiar "spiral staircase" of the DNA to deform as a first step in the separation and unwinding of its two gene-carrying strands.
"It is likely that the AAA+ rings of the replication initiators are open to allow others proteins to dock onto the initiator complex," said Berger. "These other proteins can help add layers of complexity, such as assisting with helicase loading or inactivating the initiator after replication has begun. The open rings also probably allow DNA to interact with the interior of the initiator assembly."
Bacterial cells, like the cells of Achaeans, are prokaryotes, meaning their DNA is not contained within a defined nucleus. Eukaryotes consist of plants and animals and all other organisms whose DNA is contained within a membrane-bound nucleus. Whereas DNA replication in bacteria is typically initiated at a single sites, DNA replication in eukaryotes can be an immensely complicated multi-event affair, involving the coordinated initiation and regulation of hundreds and even thousands of protein machines at different sites throughout the genome. Furthermore, the highly packaged nature of eukaryotic genomes makes it difficult for these protein machines to access the DNA. Because of this complexity, the mechanism for initiating DNA replication in eukaryotes was presumed to be much different than the prokaryote initiator.
Studies over the past decade have demonstrated that all of the multiple events that initiate DNA replication in a eukaryote are directed by a single complex of proteins called the origin recognition complex (ORC). However, until now, models of the ORC proteins have lacked sufficient detail to identify the structure of the initiator. In their Drosophila study, Nogales and Botchan and their collaborators studied fruit fly ORC using single-particle electron microscopy. Their images revealed for the first time how the ORC when bound to ATP forms a AAA+ helical structure much like the DnaA superhelix found by Berger and his team in their Eli study.
"This work provides the first view of the mechanical transitions in ORC driven by ATP in a higher organism," said Nogales. "While our studies have not yet shown the initiator wrapped around the DNA, the structural similarity to the DnaA initiator found in the Eli study suggests that there are likely to be strong mechanistic commonalities in the ways that initiators engage and remodel replication origins, as well as in how they facilitate replisome assembly."
The idea that all three domains of life share the same DNA replication initiator is new and will require some re-thinking on the part of biologists who study eukaryotes. Re-thinking will also be required for models of DNA replication that predicted initiators would have similar structures to the protein "clamps" and "clamp loaders" already identified as key mechanisms in the DNA replication process.
Said Berger, "Our work shows that there are major structural distinctions between assembled initiator and clamp loader complexes. This not only has important implications for the respective functions of these different mechanisms, it also calls into question some cherished models in the field."
The two studies by Nogales, Berger, Botchan and their colleagues also show how when nature finds a mechanism that works well, such a mechanism is conserved through evolution.
Said Nogales, "The specialization of DNA replication initiators took place a long time ago, separating them from other members of the AAA+ superfamily of proteins while maintaining an identity among themselves that reflects the importance of the replication process. Through the millions of years, evolution has added bells and whistles around this highly conserved central engine."
The Eli study was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and the National Institutes of Health (NIH). The Drosophila study was also supported by NIH, plus the U.S. Department of Energy's Office of Biological and Environmental Research and HHMI.
Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our Website at lbl/
Copies of the two scientific papers discussed in this press release can be viewed on-line at nature/nsmb/index.html
Eva Nogales can be reached by e-mail at
ENogaleslbl
James Berger can be reached by e-mail at
jmbergercalmail.berkeley.edu
Michael Botchan can be reached by e-mail at
mbotchanberkeley.edu
Contact: Lynn Yarris
DOE/Lawrence Berkeley National Laboratory/
понедельник, 15 августа 2011 г.
Team Finds Breast Cancer Gene Linked To Disease Spread
A team of researchers at Princeton University and The Cancer Institute
of New Jersey has identified a long-sought gene that is fatefully
switched on in 30 to 40 percent of all breast cancer patients, spreading
the disease, resisting traditional chemotherapies and eventually leading
to death.
The gene, called "Metadherin" or MTDH, is located in a small region of
human chromosome 8 and appears to be crucial to cancer's spread or
metastasis because it helps tumor cells stick tightly to blood vessels
in distant organs. The gene also makes tumors more resistant to the
powerful chemotherapeutic agents normally used to wipe out the deadly
cells.
In identifying the genetic mechanism at play in the metastasis of
breast cancer, the scientists may have answered one of the biggest
mysteries in cancer research and paved the way for new drugs that could
thwart the gene's diabolical actions.
"Inhibiting this gene in breast cancer patients will simultaneously
achieve two important goals -- reduce the chance of recurrence and, at
the same, time decrease the risk of metastatic dissemination," said
Yibin Kang, an assistant professor of molecular biology at Princeton,
who led the research. "Clinically, these are the two major reasons why
breast cancer patients die from the disease."
The work is described in the Jan. 6 edition of Cancer Cell.
The discovery is important for several other reasons, according to
Michael Reiss, another author of the paper and director of the Breast
Cancer Research Program at The Cancer Institute of New Jersey, a part of
the University of Medicine and Dentistry of New Jersey-Robert Wood
Johnson Medical School.
"Not only has a new metastasis gene been identified, but this also is
one of a few such genes for which the exact mode of action has been
elucidated," said Reiss, also a professor of medicine, molecular
genetics and microbiology at UMDNJ-Robert Wood Johnson Medical School.
"That gives us a real shot at developing a drug that will inhibit
metastasis."
The multidisciplinary research strategy used by the team to pinpoint
the gene in breast cancer patients also could be used to find other
genes involved in the spread of other cancers, scientists said.
"The potential health implications of this study are significant," Kang
said.
The discovery is based on three years of work, using an approach that
combines the emerging science of integrative genomics with the classical
methods of clinical research and laboratory experiments.
"This paper is a great illustration of the way in which bioinformatics
can be synergistically combined with experimental work to produce
important results," said David Botstein, director of Princeton's
Lewis-Sigler Institute for Integrative Genomics.
>From the beginning, the scientists were looking for a way to understand
the dreaded process of metastasis, the term describing what happens when
cancer spreads to distant vital organs, such as the lungs, liver, brain
and even the bones.
As the scientists well understood, patients whose breast cancer can be
confined to the breast have the best chances at survival. The five-year
survival rates, as compiled by the National Cancer Institute, illustrate
the difference between localized and metastatic cancer: 98.1 percent of
patients with localized breast cancer survive five years after
diagnosis, as opposed to 27.1 percent for patients with cancer that has
traveled beyond the lymph nodes to bodily organs, according to the
federal agency's statistics.
In recent years, researchers have used advanced techniques such as DNA
microarray technology to try and identify genetic profiles of the so
called "poor prognosis" tumors -- those that are likely to come back
after the initial treatment and are most likely to spread beyond the
breast. Such studies, though useful in predicting outcomes, have
perplexingly offered up differing gene "signatures," making it difficult
to identify overlapping, functionally relevant genes that might be
important targets for therapeutic intervention.
The scientists in this study addressed this problem by using an
innovative computational biology approach. They re-analyzed massive
clinical breast cancer databases and found that study after study showed
one area in common -- a very small region in human chromosome 8 called
8q22. They found that this area of the chromosome is repeated many times
in the genomes of poor-prognosis breast tumors. Some chromosomes
contained as many as eight copies or "repeats" of the genetic segment.
Most normal DNA sequences contain only two copies of a given gene,
conveyed from the genomes of the male and female parents.
Next, the team studied breast tumor samples collected from patients at
The Cancer Institute of New Jersey. In doing so, the researchers were
able to validate the computational prediction, confirming that the
genetic sequence identified in the database was overproduced in the DNA
of the poor-prognosis tumor samples.
The researchers went on to discover that among a handful of genes in
the 8q22 region, MTDH is responsible for the aggressive behavior of
poor-prognosis tumors. They used recombinant DNA technology to enhance
the expression of individual genes in the region, one by one, in breast
tumor cells and tested their metastatic behavior in laboratory mice.
The scientists found that MTDH-overexpressing tumors are more likely to
metastasize to the lungs, other vital organs and bones. Importantly,
these tumors were also found to be more resistant to a wide range of
chemotherapeutic agents, including paclitaxel, cisplatin and adriamycin.
When researchers genetically altered the cancer cells to reduce the
expression of MTDH, these tumor cells become less able to metastasize
and more likely to be eliminated by chemotherapy agents.
"This is probably one of the first examples of a novel class of dual
functional breast cancer genes that cause both metastasis and
chemoresistance," Kang said.
Once the team had identified the specific gene, its scientists were
able to re-examine the tumor samples. "By analyzing 250 breast tumor
samples from patients, we found that this gene is amplified and
overexpressed in over 30 to 40 percent of breast cancer cases," Kang
said. "This indicates that new drugs against Metadherin may potentially
benefit a large population of breast cancer patients."
Gene expression is the translation of information encoded in a gene
into proteins that determine an organism's characteristics. Since only a
fraction of genes in a genome are expressed in a given cell, genes that
are turned "on" are viewed by scientists as a major signal that controls
the biology of both normal and malignant cells.
Breast cancer is caused by a malignant tumor that develops from cells
in the breast. The most common sign of breast cancer is a new lump or
mass in the breast. Scientists once thought that breast cancer spreads
first to nearby tissue and underarm lymph nodes before spreading to
other parts of the body. They now believe cancer cells may break away
from the primary tumor in the breast and begin to metastasize even when
the disease is in an early stage.
The team also found that the double menaces of MTDH may be involved in
the progression of other types of cancers, including prostate cancer.
The work was funded by a Department of Defense Era of Hope Scholar
Award and grants from the National Institutes of Health, the American
Cancer Society, the Susan G. Komen Foundation and the New Jersey
Commission on Cancer Research.
The Department of Defense awards, created in 2004, were designed to
provide substantial funds and support for exceptionally talented,
emerging breast cancer researchers -- individuals who had demonstrated
extraordinary creativity, vision and productivity, according to Capt. E.
Melissa Kaime, a physician who is director of the U.S. Army
Congressionally Directed Medical Research Programs.
"This award mechanism seeks the 'best and the brightest' early-career
researchers who will challenge current dogma and convention and who are
the future innovators of breast cancer research," Kaime said. "Era of
Hope Scholar Dr. Kang has already made exciting research achievements,
including his latest manuscript in Cancer Cell, and he is only halfway
into his five-year, $3.8 million award. The Breast Cancer Research
Program sees a promising and hopeful future with Era of Hope Scholars
like Dr. Kang dedicated to ending this disease."
Guohong Hu, a postdoctoral research associate in Princeton's Department
of Molecular Biology, is the first author on the paper. In addition to
Kang and Reiss, other authors include: Robert Chong, a 2007 Princeton
graduate who is now a research assistant in Princeton's Department of
Molecular Biology; Qifeng Yang, who was at UMDNJ-Robert Wood Johnson
Medical School and is now in the Department of Breast Surgery at Qilu
Hospital of Shandong University in China; Yong Wei, a postdoctoral
research associate in Princeton's Department of Molecular Biology;
Andres Blanco, a graduate student in Princeton's Department of Molecular
Biology; Feng Li, an associate research scholar in Princeton's
Department of Molecular Biology; Jessie Au, Distinguished University
Professor in the College of Pharmacy at Ohio State University; and Bruce
Haffty, professor and chair of the Department of Radiation Oncology at
UMDNJ-Robert Wood Johnson Medical School and chief of radiation oncology
at The Cancer Institute of New Jersey.
Source
Michele Fisher
Media Relations Specialist
Office of Communications
The Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903
umdnj.edu
of New Jersey has identified a long-sought gene that is fatefully
switched on in 30 to 40 percent of all breast cancer patients, spreading
the disease, resisting traditional chemotherapies and eventually leading
to death.
The gene, called "Metadherin" or MTDH, is located in a small region of
human chromosome 8 and appears to be crucial to cancer's spread or
metastasis because it helps tumor cells stick tightly to blood vessels
in distant organs. The gene also makes tumors more resistant to the
powerful chemotherapeutic agents normally used to wipe out the deadly
cells.
In identifying the genetic mechanism at play in the metastasis of
breast cancer, the scientists may have answered one of the biggest
mysteries in cancer research and paved the way for new drugs that could
thwart the gene's diabolical actions.
"Inhibiting this gene in breast cancer patients will simultaneously
achieve two important goals -- reduce the chance of recurrence and, at
the same, time decrease the risk of metastatic dissemination," said
Yibin Kang, an assistant professor of molecular biology at Princeton,
who led the research. "Clinically, these are the two major reasons why
breast cancer patients die from the disease."
The work is described in the Jan. 6 edition of Cancer Cell.
The discovery is important for several other reasons, according to
Michael Reiss, another author of the paper and director of the Breast
Cancer Research Program at The Cancer Institute of New Jersey, a part of
the University of Medicine and Dentistry of New Jersey-Robert Wood
Johnson Medical School.
"Not only has a new metastasis gene been identified, but this also is
one of a few such genes for which the exact mode of action has been
elucidated," said Reiss, also a professor of medicine, molecular
genetics and microbiology at UMDNJ-Robert Wood Johnson Medical School.
"That gives us a real shot at developing a drug that will inhibit
metastasis."
The multidisciplinary research strategy used by the team to pinpoint
the gene in breast cancer patients also could be used to find other
genes involved in the spread of other cancers, scientists said.
"The potential health implications of this study are significant," Kang
said.
The discovery is based on three years of work, using an approach that
combines the emerging science of integrative genomics with the classical
methods of clinical research and laboratory experiments.
"This paper is a great illustration of the way in which bioinformatics
can be synergistically combined with experimental work to produce
important results," said David Botstein, director of Princeton's
Lewis-Sigler Institute for Integrative Genomics.
>From the beginning, the scientists were looking for a way to understand
the dreaded process of metastasis, the term describing what happens when
cancer spreads to distant vital organs, such as the lungs, liver, brain
and even the bones.
As the scientists well understood, patients whose breast cancer can be
confined to the breast have the best chances at survival. The five-year
survival rates, as compiled by the National Cancer Institute, illustrate
the difference between localized and metastatic cancer: 98.1 percent of
patients with localized breast cancer survive five years after
diagnosis, as opposed to 27.1 percent for patients with cancer that has
traveled beyond the lymph nodes to bodily organs, according to the
federal agency's statistics.
In recent years, researchers have used advanced techniques such as DNA
microarray technology to try and identify genetic profiles of the so
called "poor prognosis" tumors -- those that are likely to come back
after the initial treatment and are most likely to spread beyond the
breast. Such studies, though useful in predicting outcomes, have
perplexingly offered up differing gene "signatures," making it difficult
to identify overlapping, functionally relevant genes that might be
important targets for therapeutic intervention.
The scientists in this study addressed this problem by using an
innovative computational biology approach. They re-analyzed massive
clinical breast cancer databases and found that study after study showed
one area in common -- a very small region in human chromosome 8 called
8q22. They found that this area of the chromosome is repeated many times
in the genomes of poor-prognosis breast tumors. Some chromosomes
contained as many as eight copies or "repeats" of the genetic segment.
Most normal DNA sequences contain only two copies of a given gene,
conveyed from the genomes of the male and female parents.
Next, the team studied breast tumor samples collected from patients at
The Cancer Institute of New Jersey. In doing so, the researchers were
able to validate the computational prediction, confirming that the
genetic sequence identified in the database was overproduced in the DNA
of the poor-prognosis tumor samples.
The researchers went on to discover that among a handful of genes in
the 8q22 region, MTDH is responsible for the aggressive behavior of
poor-prognosis tumors. They used recombinant DNA technology to enhance
the expression of individual genes in the region, one by one, in breast
tumor cells and tested their metastatic behavior in laboratory mice.
The scientists found that MTDH-overexpressing tumors are more likely to
metastasize to the lungs, other vital organs and bones. Importantly,
these tumors were also found to be more resistant to a wide range of
chemotherapeutic agents, including paclitaxel, cisplatin and adriamycin.
When researchers genetically altered the cancer cells to reduce the
expression of MTDH, these tumor cells become less able to metastasize
and more likely to be eliminated by chemotherapy agents.
"This is probably one of the first examples of a novel class of dual
functional breast cancer genes that cause both metastasis and
chemoresistance," Kang said.
Once the team had identified the specific gene, its scientists were
able to re-examine the tumor samples. "By analyzing 250 breast tumor
samples from patients, we found that this gene is amplified and
overexpressed in over 30 to 40 percent of breast cancer cases," Kang
said. "This indicates that new drugs against Metadherin may potentially
benefit a large population of breast cancer patients."
Gene expression is the translation of information encoded in a gene
into proteins that determine an organism's characteristics. Since only a
fraction of genes in a genome are expressed in a given cell, genes that
are turned "on" are viewed by scientists as a major signal that controls
the biology of both normal and malignant cells.
Breast cancer is caused by a malignant tumor that develops from cells
in the breast. The most common sign of breast cancer is a new lump or
mass in the breast. Scientists once thought that breast cancer spreads
first to nearby tissue and underarm lymph nodes before spreading to
other parts of the body. They now believe cancer cells may break away
from the primary tumor in the breast and begin to metastasize even when
the disease is in an early stage.
The team also found that the double menaces of MTDH may be involved in
the progression of other types of cancers, including prostate cancer.
The work was funded by a Department of Defense Era of Hope Scholar
Award and grants from the National Institutes of Health, the American
Cancer Society, the Susan G. Komen Foundation and the New Jersey
Commission on Cancer Research.
The Department of Defense awards, created in 2004, were designed to
provide substantial funds and support for exceptionally talented,
emerging breast cancer researchers -- individuals who had demonstrated
extraordinary creativity, vision and productivity, according to Capt. E.
Melissa Kaime, a physician who is director of the U.S. Army
Congressionally Directed Medical Research Programs.
"This award mechanism seeks the 'best and the brightest' early-career
researchers who will challenge current dogma and convention and who are
the future innovators of breast cancer research," Kaime said. "Era of
Hope Scholar Dr. Kang has already made exciting research achievements,
including his latest manuscript in Cancer Cell, and he is only halfway
into his five-year, $3.8 million award. The Breast Cancer Research
Program sees a promising and hopeful future with Era of Hope Scholars
like Dr. Kang dedicated to ending this disease."
Guohong Hu, a postdoctoral research associate in Princeton's Department
of Molecular Biology, is the first author on the paper. In addition to
Kang and Reiss, other authors include: Robert Chong, a 2007 Princeton
graduate who is now a research assistant in Princeton's Department of
Molecular Biology; Qifeng Yang, who was at UMDNJ-Robert Wood Johnson
Medical School and is now in the Department of Breast Surgery at Qilu
Hospital of Shandong University in China; Yong Wei, a postdoctoral
research associate in Princeton's Department of Molecular Biology;
Andres Blanco, a graduate student in Princeton's Department of Molecular
Biology; Feng Li, an associate research scholar in Princeton's
Department of Molecular Biology; Jessie Au, Distinguished University
Professor in the College of Pharmacy at Ohio State University; and Bruce
Haffty, professor and chair of the Department of Radiation Oncology at
UMDNJ-Robert Wood Johnson Medical School and chief of radiation oncology
at The Cancer Institute of New Jersey.
Source
Michele Fisher
Media Relations Specialist
Office of Communications
The Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903
umdnj.edu
пятница, 12 августа 2011 г.
A Study Contradicts The 'Metabolism First' Hypothesis In The Origin Of Life
A research published in Proceedings of National Academy of Sciences rejects the theory that the origin of life stems from a system of self-catalytic molecules capable of experiencing Darwinian evolution without the need of RNA or DNA and their replication. The research, which was carried out with the participation of Mauro Santos, researcher of the Department of Genetics and Microbiology at Universitat Aut??noma de Barcelona (UAB), has demonstrated that, through the analysis of what some researchers name "compound genomes", these chemical networks cannot be considered evolutionary units because they lose properties which are essential for evolution when they reach a critical size and greater level of complexity.
The North American Space Agency (NASA) defines life as a "self-sustaining chemical system capable of Darwinian evolution". The scientific theories on the origin of life revolve around two main ideas: one focuses on genetics - with RNA or DNA replication as an essential condition for Darwinian evolution to take place - and the other focuses on metabolism. It is clear that both situations must have begun with simple organic molecules formed by prebiotic processes, as was demonstrated by the Miller-Urey experiment (in which organic molecules were created from inorganic substances). The point in which these two theories differ is that the replication of RNA or DNA molecules is a far too complex process which requires a correct combination of monomers within the polymers to produce a molecular chain resulting from the replication.
Until now no plausible chemical explanation exists for how these processes occured. In addition, defenders of the second theory argue that the processes needed for evolution to take place depend on primordial metabolism. This metabolism is believed to be a type of chemical network entailing a high degree of mutual catalysis between its components which, in turn, eventually allows for adaptation and evolution without any molecular replication.
In the first half of the 20th century, Alexander Oparin established the "Metabolism First" hypothesis to explain the origin of life, thus strengthening the primary role of cells as small drops of coacervates (evolutionary precursors of the first prokaryote cells). Dr Oparin did not refer to RNA or DNA molecules since at that time it was not clear just how important the role of these molecules was in living organisms. However he did form a solid base for the idea of self-replication as a collective property of molecular compounds.
Science more recently demonstrated that sets of chemical components store information about their composition which can be duplicated and transmitted to their descendents. This has led to their being named "compound genomes" or composomes. In other words, heredity does not require information in order to be stored in RNA or DNA molecules. These "compound genomes" apparently fulfil the conditions required to be considered evolutionary units, which suggests a pathway from pre-Darwinian dynamics to a minimum protocell.
Researchers in this study nevertheless reveal that these systems are incapable of undergoing a Darwinian evolution. For the first time a rigorous analysis was carried out to study the supposed evolution of these molecular networks using a combination of numerical and analytical simulations and network analysis approximations. Their research demonstrated that the dynamics of molecular compound populations which divide after having reached a critical size do not evolve, since during this process the compounds lose properties which are essential for Darwinian evolution.
Researchers concluded that this fundamental limitation of "compound genomes" should lead to caution towards theories that set metabolism first as the origin as life, even though former metabolic systems could have offered a stable habitat in which primitive polymers such as RNA could have evolved.
Researchers state that different prebiotic Earth scenarios can be considered. However, the basic property of life as a system capable of undergoing Darwinian evolution began when genetic information was finally stored and transmitted such as occurs in nucleotide polymers (RNA and DNA).
Source:
Maria Jesus Delgado
Universitat Autonoma de Barcelona
The North American Space Agency (NASA) defines life as a "self-sustaining chemical system capable of Darwinian evolution". The scientific theories on the origin of life revolve around two main ideas: one focuses on genetics - with RNA or DNA replication as an essential condition for Darwinian evolution to take place - and the other focuses on metabolism. It is clear that both situations must have begun with simple organic molecules formed by prebiotic processes, as was demonstrated by the Miller-Urey experiment (in which organic molecules were created from inorganic substances). The point in which these two theories differ is that the replication of RNA or DNA molecules is a far too complex process which requires a correct combination of monomers within the polymers to produce a molecular chain resulting from the replication.
Until now no plausible chemical explanation exists for how these processes occured. In addition, defenders of the second theory argue that the processes needed for evolution to take place depend on primordial metabolism. This metabolism is believed to be a type of chemical network entailing a high degree of mutual catalysis between its components which, in turn, eventually allows for adaptation and evolution without any molecular replication.
In the first half of the 20th century, Alexander Oparin established the "Metabolism First" hypothesis to explain the origin of life, thus strengthening the primary role of cells as small drops of coacervates (evolutionary precursors of the first prokaryote cells). Dr Oparin did not refer to RNA or DNA molecules since at that time it was not clear just how important the role of these molecules was in living organisms. However he did form a solid base for the idea of self-replication as a collective property of molecular compounds.
Science more recently demonstrated that sets of chemical components store information about their composition which can be duplicated and transmitted to their descendents. This has led to their being named "compound genomes" or composomes. In other words, heredity does not require information in order to be stored in RNA or DNA molecules. These "compound genomes" apparently fulfil the conditions required to be considered evolutionary units, which suggests a pathway from pre-Darwinian dynamics to a minimum protocell.
Researchers in this study nevertheless reveal that these systems are incapable of undergoing a Darwinian evolution. For the first time a rigorous analysis was carried out to study the supposed evolution of these molecular networks using a combination of numerical and analytical simulations and network analysis approximations. Their research demonstrated that the dynamics of molecular compound populations which divide after having reached a critical size do not evolve, since during this process the compounds lose properties which are essential for Darwinian evolution.
Researchers concluded that this fundamental limitation of "compound genomes" should lead to caution towards theories that set metabolism first as the origin as life, even though former metabolic systems could have offered a stable habitat in which primitive polymers such as RNA could have evolved.
Researchers state that different prebiotic Earth scenarios can be considered. However, the basic property of life as a system capable of undergoing Darwinian evolution began when genetic information was finally stored and transmitted such as occurs in nucleotide polymers (RNA and DNA).
Source:
Maria Jesus Delgado
Universitat Autonoma de Barcelona
вторник, 9 августа 2011 г.
House Subcommittee Considers Bill That Would Prohibit Genetic Discrimination
The House Energy and Commerce Subcommittee on Health on Thursday held a hearing on legislation (HR 493) to ban discrimination against U.S. residents based on the results of genetic tests, CQ HealthBeat reports. Health Subcommittee Chair Frank Pallone (D-N.J.) said that some individuals might forgo participation in genetic testing "out of concern for possible repercussions, therefore losing the opportunity to receive monitoring and preventive care for conditions in which they are at higher risk." He noted that many states have laws banning genetic discrimination, but because they vary widely, a federal standard is needed. Burton Fishman of the Genetic Information Nondiscrimination in Employment Coalition at the hearing said, "The law should not trigger liability based on an employer's mere receipt of genetic information, such as through conversation concerning a relative's illness or derived from such normative behavior as visiting the sick and consoling the bereaved." Francis Collins, director of the National Human Genome Research Institute at NIH said, "This is an issue of equity. This is an issue of justice." William Corwin -- medical director of clinical policy at Harvard Pilgrim Health Care who testified on behalf of America's Health Insurance Plans -- said the bill as drafted might limit health plans from using genetic tests to promote preventive screening and disease management programs (Carey, CQ HealthBeat, 3/8).
"Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
"Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
суббота, 6 августа 2011 г.
Bacteria Research: Dawning Of A New Age
Lowly bacteria are turning out to be much more complex than previously thought.
In the July, 2010 issue of the journal Molecular Microbiology, Loyola University Health System researchers describe an example of bacterial complexity, called "protein acetylation," which once was thought to be rare in bacteria.
This discovery that protein acetylation is common in bacteria has led to the "dawning of a new age" in bacterial research, senior author Alan Wolfe, PhD. and colleagues wrote.
Protein acetylation is a molecular reaction inside the cell. It modifies and thus affects the function of proteins, including the molecular machinery responsible for turning genes on or off.
Bacteria make up one of the three domains of life. The other two domains are archaea (single-cell organisms distinct from bacteria) and eukaryotes (which include plants and animals). Bacteria evolved before eukaryotes, but they are not as primitive as once thought.
"Bacteria have long been considered simple relatives of eukaryotes," Wolfe and colleagues wrote. "Obviously, this misperception must be modified."
For example, protein acetylation historically had been considered mostly a eukaryotic phenomenon. But recent research indicates that acetylation also has a broad impact on bacterial physiology.
"There is a whole process going on that we have been blind to," Wolfe said.
Wolfe's laboratory works with intestinal bacteria called Escherichia coli, commonly called E. coli. While some strains of E. coli can cause serious food poisoning, most strains are harmless or even beneficial.
E. coli and its 4,000 genes have been extensively studied for decades. Consequently, researchers now have the ability to quickly determine what happens when a gene is deleted or made more active. "We're explorers with lots of tools," Wolfe said.
Studying protein acetylation will improve scientists' basic understanding of how bacterial cells work. This in turn could lead to new drugs to, for example, kill or cripple harmful bacteria.
"We're in the very early days of this research," Wolfe said. "We're riding the front of the wave, and that's exhilarating. The graduate students in my lab are working practically around the clock, because they know how important this is."
Wolfe is a microbial geneticist and professor in the Department of Microbiology and Immunology at Loyola University Chicago Stritch School of Medicine. His co-authors are graduate students Linda Hu and Bruno Lima.
Wolfe's lab is supported by the Stritch School of Medicine Research Funding Committee and by a four-year $2 million grant from the National Institutes of Health.
Source:
Jim Ritter
Loyola University Health System
In the July, 2010 issue of the journal Molecular Microbiology, Loyola University Health System researchers describe an example of bacterial complexity, called "protein acetylation," which once was thought to be rare in bacteria.
This discovery that protein acetylation is common in bacteria has led to the "dawning of a new age" in bacterial research, senior author Alan Wolfe, PhD. and colleagues wrote.
Protein acetylation is a molecular reaction inside the cell. It modifies and thus affects the function of proteins, including the molecular machinery responsible for turning genes on or off.
Bacteria make up one of the three domains of life. The other two domains are archaea (single-cell organisms distinct from bacteria) and eukaryotes (which include plants and animals). Bacteria evolved before eukaryotes, but they are not as primitive as once thought.
"Bacteria have long been considered simple relatives of eukaryotes," Wolfe and colleagues wrote. "Obviously, this misperception must be modified."
For example, protein acetylation historically had been considered mostly a eukaryotic phenomenon. But recent research indicates that acetylation also has a broad impact on bacterial physiology.
"There is a whole process going on that we have been blind to," Wolfe said.
Wolfe's laboratory works with intestinal bacteria called Escherichia coli, commonly called E. coli. While some strains of E. coli can cause serious food poisoning, most strains are harmless or even beneficial.
E. coli and its 4,000 genes have been extensively studied for decades. Consequently, researchers now have the ability to quickly determine what happens when a gene is deleted or made more active. "We're explorers with lots of tools," Wolfe said.
Studying protein acetylation will improve scientists' basic understanding of how bacterial cells work. This in turn could lead to new drugs to, for example, kill or cripple harmful bacteria.
"We're in the very early days of this research," Wolfe said. "We're riding the front of the wave, and that's exhilarating. The graduate students in my lab are working practically around the clock, because they know how important this is."
Wolfe is a microbial geneticist and professor in the Department of Microbiology and Immunology at Loyola University Chicago Stritch School of Medicine. His co-authors are graduate students Linda Hu and Bruno Lima.
Wolfe's lab is supported by the Stritch School of Medicine Research Funding Committee and by a four-year $2 million grant from the National Institutes of Health.
Source:
Jim Ritter
Loyola University Health System
среда, 3 августа 2011 г.
New York State Approves Quest Diagnostics' Fragile X Syndrome Test
An accurate, faster testing option to identify female carriers and other patients with genetic abnormalities that cause Fragile X Syndrome is now available to physicians in all fifty states with the recent approval in New York. Fragile X is the leading cause of inherited mental retardation and the most common known single gene cause of autism.
XSense®, Fragile X with Reflex, from Quest Diagnostics Incorporated (NYSE: DGX), the world's leading diagnostic company, has been approved by New York State's Department of Health. XSense is the first test for Fragile X Syndrome to be approved by New York to employ a new laboratory analysis technique that bypasses the need to perform the Southern Blot DNA analysis method in 99 percent of cases. The use of Southern Blot, which can take several days to weeks to perform, has hampered the lab industry's ability to widely provide Fragile X testing. XSense results are reported in about a week for the vast majority of patients.
With the approval, Quest Diagnostics can offer the test to physicians in New York as well as in all other U.S. states. New York is the only U.S. state with an independent regulatory review process for laboratory developed tests, which are also regulated at the federal level.
"New York's approval is significant because it means a new, highly innovative genetic analysis technique for Fragile X has fulfilled state-required quality standards that are widely regarded in the lab industry as highly rigorous," said Charles Strom, M.D., Ph.D., medical director, Genetic Testing Center, Quest Diagnostics Nichols Institute. "Fragile X can be a devastating diagnosis, given the severe disability it causes many patients. While it is highly prevalent, Fragile X is not widely tested for, due in part to technical limitations with conventional tests that our XSense technique largely surmounts."
Physicians can use XSense to aid their identification of women who, as carriers, may be unaffected or slightly affected by Fragile X syndrome, but are at risk of passing it to offspring, regardless of the father's genetics. It may also aid in the diagnosis of male and female patients using blood and other specimen types. An estimated one in 260 women are genetic carriers of Fragile X Syndrome, according to the National Fragile X Foundation, although recent research by scientists at Quest Diagnostics and other organizations suggest carrier prevalence may be even higher.
"XSense is a step forward to the day when the medical community can seriously consider the option to provide population-wide quality testing for Fragile X in much the same way we now offer population screening for other hereditary disorders," said Dr. Strom.
A couple is statistically more likely to pass Fragile X to their offspring than two common hereditary disorders, cystic fibrosis or Tay-Sachs Disease, which guidelines support for wide population screening. In most states, newborns are routinely tested for cystic fibrosis. While medical guidelines recommend Fragile X testing for some patients, such as women seeking reproductive counseling with a personal or family history of mental retardation, they do not support population-based carrier or newborn testing, in part due to technical lab-testing hurdles.
A study performed and funded by Quest Diagnostics and published in the March 2010 issue of Genetics in Medicine, the official publication of the American College of Medical Genetics (ACMG), found that the XSense technique showed 100% agreement with the standard widely used lab-testing method, which requires a DNA analysis technique called Southern Blot in about 20 percent of cases. Southern Blot can take several days to weeks to perform, making it generally unsuitable for high-volume testing applications. In the study, the XSense technique bypassed the need for Southern Blot in more than 99 percent of cases.
The investigators concluded that the XSense test is highly accurate, and may be suitable for high-volume population screening and diagnostic testing on a range of patients, including women and newborns.
Earlier this month, Genetics in Medicine published a report that found there is adequate research data to support population screening of women of childbearing age for Fragile X syndrome. The report was based on a review and analysis of eleven prior studies of Fragile X screening in women of reproductive age.
About XSense®, Fragile X with Reflex
XSense, Fragile X with Reflex, test identifies abnormalities of the fragile X mental retardation 1 (FMR1) gene residing on the X chromosome. The number of times a certain pattern of DNA, called CGG, occurs determines whether a person has a premutation and is a carrier or has a full mutation and has the disorder. XSense employs a technique called triplet-primed polymerase chain reaction by capillary electrolysis (triplet-primed PCR-CE) to assess the number of CGG repeats without Southern Blot in about 99 percent of cases. Quest Diagnostics is the first U.S. company to publish peer reviewed data on this new Fragile X syndrome test technique and bring it to market. Quest Diagnostics offers XSense in alignment with current guidelines for Fragile X Syndrome testing.
About the New York State Department of Health Clinical Laboratory Evaluation Program
New York approves laboratory-developed tests that are not FDA cleared before allowing them to be performed on patients in the state. In order to gain approval, labs must validate that a test performs as it is intended, based on validation data collected according to the U.S. Center for Disease Control and Prevention's Clinical Laboratory Improvement Amendments and New York State requirements. New York is the only state that independently approves laboratory-developed tests.
Source: Quest Diagnostics
XSense®, Fragile X with Reflex, from Quest Diagnostics Incorporated (NYSE: DGX), the world's leading diagnostic company, has been approved by New York State's Department of Health. XSense is the first test for Fragile X Syndrome to be approved by New York to employ a new laboratory analysis technique that bypasses the need to perform the Southern Blot DNA analysis method in 99 percent of cases. The use of Southern Blot, which can take several days to weeks to perform, has hampered the lab industry's ability to widely provide Fragile X testing. XSense results are reported in about a week for the vast majority of patients.
With the approval, Quest Diagnostics can offer the test to physicians in New York as well as in all other U.S. states. New York is the only U.S. state with an independent regulatory review process for laboratory developed tests, which are also regulated at the federal level.
"New York's approval is significant because it means a new, highly innovative genetic analysis technique for Fragile X has fulfilled state-required quality standards that are widely regarded in the lab industry as highly rigorous," said Charles Strom, M.D., Ph.D., medical director, Genetic Testing Center, Quest Diagnostics Nichols Institute. "Fragile X can be a devastating diagnosis, given the severe disability it causes many patients. While it is highly prevalent, Fragile X is not widely tested for, due in part to technical limitations with conventional tests that our XSense technique largely surmounts."
Physicians can use XSense to aid their identification of women who, as carriers, may be unaffected or slightly affected by Fragile X syndrome, but are at risk of passing it to offspring, regardless of the father's genetics. It may also aid in the diagnosis of male and female patients using blood and other specimen types. An estimated one in 260 women are genetic carriers of Fragile X Syndrome, according to the National Fragile X Foundation, although recent research by scientists at Quest Diagnostics and other organizations suggest carrier prevalence may be even higher.
"XSense is a step forward to the day when the medical community can seriously consider the option to provide population-wide quality testing for Fragile X in much the same way we now offer population screening for other hereditary disorders," said Dr. Strom.
A couple is statistically more likely to pass Fragile X to their offspring than two common hereditary disorders, cystic fibrosis or Tay-Sachs Disease, which guidelines support for wide population screening. In most states, newborns are routinely tested for cystic fibrosis. While medical guidelines recommend Fragile X testing for some patients, such as women seeking reproductive counseling with a personal or family history of mental retardation, they do not support population-based carrier or newborn testing, in part due to technical lab-testing hurdles.
A study performed and funded by Quest Diagnostics and published in the March 2010 issue of Genetics in Medicine, the official publication of the American College of Medical Genetics (ACMG), found that the XSense technique showed 100% agreement with the standard widely used lab-testing method, which requires a DNA analysis technique called Southern Blot in about 20 percent of cases. Southern Blot can take several days to weeks to perform, making it generally unsuitable for high-volume testing applications. In the study, the XSense technique bypassed the need for Southern Blot in more than 99 percent of cases.
The investigators concluded that the XSense test is highly accurate, and may be suitable for high-volume population screening and diagnostic testing on a range of patients, including women and newborns.
Earlier this month, Genetics in Medicine published a report that found there is adequate research data to support population screening of women of childbearing age for Fragile X syndrome. The report was based on a review and analysis of eleven prior studies of Fragile X screening in women of reproductive age.
About XSense®, Fragile X with Reflex
XSense, Fragile X with Reflex, test identifies abnormalities of the fragile X mental retardation 1 (FMR1) gene residing on the X chromosome. The number of times a certain pattern of DNA, called CGG, occurs determines whether a person has a premutation and is a carrier or has a full mutation and has the disorder. XSense employs a technique called triplet-primed polymerase chain reaction by capillary electrolysis (triplet-primed PCR-CE) to assess the number of CGG repeats without Southern Blot in about 99 percent of cases. Quest Diagnostics is the first U.S. company to publish peer reviewed data on this new Fragile X syndrome test technique and bring it to market. Quest Diagnostics offers XSense in alignment with current guidelines for Fragile X Syndrome testing.
About the New York State Department of Health Clinical Laboratory Evaluation Program
New York approves laboratory-developed tests that are not FDA cleared before allowing them to be performed on patients in the state. In order to gain approval, labs must validate that a test performs as it is intended, based on validation data collected according to the U.S. Center for Disease Control and Prevention's Clinical Laboratory Improvement Amendments and New York State requirements. New York is the only state that independently approves laboratory-developed tests.
Source: Quest Diagnostics
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