Our everyday environments are full of airborne particles that are harmful to varying degrees when inhaled. Particularly damaging to our cellular DNA are the particles from the underground system in Stockholm, Sweden, according to a new doctoral thesis from Karolinska Institutet.

???Luckily, most of them do not remain in the underground for any length of time,??? says scientist Hanna Karlsson. ???However, particle levels are often very high. My results show that there is every reason to speed up the work being done to clean the air in the underground.???

Every year, some 5,300 Swedes die premature deaths from inhaling the microscopic particles of coal, asphalt, iron and other materials that pollute the city??™s air. These particles, which are the result of incomplete combustion, road surface attrition, etc. could be reduced if the right steps were taken; the problem is that it is not known which particle sources pose the greatest threat to human health.

To build up a picture of which particles are the most harmful, Dr Karlsson has compared how particles from a variety of sources affect cultured lung cells. The results, which are presented in her thesis Particularly harmful particles show that particles from the Stockholm underground are much more damaging to cellular DNA than the other sources tested (e.g. wood smoke and cars).

The airborne particles in the underground system largely comprise iron, and are formed by the abrasion of the train wheels against the rails. The damage is caused when these particles enter the body and form free radicals in the body??™s cells. Free radicals are highly reactive molecules that can prove harmful to the cell??™s DNA; although such damage can often be repaired by the cell, it can sometime remains untreated, and this increases the risk of cancer.

Another type of particle that stood out in the studies was that caused by the friction between car tyres and the road surface. The report shows that these particles trigger a powerful inflammatory response (i.e. a general defence reaction in the body). Levels of these particles are particularly high in the spring, when road surfaces dry out and cars are still fitted with studded winter tyres.

???It??™s a serious problem, as these particles exist in large concentrations in environments that people remain in for long periods,??? says Dr Karlsson.

Apart from particles from the underground and the roads, the study also examined those released by the combustion of wood, pellets and diesel. None of the other types of particle tested were totally harmless. Modern wood- and pellet-burning boilers gave off much fewer emissions than old ones, but the particles produced were no less harmful.

Karolinska Institutet is one of the leading medical universities in Europe. Through research, education and information, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine. For more information, visit ki.se.

Language Styles

British English
Underground refers to the underground, urban train system.
Subway ??” a pedestrian tunnel used for crossing streets and city squares

American English

Underground refers to anything that is under the ground ??” not a train system.
Subway refers to the underground, urban train system.

diss.kib.ki.se/2006/91-7140-972-6 Read the rest of this entry »

With new prenatal tests for Down syndrome on the horizon promising to be safer, more accurate, and available to women earlier in pregnancy, the medical community must come together and engage in dialogue about the impact of existing and expected tests, argues a new leading article published Online First by Archives of Disease in Childhood. Authored by Brian Skotko, MD, MPP, clinical genetics fellow at Children’s Hospital Boston, the article shows a steady decrease in the number of babies being born with Down syndrome since the introduction of prenatal testing and poses the question: “As new tests become available, will babies with Down syndrome slowly disappear?”

Research reviewed by Skotko showed a 15% decrease in births of babies with Down syndrome between 1989 and 2005 in the United States. In the absence of prenatal testing, researchers would have anticipated the opposite – a 34% increase in births – due to the trend of women waiting longer to have children; known to increase the chances of having a baby with Down syndrome.

Currently, expectant women have two options if they would like to receive a definitive diagnosis of Down syndrome – chorionic villus sampling (CVS) and amniocentesis – both of which are invasive and carry a risk, however small, of causing a spontaneous miscarriage. New tests expected to be introduced next year will offer a simple blood test that poses no risk to the fetus and delivers a definitive diagnosis of one or more of the genetic variants of Down syndrome – trisomy 21, translocation, or mosaicism.

Prior research conducted by Skotko found that expectant mothers who received a prenatal diagnosis felt their physicians provided them with incomplete, inaccurate, and oftentimes offensive information about the condition. Other studies have shown physicians themselves feeling unprepared and uninformed to deliver a diagnosis.

“Unless improvements are made prior to the arrival of new prenatal tests, a true collision is on its way,” says Skotko. “More women will be going through the testing process, which could lead to a lot of difficult, uncomfortable conversations between physicians and expectant parents.”

In anticipation of these tests, which could make Down syndrome the first genetic condition to be definitively diagnosed in the first trimester on a population basis, Skotko calls on the medical community to:
Develop guidelines around how health professionals should deliver a diagnosis of Down syndrome.

Assemble information packets that give accurate, current information on Down syndrome and give them to all expectant parents who receive a definitive diagnosis.

Create a standardized training program for all healthcare professionals involved in prenatal care and for volunteer parents – such as those involved in First Call programs – to complete.

Train not only the doctors of today but the doctors of tomorrow. Medical students, nurses and genetic counselors should be educated beyond the textbook and have interactions with people who have Down syndrome so that they may better understand the realities of living with the disorder.

Recently, the National Down Syndrome Society and the National Down Syndrome Congress announced the selection of a booklet (“Understanding a Prenatal Down Syndrome Diagnosis”) as a gold standard packet of information about Down syndrome, fulfilling Skotko’s second recommendation.

“The ultimate goal is to ensure families receive accurate, up-to-date, information so they are well-informed and can make decisions that are right for them,” says Skotko.

Source:
Keri Stedman

Children’s Hospital Boston Read the rest of this entry »

The Human Microbiome Project (HMP) has published an analysis of 178 genomes from microbes that live in or on the human body. The researchers discovered novel genes and proteins that serve functions in human health and disease, adding a new level of understanding to what is known about the complexity and diversity of these organisms.

The human microbiome consists of all the microorganisms that reside in or on the human body. Outnumbering cells in the human body by 10 to 1, some of the microorganisms cause illnesses, but many are necessary for good health. Currently, researchers can grow only some of the bacteria, fungi and viruses in a laboratory setting. However, new genomic techniques can identify minute amounts of microbial DNA in an individual and determine its identity by comparing the genetic signature to known sequences in the project’s data base. The paper is published in the May 21 issue of the journal Science.

“This initial work lays the foundation for this ambitious project and is critical for understanding the role that the microbiome plays in human health and disease,” said National Institutes of Health Director Francis S. Collins, M.D., Ph.D. “We are only at the very beginning of a fascinating voyage that will transform how we diagnose, treat and ultimately, prevent many health conditions.”

Launched in 2008 as part of the NIH Common Fund’s Roadmap for Medical Research, the HMP is a $157 million, five-year effort that will implement a series of increasingly complicated studies that reveal the interactive role of the microbiome in human health.

The 178 microbial genomes in this report launch the HMP reference collection that eventually will total approximately 900 microbial genomes of bacteria, viruses and fungi. These data will then be used by HMP researchers to characterize the microbial communities found in samples taken from healthy human volunteers and, later, those with specific illnesses. Samples are currently being collected for HMP from five areas of the body: the digestive tract, the mouth, the skin, the nose and the vagina.

“Although this is only the first step in making HMP medically useful, we already have learned surprising things about the diversity and complexity of the microorganisms that live in and on our body,” said Jane Peterson, Ph.D., associate director of the NHGRI Division of Extramural Researcher and a leader of the HMP effort. “The next stages of this coordinated study will begin to associate the presence or absence of specific micro-organisms with various states of health and illness.”

Researchers also conducted a preliminary survey to gain insights into the function of some of the newly identified genes and proteins unique to individual microbial strains. For instance, researchers found previously unknown proteins produced by bacteria that live in the stomach that may cause gastric ulceration, a hole in the stomach lining. In addition, they found a small number of newly identified novel proteins associated with how sugars and amino acids are metabolized.

Researchers also evaluated the microbial diversity present in the HMP reference collection. For example, they found 29,693 previously undiscovered, unique proteins in the reference collection – more proteins than there are estimated genes in the human genome. They compared their results to the same number of previously sequenced microbial genomes randomly selected from public databases. In the microbial genome from public databases, they found 14,064 novel proteins. These data, the researchers say, suggest that the HMP reference collection has nearly twice the amount of microbial diversity than is represented by microbial genomes already in public databases.

One of the primary goals of the HMP reference collection is to expand researchers’ ability to interpret data from metagenomic studies. Metagenomics is the study of a collection of genetic material (genomes) from a mixed community of organisms. Comparing metagenomic sequence data with genomes in the reference collection can help researchers determine whether they are novel or already existing sequences.

To evaluate whether the reference collection of genomes was meeting the goal above, the researchers compared 16.8 million microbial sequences found in public databases to the genome sequences in the HMP reference collection. They found that 62 genomes in the reference collection showed similarity with 11.3 million microbial sequences in public databases and 6.9 million of these – about 41 percent – correspond with genome sequences in the reference collection.

This analysis demonstrates that genomes sequenced as part of the reference collection add directly to an understanding of the human microbiome. However, researchers cautioned that at least one-third of the metagenomic sequences are still not represented by any genome in the reference collection and that this analysis focused only on the gastrointestinal tract. The authors added that additional genomes likely exist in other body sites and the completion of the reference collection should address many of the remaining organisms not accounted for in this analysis.

The initial stage of the HMP, which includes the current study, focused on bacteria, but future genome sequencing and human microbiome studies also will capture information about more complex microbes and viruses. The effort so far also has allowed researchers to create a framework for data resources and standards. In addition, the project is supporting the development of innovative technologies and computational tools, coordination of data analysis, and an examination of some of the ethical, legal and social implications of human microbiome research.

Genome sequencing work for the project is done by the HMP-funded large-scale sequencing centers: the Human Genome Sequencing Center, Baylor College of Medicine, Houston; Washington University Genome Sequencing Center, Washington University School of Medicine, St. Louis; The J. Craig Venter Institute, Rockville, Md.; and the Broad Sequencing Platform, Broad Institute of MIT/ Harvard, Cambridge, Mass.

The HMP is currently funding pilot demonstration projects by researchers that will sample the microbiomes of healthy volunteers and volunteers with specific diseases over the next year. This will allow researchers to study changes in the microbiome at particular body sites in healthy controls compared to patients affected by diseases. These studies will use samples collected from seven areas of the body: the digestive tract, the mouth, the skin, the nose, the vagina, the blood and the male urethra.

Genomes sequenced as part of the HMP and those generated by unrelated projects are publicly available from the National Library of Medicine’s National Center for Biotechnology Information, part of NIH, at ncbi.nlm.nih/genomes/MICROBES/microbial_taxtree.html. HMP data may also be accessed from its Data Analysis and Coordination Center website, hmpdacc/.

Source:
Geoff Spencer
NIH/National Human Genome Research Institute Read the rest of this entry »

US Senator, Mark Begich, along with ten other senators are spearheading a fight to stop the FDA (Food and Drug Administration) from approving the human consumption of genetically modified salmon (GM salmon). If approved, the GM salmon would be the first GM animal to be approved for the human food supply. The 11 senators, mostly from coastal states, have sent a letter to the FDA opposing the move. Sen Begich adds that dozens of organizations have also protested.

A decision on whether to approve a proposal from AquaBounty Technologies to produce and market a GM salmon, which is a cross between the Atlantic salmon and a Chinook salmon (its growth gene), as well as containing an antifreeze gene from an eel, has been postponed by the FDA.

The letter states:

There are a number of serious concerns with the current approval process and many potential human health and environmental risks that are associated with producing GE fish have not been fully or openly reviewed.

Critical information has been kept from the public and consequently, only FDA and AquaBounty know important details about the approval process for this GE salmon, or the product itself.

Begich, who coined the term “Frankenfish” when referring to this GM salmon, says he is concerned about the safety of the product. He questions whether the process for public comment on the proposal is adequate.

According to Begich, the letter is signed by 11 Senators, including himself, and is supported by 52 environmental groups, consumer groups, retailers, food businesses and commercial and recreational fisheries associations, including the Yukon River Drainage Fisheries Association, the Alaska Marine Conservation Council, and Bristol Bay Regional Seafood Development.

As the product in question is an animal to be eaten by humans, the letter states that the FDA should not be using the same process it uses when considering a new drug application.

The letter states:

Clearly this is inappropriate. Creation of a new genetically engineered species should be not be treated as an animal drug issue but undergo formal evaluation by FDA’s Center for Food Safety and Applied Nutrition to review the product’s potential health effects on humans.

The transparency of the FDA process is also questioned. The letter quotes a number of concerns, including potential environmental damage, as well as the risk of harm to wild salmon.

The letter adds:

We strongly urge you to stop the approval process immediately to allow for review and examination of the various concerns associated with genetically engineered animals, openly and with meaningful public input.

Begich quotes a recent survey by carried out by Food & Water Watch, a consumer group, which revealed that 78% of Americans do not want the GM Salmon to be approved.

The letter was signed by:

Sen. Begich (Alaska)
Sen. Lisa Murkowski (AK)
Sen. Patty Murray (WA)
Sen. Bernard Sanders (VT)
Sen. Maria Cantwell (WA)
Sen. Ron Wyden (OR)
Sen. Patrick Leahy (VT)
Sen. Kirsten Gillibrand (NY)
Sen. Barbara Mikulski (MD)
Sen. Jeff Merkley (OR)
Sen. Jon Tester (MT).

List of organizations that endorse the letter

Letter to the FDA Commissioner of Food and Drugs

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A case report published on April 7, 2009 in the World Journal of Gastroenterology reported incidental findings of a large and solitary congenital APF in a 73-year-old woman. A stubby fistula vessel between left hepatic artery and left portal vein was found in the hepatic artery selective arteriography of the patient by digital subtraction angiography. Transcatheter closure of APF by using multiple coils were performed three times and they worked. After therapy twice she suffered alimentary tract hemorrhage. The authors considered the reason of therapeutic failure as too much collateral circulation. The purpose of venae coronaria ventriculi and short gastric vein embolised was to cut off the collateral circulation.

Overall, the experience gained from this case suggests the important role of interventional radiology for the management of congenital APF with severe upper gastrointestinal bleeding caused by esophageal and fundus varices. Liver function, abdomen ultrasonography and gastroscopes should be a regular f0llow-up.

Notes:

Reference: Lu ZY, Ao JY, Jiang TA, Peng ZY, Wang ZK. A large congenital and solitary intrahepatic arterioportal fistula in an old woman.
World J Gastroenterol 2009; 15(13): 1656-1659

wjgnet/1007-9327/15/1656.asp

Correspondence to: Jian-Yang Ao, MD, Department of Ultrasound, First Affiliated Hospital, Medical College, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.

Source:
Lin Tian

World Journal of Gastroenterology Read the rest of this entry »

The Darwin 200 celebrations are currently underway. Biology letters is publishing an initial series of special features on evolution.

In this special feature on brain evolution, we showcase a number of different aspects of the study of brain evolution.

These include from similarities between nervous systems at the molecular level, hypotheses about the selective pressures that have acted on brains, as well as several other themes.

Royal Society journal Biology Letters

Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.

Biology Letters Read the rest of this entry »

White matter disease (WMD) covers a large group of disorders that affect the white matter, or myelin. In children these disorders are commonly genetic and often go undiagnosed. In new research, a team led by Ra??l Est?©vez, a lecturer from the Department of Physiological Sciences II, based at the UB’s Bellvitge Health Sciences Campus, working with the researcher Marjo van der Knaap, from the University Medical Centre at VU University Amsterdam, have identified mutant GLIALCAM as responsible for 25% of cases of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare genetic disease affecting cerebral myelin.

Also participating in the study, which has been published and selected as a featured article in The American Journal of Human Genetics, were Tania L??pez-Hern??ndez, co-principal author and a postdoctoral fellow at the UB, and the researchers Albert Mart?­nez, from the Institute of Biomedical Research (IRB Barcelona), and Virginia Nunes, a lecturer at the UB and researcher for the Bellvitge Biomedical Research Institute (IDIBELL).

Myelin is required for the correct propagation of nerve impulses between neurons, enabling the brain to send the signals that make us move. In children, diseases affecting this substance are largely genetic and affect a single gene. In adults, the diseases present as inflammatory conditions such as multiple sclerosis. “In the specific case of infant WMD, every type is rare or extremely rare, but if we consider all cases as a single group the incidence is high 1 patient for every 1,000 individuals,” explains Ra??l Est?©vez, ICREA Acad??mia award winner and a member of the Centre for Biomedical Network Research on Rare Diseases (CIBERER). “In addition,” he adds, “in a high percentage of children with myelin disorders the diagnosis is not clear and no real conclusions can be reached.”

Thanks to the identification in recent years of abnormal patterns in brain MRIs, researchers have been able to define new diseases. In 1995 experts discovered an autosomal recessive myelin disorder called megalencephalic leukoencephalopathy with subcortical cysts (MLC). In 2001 the gene responsible for 75% of the cases of this disease, MLC1, wa discovered and scientists found that other cases existed that were not caused by mutations of this gene. Of the remaining 25% of patients, two clinical phenotypes were observed: in the first case, the clinical progression, showing progressive degeneration, is the same as observed in the larger group; in the second case, the disease improves or disappears altogether. The common feature in all patients is the presence of macrocephaly, which may be accompanied by learning difficulties and autism.

The study published in The American Journal of Human Genetics takes as its starting point the genetic heterogeneity of the disease and looks for other possible mutations behind its development, combining biochemical and genetic studies. The results show that patients presenting a progressive degeneration of their condition exhibit two mutations in the GLIALCAM gene, whose related protein is GlialCAM, while others exhibit only a single mutation in the same gene, which suggests a pattern of autosomal-dominant inheritance. The study, which also describes the biochemical defects observed in the disease, has revealed that mutant GLIALCAM can also lead to benign familial macrocephaly and macrocephaly with mental retardation, with or without autism.

“Although we have yet to determine the exact function of GLIALCAM, our research has shown that further collaborative multi-disciplinary translational studies will be required to learn more about the causes of these rare diseases and to find new treatments,”

Sources: Universidad de Barcelona, AlphaGalileo Foundation. Read the rest of this entry »

One of the ways in which alcohol dependence (AD) may develop is through alcohol’s effects on neural signaling, such as modulation of ??-aminobutyric acid type A (GABAA) receptors. Alcohol may indirectly modulate GABAA receptor function by increasing levels of neuroactive steroids in blood. A new study has found linkages between AD and single nucleotide polymorphisms (SNPs) in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids, which suggests a genetic link between neuroactive steroids and risk for AD.

Results will be published in the May 2011 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

“Although alcohol’s biochemical effects on the nervous system are not completely known, the immediate effect of alcohol on how we feel and function as well as the long-term development of tolerance to alcohol are thought to be mediated by neurotransmitter receptors, especially GABAA receptors,” said Jonathan Covault, associate professor of psychiatry at the University of Connecticut Health Center and corresponding author for the study.

GABAA receptors are primarily responsible for dampening brain activity, Covault explained, and balance the other major class of neurotransmitter receptors – glutamate receptors – that are responsible for enhancing excitatory brain activity. Healthy brain function relies on a relative balance of these two signaling systems.

“For example,” he said, “excess excitatory relative to inhibitory receptor activity can result in seizures. The acute dampening effects of alcohol, such as disinhibition and sedation, are in large part due to alcohol effects on enhancing GABAA receptor function. Changes in the production of GABAA and glutamate receptors after chronic alcohol use also contribute to withdrawal symptoms, which can be medically serious and include delirium or seizures. The mainstay of medical treatment for alcohol withdrawal is to replace the effects of alcohol on stimulating GABAA receptors with medications – valium, librium or other benzodiazapines – that have similar effects as alcohol on enhancing GABAA receptor activity but can be gradually reduced in a controlled fashion.”

“Previous studies have shown that neuroactive steroids contribute to alcohol sensitivity in rats and subjective feelings produced by alcohol in humans,” said A. Leslie Morrow, John Andrews Distinguished Professor in the departments of psychiatry and pharmacology, and associate director of the Bowles Center for Alcohol Studies, both at the University of North Carolina School of Medicine. “Since low alcohol sensitivity has been linked to risk for alcoholism in humans, it is possible that low neurosteroid responses to alcohol may be linked to this disease.”

“The detailed mechanisms by which alcohol modulates GABAA or glutamate receptors are still not well understood,” added Covault. “How the body controls the production of neuroactive steroids is poorly understood, but stress and alcohol are two triggers shown to increase neuroactive steroids in the bloodstream and brain of laboratory rats. Laboratory studies suggest that many of the immediate effects of alcohol may be the result of alcohol on the production and metabolism of neuroactive steroids.”

Covault and his colleagues genotyped SNPs in the genes encoding two key enzymes – 5?±-reductase, type I (5?±-R) and 3?±-hydroxysteroid dehydrogenase, type 2 (3?±-HSD), both of which are expressed in the human brain – in 1,083 participants living in Connecticut (583 males, 500 females): 531 with AD, and 552 individuals without AD.

“Results indicate that naturally occurring common genetic variations in two key enzymes required for the production of neuroactive steroids may influence the risk of developing AD,” said Covault. “This finding is among the first evidence that some behavioral effects of alcohol are related to the production of neuroactive steroids. Specifically, genetic variation in each of two genes coding neuroactive steroid biosynthetic enzymes was more common in controls than AD participants, suggesting that protective genetic variations may result in more neuroactive steroids being produced in response to alcohol, thereby increasing the acute effects of alcohol – particularly sedating effects – which tend to limit a person’s use of alcohol.”

“This study brings scientists one step closer to understanding genetic and biochemical factors that underlie risk for alcoholism,” said Morrow. “Such advances will surely lead to better treatments for alcoholism. We now have both genetic and behavioral studies linking neuroactive steroids to alcohol effects in humans. More studies of neuroactive steroids in humans are needed.

Covault concurs. “While much more work is needed to understand how variation in neuroactive steroid metabolism may influence an individual’s predisposition to alcohol use problems, this report opens the door to new avenues of investigation and the potential development of new medical interventions for alcohol use problems.”

Source:
Jonathan Covault, M.D., Ph.D.
University of Connecticut School of Medicine

A. Leslie Morrow, Ph.D.
University of North Carolina School of Medicine

Alcoholism: Clinical & Experimental Research Read the rest of this entry »

Despite dramatically improved survival rates for childhood acute lymphoblastic leukemia (ALL), relapse remains a leading cause of death from the disease. Work led by St. Jude Children’s Research Hospital investigators identified mutations in a gene named CREBBP that may help the cancer resist steroid treatment and fuel ALL’s return.

CREBBP plays an important role in normal blood cell development, helping to switch other genes on and off. In this study, researchers found that 18.3 percent of the 71 relapsed-ALL patients carried alterations in the DNA sequence of CREBBP. In contrast, the gene’s sequence was changed in just one of the 270 young leukemia patients whose cancer did not return.

Investigators say the gene is a potential indicator of relapse risk because of the high frequency of CREBBP mutations in relapsed patients and evidence the changes persisted from diagnosis or emerged at relapse from subpopulations of leukemia cells present from the beginning. Researchers also found evidence the changes occur in important regulatory regions of the gene and affect cell function, including how cancer cells respond to the steroids that play an important role in cancer treatment. The work appears in the March 10 issue of the scientific journal Nature.

“This study gives us further evidence that detailed genomic studies can identify important mutations that influence tumor response to treatment,” said Charles Mullighan, M.D., Ph.D., assistant member of the St. Jude Department of Pathology. Mullighan and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are co-first authors. Mullighan is also the corresponding and senior author.

In the same issue of Nature, investigators also reported that deletions and deactivating mutations in CREBBP and a related gene known as EP300 occurred in about one-third of patients identified with one of the two most common subtypes of B-cell non-Hodgkin lymphoma. Mullighan is one of that study’s five St. Jude co-authors.

Previous reports have linked deletions or chromosome rearrangements involving CREBBP to rare cases of acute leukemia. But this is the first study linking changes in the gene’s DNA sequence to leukemia and lymphoma, cancers of the blood and bone marrow.

ALL is the most common childhood cancer. While ALL cure rates have climbed to 90 percent, the disease is often deadly if it returns. This study was designed to advance understanding of the biological basis of treatment failure. “The results of this study emphasize that there are additional genetic changes that help determine whether a child does well or relapses,” Mullighan said.

The findings stem from the largest DNA sequencing project yet for ALL, which is diagnosed in about 3,000 U.S. children annually. Researchers from St. Jude and the National Cancer Institute tracked changes in 300 genes from 23 young ALL patients. For each gene, researchers compared the DNA makeup in the patient’s normal cells with the sequence at diagnosis and relapse.

The effort turned up 52 non-inherited mutations in 32 genes, many for the first time. The group included four in CREBBP. When researchers checked another 341 young leukemia patients for alteration in CREBBP, they found that 13 of the 71 relapsed-ALL patients carried changes. In two more, pieces of CREBBP’s DNA were deleted.

“The robust and accurate analytical method that we developed for processing such a large data volume made discovery of the CREBBP mutations possible,” Zhang said. “This exciting finding illustrates that genomic sequencing can provide insight into not only disease initiation, but progression and prognosis as well.”

Fourteen mutations were found scattered throughout CREBBP. The list includes an alteration also linked to Rubinstein-Taybi syndrome, a rare inherited multisystem developmental disorder, as well as mutations linked to the cell’s steroid response. Four alterations occurred in the region of the gene that regulates DNA expression through a process of chemical modification known as acetylation. Working in mouse cells growing in the laboratory, researchers showed that CREBBP mutations disrupted acetylation of key DNA targets.

When researchers treated CREBBP-mutated leukemia cells growing in the laboratory with the steroid dexamethasone, a majority showed resistance to the drug. The study included cells from nine ALL subtypes. But researchers found most of the cells proved sensitive to another drug. That drug, vorinostat, uses a different mechanism to impact acetylation. Researchers now plan to test vorinostat in a mouse model of relapsed ALL.

The other authors of this paper are Lawryn Kasper, Stephanie Lerach, Debbie Payne-Turner, Sue Heatley, Linda Holmfeldt, J. Racquel Collins-Underwood, Jing Ma, Ching-Hon Pui, Sharyn Baker, Paul Brindle and James Downing, all of St. Jude; Letha Phillips, formerly of St. Jude, and Kenneth Buetow, NCI Center for Bioinformatics and NCI Laboratory of Population Genetics.
The work was supported in part by supported in part by a National Cancer Institute Cancer Center Support Grant and ALSAC.

Sources: St. Jude Children’s Research Hospital, AlphaGalileo Foundation. Read the rest of this entry »

The circadian clocks that set the rhythmic motion of our bodies for wakeful days and sleepy nights can also set us up for vascular disease when broken, Medical College of Georgia researchers say.

Mice with mutated or missing “clock” genes are prone to thick, inflexible blood vessels with narrow passageways, unhealthy changes typically associated with risk factors such as smoking, high blood pressure and cholesterol, according to research in this week’s issue of Circulation.

“Having a bad or broken clock seems to promote vascular disease,” says Dr. Daniel Rudic, vascular biologist in the MCG Schools of Medicine and Graduate Studies and the study’s corresponding author.

The findings suggest increased disease risk for those with mutated clocks, shift workers whose schedule are routinely in conflict with their natural rhythms, as well as others with poor sleep patterns. They also support the merit of developing time-released meds that are in sync with circadian rhythms.

Clock genes are ubiquitous and scientists are finding they seem to have different roles in different tissues. Clocks in the brain that regulate waking and sleeping interact with clocks throughout the body. But researchers are finding the body clocks also can act autonomously, playing a role in a variety of different conditions such as obesity and diabetes.

Inside blood vessels, MCG researchers found that clocks regulate key signaling that enables blood vessel dilation and remodeling. Mice with missing or mutated clock genes have significantly less AKT, an enzyme that promotes the blood-vessel relaxing molecule nitric oxide, and less of nitric oxide precursor eNOS. In animal models of vascular disease, the altered or missing clocks dramatically accelerated the unhealthy vascular response. In aged mice, the response is even worse, including a predisposition for developing clots.

Yet mice with mutated rather than missing clock gene fared much better in normal light-dark cycles than those in constant darkness. It was only in constant darkness that vascular injury occurred.

“The dysfunction is clearly light-cycle dependent, demonstrating these effects are related to circadian rhythm,” Dr. Rudic says. The importance of circadian rhythm on vascular health indicates “inherent circadian defects may be prevented from producing pathology if one maintains a rhythmic environment,” write Drs. John F. Keaney Jr. and David R. Weaver of the University of Massachusetts in an accompanying editorial.

But that may have nothing to do with a good night’s sleep. “We believe there may be defects in the circadian rhythm that have nothing to do with behavioral aberrations,” Dr. Rudic says. In fact, a subset of hypertensive people sleep just fine but a defective blood pressure rhythm precludes the usual nighttime dip – a risk factor for cardiovascular disease.

This suggests that clocks may work normally in the brain but malfunction in blood vessels and other tissues to bring on hypertension and vascular disease, the MCG researchers say.

The researchers want to better understand how the circadian clock controls signaling and vascular disease in blood vessels. Is the central clock in the brain sending bad information to the blood vessels or are the local blood vessel clocks the culprit? Conversely, can vascular disease disrupt the clock? Answering such questions will help determine whether therapy to block the damage is possible.

In fact, it may mostly be about timing. “We know blood pressure has a rhythm and we know contraction and relaxation of blood vessels have a rhythm,” Dr. Rudic says. “What happens if you have a broken clock in the long term? What happens if you are a night shift worker or somebody who can’t sleep? If our timing is off inside our blood vessels, we are vulnerable.”

Dr. Ciprian B. Anea, MCG postdoctoral fellow in pharmacology and toxicology and the study’s first author uses the sunflower, which opens just before the sun rises, to describe the importance of the circadian rhythm to well being. “It just opens, waiting for the sun to catch all the energy and save it for its metabolism.” Left in the dark, a sunflower still keeps its schedule.

“This is how the circadian rhythm works,” Dr. Anea says. “It prepares us for daylight, starts the metabolism in the cell. When you disturb the mechanism, bad things can happen.”

“We are just scratching the surface of understanding the circadian clock and its impact in humans,” Dr. Rudic says. “Clearly it’s been established that heart attack and stroke typically happen in the morning when blood pressure tends to peak. We need to know more about what happens to these genes and clock proteins in conditions of human disease.”

Notes:

Other co-authors include Dr. Maoxiang Zhang, postdoctoral fellow; G. Bryan Simkins, MCG research assistant; Drs. David W. Stepp and David J. Fulton, MCG researchers; and Dr. Guy Reed, former MCG cardiology chief.

Source:
Toni Baker

Medical College of Georgia Read the rest of this entry »