The second DNA string is also important

The FANTOM Consortium for Genome Exploration Research Group and Karolinska Institutet announce the publication of "Antisense Transcription in the Mammalian Genome" in Science, September 2nd 2005.


It has been known for over half a century that our genetic material occurs as a double strand of DNA molecules. Only one of these strands - the so-called sense strand - encodes for proteins, the building blocks of our cells that in turn make up our bodies. Then what about the other DNA strand - the antisense strand - can it also exert functions?

The answer is yes, it can produce so-called antisense genes that are read in our cells in the opposite direction of the real - sense - genes. This phenomenon has previously been regarded as rare, but scientists now show that it is actually the rule rather than the exception. More importantly, these antisense genes are now shown to be extensively used to modulate the expression of the conventional - sense - genes in our cells. Antisense genes are therefore likely to participate in the control of many, perhaps all, cell and body function.


These findings are also of interest because synthetic - man made - antisense molecules have been widely used to inhibit conventional genes, including applications as anti-viral and anti-cancer drugs, which are currently on the market or in clinical trials. It can now be argued that this same principle already has been used by nature on a massive scale.


Many of the described antisense genes are also unusual because they do not encode for proteins and therefore do not fit into the classical definition of a gene.

This concept of non-protein-coding RNA is supported by the data in an accompanying report entitled "The Transcriptional Landscape of the Mammalian Genome" by the FANTOM Consortium in the same issue of Science.

Since mammals, like humans and mice only have slightly more conventional genes (around 22,000) than a simple worm, the results clearly indicate that while proteins comprise the essential components of our cells, the development of multicellular organisms like mammals is controlled by vast amounts of regulatory noncoding RNAs that until recently were not suspected to exist or be relevant to our biology.

Moreover, since most proteins are similar among mammals it also suggests that many of the differences between species may be embedded in the differences in the RNA regulatory control systems, which are evolving much faster than the protein components.


If correct, these findings will radically alter our understanding of genetics and how information is stored in our genome, and how this information is transacted to control the incredibly complex process of mammalian development, with implications for the future of biological research, medicine and biotechnology.


Both of these publications are part of a long-standing international effort and represent an enormous body of work.


Prof. Claes Wahlestedt who is affiliated with Karolinska Institutet in Sweden as well as Scripps Florida and the RIKEN Genomic Sciences Center in Japan can be contacted for further information: Tel. +46-70-5848337, Email: claes.wahlestedtcgb.ki.se


Peer reviewed publication and references

"Antisense Transcription in the Mammalian Genome" by S. Katayama, Y. Tomaru, T. Kasukawa, K. Waki, M. Nakanishi, M. Nakamura, H. Nishida, C.C. Yap, M. Suzuki, P. Carninci, Y. Hayashizaki, C. Wells, M. Frith, T. Ravasi, K.C. Pang, J. Hallinan, J. Mattick, D.A. Hume, L. Lipovich, P.G. Engstrom, Y. Mizuno, M.A. Faghihi, A. Sandelin, A.M. Chalk, S. Mottagui-Tabar, Z. Liang, B. Lenhard and C. Wahlestedt in Science, September 2nd 2005.


Reference URL

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Gene's Effects In Blood Vessels And High Blood Pressure In Older Adults

Scientists have identified the gene that sets off a sequence of events in the blood vessels of otherwise healthy adults that can lead to high blood pressure. The disease process eventually makes conditions in vessels ripe for the creation of blockages that can cause heart attacks, strokes and circulatory problems.



The finding in a study led by Ohio State University researchers might lead to new therapeutic options for high blood pressure, especially hypertension associated with aging. Obesity and aging contribute to increasing cases of high blood pressure, which currently affects an estimated 50 million Americans.



Despite more intensive treatments available for hypertension, little has been done to prevent it. A change in the structure of the blood vessels, called vascular remodeling, increases with age and triggers the onset of the disease. When remodeling occurs, blood vessel walls increase in thickness, decreasing the diameter of the channel through which blood normally flows.



The gene, called profilin 1, has been traced to a series of interactions within the smooth muscle cells of blood vessels that causes those cells to increase in size. This in turn narrows the channel through which blood flows, causing stress on vessel walls, injuring the lining of the vessel walls and making it easier for blockages to develop. By identifying this pathway, researchers hope to pinpoint the most effective therapeutic target to interfere with the disease process.



The researchers used genetically altered mice that produce excessive amounts of the human profilin 1 gene in the vascular smooth muscle cells and observed the changes to the vessels that followed, which led to high blood pressure by the time the mice were 6 months old - the rough equivalent to middle age in humans.



"We created the disease in the animals and then went backwards to understand how the disease developed. This is an important finding because vascular disease originates in the smooth muscle cells, which have significant impact on the dysregulation of blood pressure that leads to heart disease," said Hamdy Hassanain, assistant professor of anesthesiology at Ohio State University and senior author of the study. Hassanain also is an investigator in Ohio State's Davis Heart and Lung Research Institute.



The findings were published in the Dec. 28, 2007 issue of the Journal of Biological Chemistry.
















Blood vessels contain three important layers - the endothelium that lines the vessel walls, the smooth muscle cells responsible for regulating blood flow, and the lumen, the open channel through which blood travels. In healthy young humans, the production of compounds by the cells in these layers remains balanced, allowing for normal vessel function and unrestricted blood flow.



Hassanain developed a transgenic mouse that produces excess human profilin 1 in the smooth muscle cell area with the intent to cause stress in the vessel walls that leads to hypertrophy, or an enlargement of the smooth muscle cells that eventually leads to structural and functional changes in the entire vessel. The mice were developed to test the theory that the impaired regulation of the profilin 1 gene would eventually lead to high blood pressure, and observe how that happens.



"Vascular remodeling is a known problem as people get older. Their blood vessels tend to stiffen, even in healthy adults. This causes stress on the vessels, which leads to hypertension," Hassanain said.



At the heart of the vessel activities is a protein called actin within the smooth muscle cells, and its relationship to profilin 1. In the presence of too much profilin1, actin is transformed from a loosely configured protein into a more rigid fibrous state. This change in actin's nature increases the size and the stiffness of smooth muscle cells.



The cells undergo other changes that prepare them for cell division, but under these conditions, the vessel lining releases a substance, nitric oxide, that won't allow the cells to divide. The smooth muscle cells' resulting growth pushes inward, putting pressure on the lumen and restricting blood flow, resulting in high blood pressure.



"Profilin 1 is a tool that triggers events that make the vessel more constricted and leads to the signal that results in vascular remodeling. Because we have understood the pathway of the disease process, we might be able to control vascular remodeling," Hassanain said.



Once a vessel is remodeled, more trouble is typically ahead. Diseased vessels are often characterized by injuries to the endothelium, where the lining of the vessel loses its protective layer. Once the lining is injured and vulnerable, smooth muscle cells will start to migrate inward, creating sticking points for fats, debris and other blood remnants.



"That's the first hint of plaque. The smooth muscle cell migration is the tip of the iceberg of the plaque," Hassanain said. "We're talking about all vessels, but when we're talking about this narrowing effect in the brain, this could lead to stroke, and in the coronary artery, it could lead to heart attack. It's all the same phenomenon."







Other Ohio State co-authors of the study are Mazin Alhaj, Maqsood Chotani, Zeinb Aboelnaga, Mohamed Hassona, Gerard Nuovo and Jay Zweier, all of the Davis Heart and Lung Research Institute; Osama El-Sayed of cardiology; and Sheik Wisel of surgery; additional co-authors are Mariana Morris of Wright State University and Pascal Goldschmidt-Clermont of the University of Miami. First author Moustafa Moustafa-Bayoumi completed his Ph.D. in Hassanain's lab at Ohio State and is now at California State Polytechnic University .



Source: Hamdy Hassanain


Ohio State University

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It's Only Heartburn...or Is It? Chronic Heartburn A Risk Factor For Precursor To Esophageal Cancer

If you have or have
ever had chronic heartburn, you may be at risk for Barrett's esophagus, a
serious complication of chronic, severe gastroesophageal reflux disease
(GERD). Barrett's esophagus has been recognized as a major risk factor for
developing cancer of the esophagus, the seventh deadliest cancer in men in
the United States.



Barrett's esophagus is marked by cellular changes in the lining of the
esophagus, which can progress to low-grade, and then high-grade dysplasia
-- a level that is highly pre-malignant. These abnormal cellular changes
can lead to a type of cancer called esophageal adenocarcinoma, the fastest
rising malignancy in the United States, according to the National
Institutes of Health.



The Valley Hospital's Center for Barrett's Esophagus and GERD provides
cutting-edge diagnostic, treatment, management, and research services for
these related conditions. The Center is one of the most comprehensive on
the East Coast and unique to northern New Jersey. The physician team
includes board-certified gastroenterologists and thoracic surgeons.



Diagnostic and treatment methods available at the Center include
endoscopy, medications to reduce acid, minimally invasive surgical
procedures to repair hiatal hernias and to prevent acid reflux,
radiofrequency ablation to destroy abnormal cells, endoscopic mucosal
resection to remove nodules within Barrett's esophagus, and esophageal
cancer surgery.



Robert J. Korst, M.D., Medical Director of The Valley Hospital's Daniel
and Gloria Blumenthal Cancer Center, and Director of Thoracic Surgery, says
he and physicians at the Center for Barrett's Esophagus and GERD must take
a two-prong approach to treating Barrett's esophagus that both destroys the
abnormal lining and stops acid reflux.



"Radiofrequency ablation can get rid of the lining, but if the GERD is
not controlled, those abnormal cells can grow back and put the patient at
risk for cancer once again," he adds.




If Barrett's esophagus progresses into high-grade dysplasia or cancer,
the entire esophagus must be removed. Dr. Korst specializes in the
treatment and research of esophageal cancer and is highly experienced in
using both laparoscopic and traditional surgical methods to remove the
esophagus and construct a new one by stretching the stomach.



Barrett's esophagus is most prevalent in middle aged and elderly
Caucasian men but can affect anyone, even those who do not have obvious
symptoms of gastroesophageal reflux disease.


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Experimental Treatment For Type 1 Diabetes Patients Shows Promise

New research monitoring the effects of Islet cell transplantation resulted in near-normal metabolic control and decreased hypoglycemia. This research will be presented at the American Association of Clinical Endocrinologists (AACE) 17th Annual Meeting & Clinical Congress, on Friday, May 16th, at the Walt Disney World Dolphin Resort in Orlando.


During the 18 month study, physicians used Continuous Glucose Monitoring Systems to monitor the effects of the islet cell transplant procedure on patients with type 1 diabetes. The results were intriguing.


"Our findings suggest that the majority of patients with Type 1 diabetes who have received an islet transplant benefit from near normal metabolic control, with fewer and shorter episodes of hypoglycemia," said Lisa Gorn, DO, the study's primary author. "These patients also spent longer periods of time in normoglycemia overall.


At the 2008 AACE Annual Meeting diabetes will be taking center stage. A special symposium titled "Clinical Trials Targeting Glycemia: What Do We Expect to Learn?" will consider the impact of glucose control through studies including ACCORD, ADVANCE, VADT, and others. Related sessions of interest include "Insulin Resistance and Atherosclerosis: The Missing Link," and "Hypoglycemia: The Limiting Factor in the Glycemic Management of Diabetes."


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Non-Polyploid Colon Regions Are Linked To Colorectal Cancer - And More Common Than Previously Thought

Flat,
non-polyploid colorectal neoplasms (NP-CRNs) are difficult to detect,
but when examined, they appear to be common. Additionally they may have
a stronger association with colorectal cancer than polyps, which are
more routinely observed in examination, according to a study published
on March 5, 2008 in JAMA



Colorectal cancer, sometimes
simply called colon cancer, encompasses cancerous growths in the large
intestines and appendix. It is the second leading cause of cancer death
in the United States. Prevention strategies have focused on detecting
and removing polyploid neoplasms, which are abnormal growths resembling
polyps. More recently, however, it has been shown that colorectal
cancer can develop from NP-CRNs, which are flat or depressed
in
shape. These can be more difficult to detect, according to the authors
of the study: "Nonpolypoid colorectal
neoplasms are more difficult to detect by colonoscopy or computed
tomography colonography because the subtle findings can be difficult to
distinguish from those of normal mucosa [membrane]. As compared with
surrounding normal mucosa, NP-CRNs appear to be slightly elevated,
completely flat, or slightly depressed."



Since information is
limited regarding the true significance of NP-CRNs in colorectal cancer
development, Roy M. Soetikno, M.D.,
M.S., and colleagues with the Veterans Affairs Palo Alto Health Care
System, Palo Alto, California, investigated data from 1,819 patients
undergoing elective colonoscopy, in the hope of estimating the
frequency of NP-CRNs and to characterize the relationship of NP-CRNs to
colorectal cancer.



Patients were also classified into subgroups according to their
situations: the screening group, of asymptomatic
patients who had undergone average risk-screening colonoscopies; the surveillance
group, who had a personal or hereditary history of colorectal cancer;
or the symptomatic
group, who showed symptoms and indications associated with colorectal
neoplasms, including anemia, rectal bleeding, constipation, diarrhea,
positive results from a fecal occult blood test, weight loss, abdominal
pain, and inflammatory bowel disease.



In the whole group, NP-CRNs were present in 9.35% of patients.
According to subpopulation, the screening group showed 5.84%,
surveillance showed 5.84%, and symptomatic showed 6.01%. In cancers
that had not spread, or had spread in the tissue beneath the mucous
membrane the overall prevalence was 0.82%, while prevalence in the
screening population was 0.32%. It was also observed in the
surveillance and screening populations.



Overall, NP-CRNs were almost 10 times more likely to contain cancerous
tissue than polyploid lesions, regardless of size. The
depressed type of NP-CRNs showed the highest risk (33%.) NP-CRNs
containing cancer were generally smaller in diameter when compared with
polyploid cancerous regions.



"In conclusion, in
this population of patients at a single Veterans Affairs hospital,
NP-CRNs were a relatively common finding during colonoscopy. They were
more likely to contain carcinoma compared with polypoid neoplasms,
independent of lesion size. Recent studies have pointed out differences
in the genetic mechanisms underlying nonpolypoid and polypoid
colorectal neoplasms. Future studies on NP-CRNs should further evaluate
whether the diagnosis and removal of NP-CRNs has any effect on the
prevention and mortality of colorectal cancer and particularly focus on
their genetic and protein abnormalities," write the authors.



Editorial: Nonpolypoid Colorectal Neoplasia in the United
States



David Lieberman, M.D., of Oregon Health
& Science University, Portland VA Medical Center, Portland,
Ore.,
contributed an additional editorial in which he comments on the
findings of Soetikno and colleagues. "[Nonpolypoid
colorectal neoplasms] may be biologically distinct from polypoid
lesions and appear to be more likely to harbor malignant features.
Detection and complete removal at colonoscopy may be challenging. The
current study emphasizes the importance of quality in the performance
of colonoscopy," he writes. "The optimal methods for enhancing
colonoscopic imaging of NP-CRNs are uncertain. ??¦ Additional studies are
needed to determine whether imaging modalities such as computed
tomography colonography will be able to detect NP-CRNs. Finally,
longitudinal studies are needed to determine whether patients with
NP-CRNs require more intensive colonoscopic surveillance compared with
patients with polypoid lesions of similar size and histology."



Prevalence of Nonpolypoid (Flat and Depressed) Colorectal Neoplasms in
Asymptomatic and Symptomatic Adults

Roy M. Soetikno; Tonya Kaltenbach; Robert V. Rouse; Walter Park;
Anamika Maheshwari; Tohru Sato; Suzanne Matsui; Shai Friedland

JAMA. 2008; 299(9):1027-1035.

Click
Here For Abstract



Nonpolypoid Colorectal Neoplasia in the United States: The
Parachute Is Open

David Lieberman

JAMA. 2008; 299(9):1068-1069.

Click
Here For Extract



Anna Sophia McKenney

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MIT's MicroRNA 'Sponges' Could Aid Cancer Studies

MIT researchers have developed a new way to study the
function of microRNA, tiny strands of genetic material that help
regulate at least 25 percent of a cell's genes.



The new technique could shed light on microRNA's hypothesized role in
tumor development. Malfunctions in microRNA have been linked with
cancer, but very few direct relationships have been established
between specific microRNAs and the genes they regulate.



That could change, however, now that MIT Institute Professor Phillip
Sharp and his colleagues have found a way to inhibit the activity of
microRNA by genetically altering cells.



The technique, described in the August 12 online issue of Nature
Methods, could "provide a tool to identify specific genes that are
being regulated by microRNAs," said Sharp.



MicroRNA consists of short strings of about 22 nucleotides, the
building blocks that make up RNA and DNA. MicroRNA binds to messenger
RNA (mRNA), preventing it from delivering protein assembly
instructions, thereby inhibiting gene expression.



Sharp, who is affiliated with MIT's Biology Department and Center for
Cancer Research, said microRNA exists in every cell and controls a
wide range of cell regulatory activities.



The MIT team has found a way to block microRNA activity by tricking
cells into producing a microRNA "sponge," which soaks up microRNA and
renders it ineffective. By de-activating microRNA, researchers can
observe the resulting effects and determine which genes the microRNA
is targeting.



The new technique could shed more light on microRNA's role in tumor
development: Earlier studies have shown that a type of microRNA known
as let-7 inhibits a cancer-inducing gene called RAS. Abnormally low
levels of let-7 have been found in some types of tumor, said Sharp.



Sharp and MIT biology graduate student Margaret Ebert, lead author of
the paper, decided to block microRNA activity by creating a gene that
produces microRNA sponges and inserting it into their target cells.
Each sponge can bind up to six microRNA molecules, but they could be
engineered to bind more.



The sponge gene also includes a "reporter" gene that causes the cell
to become fluorescent if it has taken up the gene, so the researchers
can know for sure whether the microRNA sponge is being produced in a
particular cell.



Ebert said the new sponge technique is an improvement over an older
method that involves blocking microRNA activity with artificially
synthesized strands of RNA, known as oligos. One advantage is the
inclusion of the reporter gene; another is that the sponge genes can
be expressed continuously, while oligos do not remain in the cell
forever.



More importantly, the sponge technique could be used to create
transgenic animals that express the sponge in all of their cells,
allowing researchers to study microRNA function at the organismal
level. With such animals, sponge genes could be designed so that the
researchers can control when and where they are expressed.



Joel Neilson, a postdoctoral associate in the Center for Cancer
Research, is also an author on the paper. The research was funded by
the National Cancer Institute, the National Institutes of Health, a
Howard Hughes Medical Institute Predoctoral Fellowship, a Paul and
Cleo Schimmel Scholarship, and the Cancer Research Institute.



The MIT Center for Cancer Research (CCR) was founded in 1974, and is
one of eight National Cancer Institute-designated basic research
centers. Its mission is to apply the tools of basic science and
technology to determine how cancer is caused, progresses and responds
to treatment.


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Women's Advocates Call On The IOM To "Seize This Historic Opportunity" To Help Millions Of Women Suffering From Neglected Chronic Pain Disorders

Today, leading women's health advocates called on the Institute of Medicine (IOM), through the release of the first Congressionally-mandated report on the state of our nation's effort to eradicate chronic pain, to "seize this historic opportunity" to help the millions of afflicted American women suffering from prevalent, longtime neglected pain disorders.



In a letter sent today to Dr. Phillip Pizzo, Chair of the IOM Committee on Advancing Pain Research, Care and Education, organizational leaders of the Campaign to End Chronic Pain in Women thanked the IOM for their important work and called on the special Committee to be bold in its recommendations, which are expected by the end of June. The letter notes that up to 50 million women in America suffer from one or more of the following prevalent, neglected and poorly understood chronic pain conditions that frequently co-occur and disproportionately affect women: chronic fatigue syndrome, endometriosis, fibromyalgia, interstitial cystitis, TMJ disorders and vulvodynia, at an annual cost of up to $80 billion a year.



They called on the IOM to recommend a concerted and coordinated effort to confront this costly problem: "The report should call on our nation's leaders to enact a long overdue, concerted, coordinated, and serious effort to tackle this costly problem through an expanded collaborative research effort and improved clinical care. Doing so has the potential to not only lead to an improved quality of life for millions of Americans, but will start the process of reducing wasteful and inefficient health care spending."



Last year Congress directed the IOM to develop recommendations on how to significantly improve the state of our nation's pain research, medical management and educational efforts. This report is expected to be delivered to Congress by June 30, 2011. Since the IOM study began in November 2010, the Campaign has, on every available opportunity, submitted oral and written testimony; today's letter outlined essential elements of the solution to this complex problem.



"Through the release of this report, the IOM has a historic opportunity to redefine how our nation confronts our chronic pain epidemic," said the Campaign leaders. "These recommendations hold the promise of stimulating long-overdue improvements in the quality of medical care provided to millions of chronic pain sufferers."



Source:

Campaign to End Chronic Pain in Women

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