Do we have to kill the last CML cell?

Previous experience in the treatment of chronic myeloid leukaemia (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR; no detectable BCR–ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemia, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemic cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemic clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR–ABL-positive cells that may persist after effective therapy of CML.

source: nature oncology

Zebrafish: A Model System to Study Heritable Skin Diseases

Heritable skin diseases represent a broad spectrum of clinical manifestations due to mutations in ~500 different genes. A number of model systems have been developed to advance our understanding of the pathomechanisms of genodermatoses. Zebrafish (Danio rerio), a freshwater vertebrate, has a well-characterized genome, the expression of which can be easily manipulated. The larvae develop rapidly, with all major organs having developed by 5–6 days post-fertilization, including the skin, consisting of the epidermis comprising two cell layers and separated from the dermal collagenous matrix by a basement membrane. This perspective highlights the morphological and ultrastructural features of zebrafish skin, in the context of cutaneous gene expression. These observations suggest that zebrafish provide a useful model system to study the molecular aspects of skin development, as well as the pathogenesis and treatment of select heritable skin diseases.

source: nature dermatology

Are dietary patterns in childhood associated with IQ at 8 years of age?

Little is known about the effects of overall diet in childhood and intelligence later in life.

Methods The current study, based on the Avon Longitudinal Study of Parents and Children, uses data on children’s diet reported by parents in food-frequency questionnaires at 3, 4, 7 and 8.5 years of age. Dietary patterns were identified using principal-components analysis and scores computed at each age. IQ was assessed using the Wechsler Intelligence Scale for Children at 8.5 years. Data on a number of confounders were collected, and complete data were available for 3966 children.

Results After adjustment, the ‘processed’ (high fat and sugar content) pattern of diet at 3 years of age was negatively associated with IQ assessed at 8.5 years of age—a 1 SD increase in dietary pattern score was associated with a 1.67 point decrease in IQ (95% CI −2.34 to −1.00; p<0.0001). The ‘health-conscious’ (salad, rice, pasta, fish, fruit) pattern at 8.5 years was positively associated with IQ: a 1 SD increase in pattern score led to a 1.20 point increase in IQ (95% CI 0.52 to 1.88; p=0.001).

Conclusion There is evidence that a poor diet associated with high fat, sugar and processed food content in early childhood may be associated with small reductions in IQ in later childhood, while a healthy diet, associated with high intakes of nutrient rich foods described at about the time of IQ assessment may be associated with small increases in IQ.

source: BMJ

Scientists find ‘core pathway’ causing declining health in old age

New evidence implicates telomere loss as primary trigger

Scientists at Dana-Farber Cancer Institute say they have identified the root molecular cause of a variety of ills — waning energy, failure of the heart and other organs, metabolic disorders like diabetes — brought on by advanced age.

“What we have found is the core pathway of aging connecting several age-related biological processes previously viewed as independent of each other,” said Ronald A. DePinho, MD, senior author of a report posted online by the journal Nature. The first author, Ergun Sahin, MD, is a member of the DePinho lab.

DePinho, who is the director of Dana-Farber’s Belfer Institute for Applied Cancer Science, said that although the studies were conducted in mice, “The findings bear strong relevance to human aging as this core pathway can be directly linked to virtually all known genes involved in aging as well as current targeted therapies designed to mitigate the toll of aging on health.”

The scientists found that the basic cause of age-related health decline is malfunctioning telomeres — the end-caps on cells’ chromosomes that protect them against DNA damage. As cells reach their pre-determined limit of times that they can divide, the telomeres become shortened and frayed, making the chromosomal ends vulnerable to increased rates of unrepaired DNA damage.

Faced with this increasing reservoir of injured DNA, cells activate a gene, p53, that sounds an alarm and shuts down the cells’ normal growth and division cycle, ordering them to rest until the damage can be repaired or, if not, to self-destruct.

Scientists previously had blamed this emergency shutdown and cell death for the age-related deterioration of organs whose cells divide rapidly and are rejuvenated by reserves of adult stem cells. Such tissues include skin, intestinal lining and blood cells, among others, which generate trillions of new cells each day of life.

However, left unanswered is how cells with less cell division, such as the heart or the liver, sustain equivalent levels of aging. The scientists felt if they could answer this mystery, they might gain new insights into how DNA damage might lead to age-related decline across all organs.

The new findings demonstrate that the telomere dysfunction and activation of p53 also trigger a wave of cellular and tissue degeneration that links telomeres to well-known mechanisms of aging that are not simply related to rapid growth and division. In other words, telomere dysfunction is not just one culprit in the declining health of advanced age — it’s the kingpin, according to DePinho and his colleagues.

(DePinho published a study in Nature in January that demonstrated that it was possible to reverse the symptoms of extreme aging in mice by increasing their levels of telomerase, the enzyme that maintains health of the telomeres.)

In this new larger role, that telomere dysfunction also sets off an array of reactions leading to diminished health and longevity. For example, muscles suffer a loss of mitochondria — a cell’s chemical power plant — causing waning vitality and failure of the heart and other organs. Risks of metabolic disorders such as diabetes are increased.

In addition, the process weakens the body’s antioxidant defenses against the damaging molecules known as reactive oxygen species, or “free radicals” that accumulate with age and exposure to stress. Until now, some researchers had labeled the decline in mitochondria or the buildup of free radicals as the primary causes of age-related ills. The new work integrates these seemingly disparate mechanisms into one unified theory of aging.

Telomere dysfunction causes this wave of metabolic and organ failure, the scientists found, because when the p53 gene is activated, it represses the functions of two master regulators of metabolism — PGC1?alpha and PGC1?beta. This dialing down of the regulators diminishes metabolic processes needed to provide energy and resist stress. In the mouse experiments, the scientists showed that “knocking out” p53 in mice released the brakes on PGC1?alpha and PGC1?beta.

“This is the first study that directly links telomere dysfunction to regulators of the mitochondria and anti-oxidant defense via p53,” DePinho said. “The discovery of this new pathway of aging integrates a lot of different ideas people have had and gives us a better understanding of the aging process.” By unifying several major aging pathways under the umbrella of telomere dysfunction, he said the findings may yield new targets for therapies.

The discoveries also may underlie the relatively sudden and rapid failure of the body leading to the end of life.

“Because telomere dysfunction weakens defenses against damage by free radicals, or reactive oxygen species,” DePinho explained, “we think this exposes telomeres to an accelerated rate of damage which cannot be repaired and thereby results in even more organ deterioration. In effect, it sets in motion a death spiral.”

source: dana faber cancer center

Researchers offer sweeping view of prostate cancer genome, yielding deep insights into cancer growth

Using whole genome sequencing and multiple tumor samples, researchers uncover genetic missteps

For the first time, researchers have laid bare the full genetic blueprint of multiple prostate tumors, uncovering alterations that have never before been detected and offering a deep view of the genetic missteps that underlie the disease. The study, made possible by key advances in whole genome sequencing and analysis, points to several new prostate cancer genes and a critical category of genomic changes as important drivers of prostate cancer growth. The work was led by researchers from the Broad Institute, Dana-Farber Cancer Institute and Weill Cornell Medical College and appears in the February 10th issue of the journal Nature.

Unlike other sequencing methods that target specific sections of the genome, whole genome sequencing enables researchers to look across the entire DNA landscape of a tumor, making it possible to discern global changes and patterns. Senior authors Levi Garraway and Mark Rubin and their colleagues used this strategy to view the complete genomes of seven prostate tumors and compare them to normal tissue samples to find regions of abnormality.

“Whole genome sequencing gives us fascinating new insights into a category of alterations that may be especially important in prostate cancer,” said Garraway, a senior associate member of the Broad Institute and a medical oncologist and assistant professor at the Dana-Farber and Harvard Medical School.

Prostate cancer is the second most lethal cancer in American men, responsible for more than 30,000 deaths and more than 200,000 new cases each year. A major goal of prostate cancer research is to identify potential drug targets as well as genetic characteristics within tumors that could distinguish indolent and aggressive forms of the disease, and ultimately improve diagnostics and treatment.

Rubin, the Homer T. Hirst Professor of Oncology in Pathology and vice chair for experimental pathology at Weill Cornell Medical College, compares the Nature study to looking not just for spelling errors in the genome, but also for whole paragraphs or sections of genomic text that have been rearranged. “One of the big surprises is the fact that prostate cancer doesn’t have a large number of misspellings, but instead has a large, significant number of rearrangements,” said Rubin. “We would never have guessed that there were so many genomic alterations of this type before now because we didn’t have the right tools to look for them.”

These alterations are known as genomic rearrangements — a kind of shuffling that occurs when a piece of DNA from one part of the genome breaks off and reattaches itself in another location. These rearrangements can create new genes (called “fusion genes”), allow a gene to operate unchecked, or prevent a gene from even working at all. Such changes can set a cell on a path toward cancer. By looking for genes affected by these rearrangements in multiple prostate cancer samples, the researchers unearthed new genes tied to the disease and found new mechanisms that may be driving cancer as a whole.

“This first whole genome view shows us tantalizing evidence for several new prostate cancer genes that likely would have remained undiscovered had we not been taking a genome-wide approach,” said Garraway.

Several tumors contained rearrangements disrupting the gene that codes for the protein CADM2, part of a family of proteins that prevent tumors from forming (known as “tumor suppressors”). Three samples also contained mutations involving members of the heat shock protein family, molecules that play an important, protective role and keep proteins from losing their proper shape. Anti-cancer drugs that inhibit these proteins are currently in clinical trials, but it is not yet clear whether prostate cancers will be vulnerable to such drugs.

Other recurring genomic rearrangements involve the genes PTEN and MAGI2. PTEN is a well-known tumor suppressor gene and MAGI2 appears to be its helpmate; mutations to one or both genes may set cells on the path toward becoming cancerous. Drugs that inhibit the pathway these genes influence are also being developed, raising the possibility that the drugs could be applied to prostate cancer.

In addition to uncovering new and suspected genes, whole genome sequencing has also given Garraway, Rubin and their colleagues insights into how genomic rearrangements arise in the first place. With a catalog of rearrangements in hand, the researchers looked for where breaks and reattachments tended to occur, and found that these events are not distributed randomly across the genome. Rather, in some tumors these events tend to take place in areas of the genome that are inactive or silent, while in other tumors they occur in regions that are highly active. This pattern suggests that mistakes made by cells while turning genes on and off might give rise to DNA rearrangements and therefore play a formative role in cancer’s development.

The researchers’ findings may also provide a key starting point for the development of new diagnostic tools for prostate cancer. Currently, when patients are diagnosed with prostate cancer, it is almost impossible for doctors to determine if the disease will advance quickly and therefore require aggressive treatment, or whether the tumors will remain slow-growing, necessitating a wait-and-see approach. “This study could enhance our ability to develop new, diagnostic markers for prostate cancer,” said Rubin. “We can also imagine eventually developing more personalized diagnostic tools for patients with recurrent tumors, to essentially follow the tumors’ progression by testing for new genomic alterations.”

Although the researchers’ findings need to be studied further and extended to larger numbers of tumor samples, this initial analysis has opened up many new avenues of investigation, underscoring the power of applying whole genome sequencing to cancer.

“Many of these features were invisible before,” said Garraway. “Now, we’re realizing that by sequencing whole genomes in prostate cancer, there’s a lot more to see. These discoveries are teaching us a great deal about prostate cancer biology that we simply hadn’t appreciated previously.”

source: dana faber cancer center

New Treatment for Celiac Disease?

Research Shows Blocking a Protein May Reverse Celiac Disease Symptoms


serious woman

Feb. 9, 2011 — Blocking an inflammatory protein called interleukin-15 (IL-15) may help treat the symptoms of celiac disease and prevent the development of celiac disease in certain at-risk people, according to new research in mice published in Nature.

Celiac disease is an autoimmune and inflammatory condition that is triggered by gluten, the protein found in wheat, barley, and rye. When people with celiac disease eat gluten, it triggers an inflammatory response that damages the lining of the small intestine. Symptoms include gas, bloating, cramping, and constipation. People with celiac disease are also at risk for nutritional shortfalls including vitamin B12, vitamin B1 (thiamine), vitamin K, vitamin D, calcium, iron, and folate. Risk factors for developing celiac disease include family history of celiac disease and/or a personal or family history of other autoimmune diseases, including rheumatoid arthritis (RA).

Gluten-free diets are the treatment of choice for celiac disease. Such foods are becoming increasingly available because of the dramatic uptick in rates of celiac disease and other conditions that may respond to gluten-free diets.

In the new study, researchers blocked IL-5 in mice genetically altered to have celiac disease and found that the disease symptoms were reversed, and the mice were once again able to eat gluten.

Is Blocking IL-15 the Key to Treating Celiac Disease?

“We have identified one mechanism by which people lose tolerance to gluten,” says author Bana Jabri, MD, PhD, an associate professor of medicine and pathology and co-director of the Digestive Disease Research Core Center at the University of Chicago. “IL-15 may be a critical element that drives the loss of tolerance to gluten, and we can now think about pathways to block it and potentially develop therapies for celiac disease.”

Medications that block IL-15 are being developed for other inflammatory diseases, including RA.

The new research also shows that retinoic acid, a vitamin-A derivative found in acne treatments such as Retin-A and Accutane, may be complicit in the onset of celiac disease.

“Vitamin A in these patients is a bad idea,” she says. “Patients at risk should be careful about using retinoids.” This may even include topical retinoids if they can enter the bloodstream, she says.

Those two molecules act together to promote inflammation, she says. “The vitamin A derivative seems to fuel the IL-15, but if you block IL-15, retinoids are OK,” she says.

More Celiac Treatments Needed

“In the U.S., we need to increase awareness and diagnosis of celiac disease because less than 10% of patients are diagnosed,” she says. “A gluten-free diet is currently the treatment of choice, but some patients only respond partially, and it is still socially a handicap.”

The race is on to develop new therapies to treat or prevent celiac disease, she says.

“At this point, the new study holds theoretic promise,” says Gerard Mullin, MD, an associate professor of medicine at Johns Hopkins School of Medicine and the director of Integrative Nutrition Services at the Johns Hopkins Hospital in Baltimore.“IL-15 may be a major player in driving the inflammatory response in celiac disease, and if we block it, you can tolerate gluten.

“A drug that blocks IL-15 may be most beneficial in people with really aggressive disease that doesn’t respond to conventional dietary measures,” Mullin says. For people with celiac disease, “today’s day and age is better to live in than 10 years ago due to increased availability of gluten-free foods and gluten-free menu options.”

Celiac disease is on the rise in the U.S., he says.

“The prevalence has jumped four to five times since the 1940s, but we are not clear why,” Mullin says. “Many food experts have speculated that it is the way grains are processed here, but we do see it in Italy and other places.”

Diagnosing celiac disease is not always straightforward, he says. Blood tests that look for the presence of certain antibodies are the first step. If the results are positive, many doctors will order a biopsy of the small intestine to confirm the diagnosis. This biopsy can also help assess the degree of damage, but “even the biopsy can miss it,” he says.

Richard Desi, MD, a gastroenterologist at the Melissa L. Posner Institute for Digestive Health and Liver Disease at Mercy Medical Center in Baltimore, says that blocking IL-15 may well help some people with celiac disease.

“This may not be it for everybody, but maybe it can help some people,” he says. “We are starting to understand celiac disease a lot more and diagnose it a lot more. The hope is that we will be able to come up with a treatment that doesn’t just involve a gluten-free diet.”

Wireless Sensor Monitors Heart Failure Patients

Study Suggests Experimental Device May Cut Hospitalization Rate for People With Heat Failure


heart monitor graphic

Feb. 9, 2011 — An implanted wireless monitoring device about the size of a paper clip reduced hospitalizations among heart failure patients by 39%, a study shows.

The experimental implant is designed to measure pressure in a pulmonary artery, which is a leading indicator of how well a patient’s heart failure is being managed with drugs.

The study is published in The Lancet.

Atlanta-based company CardioMEMS, which paid for the study, hopes to win FDA approval to market the device for use by patients with heart failure later this year.

Just as frequent blood sugar readings help with adjusting insulin for diabetes, the thinking is that closely monitoring pulmonary artery pressure can help adjust medications for heart failure patients.

As the researchers had hoped, study participants with the devices had fewer hospitalizations than those who got standard care, says study researcher William T. Abraham, MD, who directs the Ohio State University Medical Center’s division of cardiovascular medicine.

“We showed that by monitoring pressure precisely every day and adjusting medications to keep pressures in or near the normal range, patients felt better and spent less time in the hospital,” Abraham says.

Expensive Care for Heart Failure

About 5.8 million Americans have heart failure, at a cost to the nation of about $39 billion a year in health care services, medications, and lost productivity, according to the CDC.

Heart failure-related hospitalizations account for about half of that figure, Abraham tells WebMD.

The study included patients with moderate heart failure who had at least one prior hospital admission for heart failure. The patients were treated at 64 centers across the country.

About half the patients underwent a catheterization procedure to place the small wireless sensor in a pulmonary artery while the other half received standard medical care.

A special pillow containing an antenna simultaneously powers the sensor and takes a pressure reading via radio waves that are harmless to the patient, Abraham says.

Once a day, the patients lay on the pillow and pushed a button to turn the device on. The reading was then taken and sent through a wireless connection to a secure web site.

Doctors and nurses could also have the readings sent to their smart phones, and the device even alerts the provider when pressure readings indicate a problem.

No Batteries or Moving Parts

Over 15 months of use, 253 heart failure-related hospitalizations occurred in the 280 patients who did not have the devices vs.153 hospitalizations in the 270 patients who did get them.

One of the main advantages of the sensor is that it does not require batteries, Abraham says.

“There are no moving parts and nothing to wear out or replace,” he says.

The FDA failed to approve an earlier version of a wireless heart-monitoring device, made by the company Metronics. And efforts by another company to market a wireless cardiac device designed to monitor arrhythmia were also unsuccessful.

Abraham says the CardioMEMS device should cost between $10,000 and $20,000.

“When you consider that one heart failure hospitalization may cost in the neighborhood of $10,000 to $15,000 you can see that it makes economic sense in patients who are at risk for hospitalization,” he says.

Long Island Jewish Medical Center cardiologist Bruce Goldner, MD, calls the findings impressive. But he tells WebMD that he would like to see additional studies to confirm them with longer patient follow-up.

“These patients were followed for around 600 days and the major complication rate was low (1.4%),” he says. “But we can’t really say if more complications will be seen with longer-term use.”

Storytelling to Improve Blood Pressure

Benefits of a culturally appropriate storytelling intervention were similar to those of antihypertensive drugs.

Can patient-to-patient storytelling, i.e., narrative communication, help to lower blood pressure? In this study of hypertensive black patients in Alabama, researchers identified patients in focus groups who clearly and persuasively described their experiences with hypertension; selected patients served as storytellers on DVDs and offered lessons about how to interact with physicians and how to achieve better medication adherence, diet, and exercise. The 231 study participants randomly received either the storytellers’ DVDs or DVDs about general health issues unrelated to hypertension. Intervention patients spent an average of 88 minutes watching the storytellers’ DVDs.

Patients in both groups who had controlled hypertension at baseline exhibited no significant changes in blood pressure 6 to 9 months later. However, intervention patients with uncontrolled hypertension at baseline exhibited significant reductions in mean blood pressure — 15 mm Hg systolic (vs. 3 mm Hg in controls) and 3 mm Hg diastolic (vs. no change in controls).

Comment: In this randomized trial, storytelling by black patients for black patients achieved dramatic reductions in blood pressure — 15 mm Hg systolic and 3 mm Hg diastolic relative to controls. With this approach, the authors note, “listeners may be influenced if they actively engage in a story, identify themselves with the storyteller, and picture themselves taking part in the action.” The magnitude of the effect is similar to that of antihypertensive medications. If the study can be replicated and if the benefits are sustained over time, the intervention would be a substantial achievement — one that would also force us to reevaluate how we deliver messages to our increasingly diverse patient populations.

Jamaluddin Moloo, MD, MPH

Published in Journal Watch General Medicine February 10, 2011

Prenatal Exposure to Diagnostic X-Rays Associated with Nonsignificant Increase in Pediatric Cancers

A BMJ study suggests a slightly — albeit nonsignificant — increased risk for childhood cancer from diagnostic x-rays in utero and in early childhood.

Researchers assessed prenatal and early childhood exposure to radiation and ultrasounds through parental interviews and medical records of some 2700 children with cancer and 4900 age- and sex-matched controls in the U.K.

They found a modestly increased risk for all cancers after prenatal exposure to x-rays, but this result was not statistically significant. Similarly, they found a nonsignificant increase in cancer risk after exposure to diagnostic radiography in early infancy (0 to 100 days). With radiographs in early infancy, the risk for lymphoma reached statistical significance, but it was only based on seven cases. Ultrasound scans were not associated with cancer.

The authors conclude that their results, “which indicate possible risks of cancer from radiation at doses lower than those associated with computed tomography scans, suggest a need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages.”