U.S. Department of Health and Human Services

NATIONAL INSTITUTES OF HEALTH NIH News

National Cancer Institute (NCI)

Embargoed for Release: Monday, January 31, 2011

Results of an intermediate stage clinical trial of several dozen people provides evidence that a method that has worked for treating patients with metastatic melanoma can also work for patients with metastatic synovial cell sarcoma, one of the most common soft tissue tumors in adolescents and young adults. This study is the first to use genetically modified immune cells, in a technique known as adoptive therapy, to cause cancer regression in patients with a solid cancer as opposed to melanoma. This approach represents a method for obtaining immune cells from any cancer patient and converting them into ones that can recognize cancer cells expressing the target antigen, NY-ESO-1, according to researchers at the National Cancer Institute. The study appeared in the Jan. 31, 2011, issue of the Journal of Clinical Oncology.

NY-ESO-1 is a protein found in up to 50 percent of melanomas and cancers of the breast, prostate, esophagus, lung, and ovary, and in 80 percent of synovial sarcomas. “Since NY-ESO-1 is expressed in a substantial number of cancers, beside melanoma and synovial sarcoma, it is an attractive target for immune-based therapies against these cancers as well,” said lead investigator Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research.

This work builds upon previously published results in patients with metastatic melanoma. Those studies showed that metastatic melanoma patients could be treated by infusion with their own genetically modified T cells, or white blood cells, that had receptors on their surfaces that recognized an antigen on the melanoma cells.

In this study, 17 patients with synovial cell sarcoma or metastatic melanoma, whose tumors expressed NY-ESO-1, received therapy with their own immune cells engineered to express a T cell receptor capable of recognizing the NY-ESO-1 antigen. To perform this treatment, the investigators isolated normal white blood cells, called lymphocytes, from each patient’s blood and modified these cells by inserting the gene encoding the anti-tumor T cell receptor into them. These genetically modified cells were then able to recognize and destroy NY-ESO-1-expressing cancer cells. The results showed tumor regression in four of the six patients with synovial cell sarcoma and in five of the 11 melanoma patients. A partial response that lasted 18 months was observed in one of the synovial cell sarcoma patients, while two of the melanoma patients demonstrated complete ongoing regression responses that lasted 20 months or longer, which for patients with these diseases, is significant.

“Now that we have shown that a patient’s own cells genetically engineered to express a receptor against the NY-ESO-1 antigen can mediate tumor regression, we will be optimizing this treatment and extending it to the treatment of patients with other common cancers,” said Rosenberg.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at <www.cancer.gov> or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.

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REFERENCE: Robbins PF, et al., Tumor regression in patients with metastatic synovial sarcoma and melanoma using engineered lymphocytes reactive with NY-ESO-1, Journal of Clinical Oncology, DOI: 10.1200/JCO.2010.32.2537, January 31, 2011.

U.S. Department of Health and Human Services

NATIONAL INSTITUTES OF HEALTH NIH News

For Immediate Release: Monday, January 31, 2011

Classroom aids enhance study of learning and the brain

An NIH researcher has captured video images of a previously unknown form of communication between brain cells that might hold clues to the way learning shapes the brain.

The videos, offered as a resource for educators teaching high school, undergraduate and graduate students, are available on the Web from Science Signaling.

These newly recorded signals are emitted along the length of nerve fibers.  Earlier research has documented the transmission of signals across the synapse-a gap between individual nerve cells, known as neurons.  The new videos show that when neurons communicate, electrical signals emitted along the length of neurons stimulates nearby brain cells known as glia, or glial cells.  As a result, the glial cells begin making a substance called myelin, which coats the nerve fibers and allows electrical charges to travel with greater speed through the brain’s networks.

Other studies have shown that the process of myelination underlies learning and is crucial for the development of new skills.

Additional research might help clarify how signaling between neurons and glial cells triggers myelination and influences skill development, according to R. Douglas Fields, Ph.D., of the Nervous Systems Development and Plasticity Section of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The teaching resource on the Science Signaling website features short video clips that document these previously unknown non-synaptic signals.

“For the last 100 years researchers have studied how information traverses the brain, crossing synapses and traveling from one nerve cell to the next,” said Dr. Fields.  “We can now see another type of communication, in which cells along a neuron’s length can sense the chemical signals the neuron releases.”

To detect these signals, Dr. Fields observed neurons under a microscope.  Nerve fibers, or axons, are long projections that stretch between neurons.  The longest human axon stretches from the base of the spine to the big toe.  Working with the corresponding neuron of mice, Dr. Fields stimulated the neuron with electrical charges and recorded his findings in three videos now available on the Science Signaling website: http://stke.sciencemag.org/cgi/content/full/sigtrans;4/155/tr1.

— Movie 1 shows an increase in the transmission of light through the axons after they are stimulated to fire impulses.  To conduct this experiment, the researchers shone a light through the axon and measured the amount of light that passed through it.  The increased transmission of light is caused by the microscopic swelling of the axons, which reduces the scattering of light passing through them.

— As an electrical charge travels the length of the axon, the wall of the axon becomes porous and the axon swells with water.  At a certain point, the axon must relieve the pressure to keep from bursting, so it releases water and a chemical called adenosine triphosphate, or ATP, in the process.  ATP serves as a signal, and is intercepted by nearby glial cells.  Movie 2, taken over the course of a minute, shows the axon swell as charges pass along its length (bottom left).  As the axon swells, more light from the microscope passes through.  Increases in light intensity appear as warmer colors in the video.

— The red dots in Movie 3 mark ATP as it is released from the round neuron in the center of the image.  The red dots are visible because ATP combined with a special enzyme that Dr. Fields deposited near the axons.  When ATP binds to the enzyme, a photon of light is released (red spots).  This time lapse video was filmed over the span of 10 minutes.

Originally, glial cells were thought to serve only as a kind of glue, holding neurons in place while the neurons conducted the brain’s important business of communication.  For years, Dr. Fields observed neurons under a microscope, exposing them to a dye that glowed in the presence of calcium.  After the neurons had been stimulated, they would give off a flash of light, the tell-tale indicator that they transmitted an impulse, releasing calcium in the process.

One day, on a hunch, he put glial cells next to some neurons, added the dye, and repeated the process.  To his surprise, the glial cells lit up along with the neurons.  Apparently, the calcium had passed from the neuron into the glial cell, an indication that the two cell types had communicated, using calcium as a signal. The observation led to years of research, culminating in the work described in the Science Signaling article.

“It’s humbling, really,” Dr. Fields said.  “We had taken glial cells for granted for so many years and we’ve since come to see that they’re not just supporters of neurons, but integral partners that enable learning and the acquisition of new skills to take place.”

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.  For more information, visit the Institute’s Web site at <http://www.nichd.nih.gov/>.

The National Institutes of Health (NIH) – The Nation’s Medical Research Agency – includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit <http://www.nih.gov>.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.

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The html version of this release contains an image at: <http://www.nichd.nih.gov/news/releases/images/Release_Neuron_Glial_large.jpg>

WorldHealth.net

Atherosclerosis, a component of heart disease, occurs with a build-up along the artery wall of fatty materials such as cholesterol. Numerous studies have suggested that high levels of high-density lipoprotein (HDL, “good”) cholesterol associates with a reduced risk of cardiovascular disease  Daniel J. Rader, from the University of Pennsylvania (Pennsylvania, USA), and colleagues have studied the role of cholesterol efflux capacity, a marker of high-density lipoprotein (HDL) cholesterol function that serves as a direct measure of the efficiency by which a person’s HDL removes cholesterol that accumulates in arterial plaque.  The team measured cholesterol efflux capacity in 203 healthy subjects who underwent assessment of carotid artery intima-media thickness, a measure of arthrosclerosis.  An inverse relationship was noted between cholesterol efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. After an age- and gender- adjusted analysis, increasing efflux capacity conferred decreased likelihood of having coronary artery disease. The researchers conclude that: “Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. “

Amit V. Khera, Marina Cuchel, Margarita de la Llera-Moya, Amrith Rodrigues, Megan F. Burke, Kashif Jafri, Benjamin C. French, Julie A. Phillips, Megan L. Mucksavage, Robert L. Wilensky, Emile R. Mohler, George H. Rothblat, Daniel J. Rader. “Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis.”  N Engl J Med, January 13, 2011, 364: 127 – 135.

Read more………….

Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis

Amit V. Khera, M.D., Marina Cuchel, M.D., Ph.D., Margarita de la Llera-Moya, Ph.D., Amrith Rodrigues, M.S., Megan F. Burke, B.A., Kashif Jafri, B.A., Benjamin C. French, Ph.D., Julie A. Phillips, Ph.D., Megan L. Mucksavage, M.Sc., Robert L. Wilensky, M.D., Emile R. Mohler, M.D., George H. Rothblat, Ph.D., and Daniel J. Rader, M.D.

N Engl J Med 2011; 364:127-135January 13, 2011

Background

High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.

Methods

We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants.

Results

The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.

Conclusions

Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)

Drs. Khera and Cuchel contributed equally to this article.

Supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (HL22633 and P50 HL70128) and the National Center for Research Resources (M01 RR00040 and UL1-RR-024134) and a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. Dr. Khera was supported by a medical student research fellowship from the Howard Hughes Medical Institute, and Dr. Cuchel by a K23 award (HL077146) from the NHLBI.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the Cardiovascular Institute (A.V.K., A.R., M.F.B., K.J., B.C.F., M.L.M., R.L.W., E.R.M., D.J.R.), the Institute for Translational Medicine and Therapeutics (A.V.K., M.C., A.R., M.F.B., K.J., M.L.M., D.J.R.), and the Department of Biostatistics and Epidemiology (B.C.F.), University of Pennsylvania; and the Division of Gastroenterology and Nutrition, Children’s Hospital of Philadelphia (M.L.-M., G.H.R.) — both in Philadelphia; and the Institute for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, NJ (J.A.P.).

Address reprint requests to Dr. Cuchel or to Dr. Rader at the University of Pennsylvania School of Medicine, 654 BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104, or at mcuchel@mail.med.upenn.edu or rader@mail.med.upenn.edu.

WorldHealth.net

High blood pressure (hypertension), a condition where the systolic blood pressure is greater than 140 mmHg and the diastolic measurement is over 90 mmHg, is a major risk factor for cardiovascular disease.   Blueberries and strawberries are rich in a type of flavonoid compound known as anthocyanin.  Eric Rimm, from Harvard School of Public Health (Massachusetts, USA), and colleagues analyzed data collected on  133,914 women and 23,043 men, surveying the subjects on their dietary intakes of flavonoids.  At the close of the follow-up period of 14 years, 5629 cases of hypertension were documented in men and  29,018 cases in women.  The team found that the highest average intakes of anthocyanins (ranging from 16.2 to 21.0 milligrams per day) were associated with an 8% decrease in the risk of hypertension. Notably, the researchers observed that  a significant 10% reduction in the risk of hypertension was observed in subjects ages 60-plus who consumed more than one serving of blueberries per week, as compared with people in the same age group consuming no blueberries.  Noting that: “Anthocyanins [demonstrate] vasodilatory properties …  from specific structural similarities (including the B-ring hydroxylation and methyoxylation pattern),” the team explains that the underlying biological mechanisms by which flavonoids regulate blood pressure include the effects of flavonoids on vascular blood flow, vascular reactivity, and glucose uptake.

Aedín Cassidy, Eilis J O’Reilly, Colin Kay, Laura Sampson, Mary Franz, JP Forman, Gary Curhan, Eric B Rimm.  “Habitual intake of flavonoid subclasses and incident hypertension in adults.”  Am J Clin Nutr, February 2011, 93: 2 338-347; doi:10.3945/ajcn.110.006783.

Read more………….

Habitual intake of flavonoid subclasses and incident hypertension in adults1,2,3

1. Aedín Cassidy,

2. Éilis J O’Reilly,

3. Colin Kay,

4. Laura Sampson,

5. Mary Franz,

6. JP Forman,

7. Gary Curhan, and

8. Eric B Rimm

+ Author Affiliations

1.        1From the School of Medicine, University of East Anglia, Norwich, United Kingdom (AC and CK); the Departments of Nutrition (EJO, LS, MF, and EBR) and Epidemiology (JPF, GC, and EBR), Harvard School of Public Health, Boston, MA; and the Channing Laboratory (JF, GC, and ER) and Renal Division (JF and GC), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.
  • 2 Supported by Public Health Service grants HL34594, HL35464 and HL079929 from the Department of Health and Human Services, National Institutes of Health.
  • 3 Address correspondence to E Rimm, Departments of Nutrition and Epidemiology, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115. E-mail: erimm@hsph.harvard.edu.

Abstract

Background: Dietary flavonoids have beneficial effects on blood pressure in intervention settings, but there is limited information on habitual intake and risk of hypertension in population-based studies.

Objective: We examined the association between habitual flavonoid intake and incident hypertension in a prospective study in men and women.

Design: A total of 87,242 women from the Nurses’ Health Study (NHS) II, 46,672 women from the NHS I, and 23,043 men from the Health Professionals Follow-Up Study (HPFS) participated in the study. Total flavonoid and subclass intakes were calculated from semiquantitative food-frequency questionnaires collected every 4 y by using an updated and extended US Department of Agriculture database.

Results: During 14 y of follow-up, 29,018 cases of hypertension in women and 5629 cases of hypertension in men were reported. In pooled multivariate-adjusted analyses, participants in the highest quintile of anthocyanin intake (predominantly from blueberries and strawberries) had an 8% reduction in risk of hypertension [relative risk (RR): 0.92; 95% CI: 0.86, 0.98; P < 0.03] compared with that for participants in the lowest quintile of anthocyanin intake; the risk reduction was 12% (RR: 0.88; 95% CI: 0.84, 0.93; P < 0.001) in participants ≤60 y of age and 0.96 (0.91, 1.02) in participants >60 y of age (P for age interaction = 0.02). Although intakes of other subclasses were not associated with hypertension, pooled analyses for individual compounds suggested a 5% (95% CI: 0.91, 0.99; P = 0.005) reduction in risk for the highest compared with the lowest quintiles of intake of the flavone apigenin. In participants ≤60 y of age, a 6% (95% CI: 0.88, 0.97; P = 0.002) reduction in risk was observed for the flavan-3-ol catechin when the highest and the lowest quintiles were compared.

Conclusions: Anthocyanins and some flavone and flavan-3-ol compounds may contribute to the prevention of hypertension. These vasodilatory properties may result from specific structural similarities (including the B-ring hydroxylation and methyoxylation pattern).