Icon molecule created to target and destroy blood vessels that feed tumors
In a study partly funded by the National Institutes of Health, published in the October 9 2001 issue of Proceedings of the National Academy of Sciences (http://www.pnas.org), Yale University researchers announced the development of an immunoconjugate, or icon molecule that causes the immune system to destroy tumor blood vessels without harming normal vessels. The molecule was created by combining a targeting domain utilizing mouse factor VII which binds to a substance known as tissue factor found in tumors, with the region of an antibody that activates an immune attack against cells that bind to the molecule.
Immunodeficient mice were injected with human prostate tumor or melanoma cells which led to development of tumors. This was followed by intratumoral delivery of a gene that manufactures the icon. The immune attack caused by the icon resulted in regression of the tumors, with the mice appearing to be free of tumor cells by the end of the experiments.
Lead researcher and professor of molecular biophysics and biochemistry at Yale University, Alan Garen summarized, "Our study resulted in the eradication of injected tumors and also of other tumors in mice that had not been injected. This serves as a model of metastatic cancer. None of the normal tissues in the mouse appeared to be harmed by our procedure. The normal blood vessels survive because they do not express tissue factor and therefore do not bind the icon . . . This icon should work against all types of tumors that contain blood vessels. The icon that will be used in a clinical trial is derived entirely from human components and therefore should not be significantly immunogenic, which is an advantage over antibodies used in this kind of study."
Probiotic prevents kidney stones
University of Florida researchers in collaboration with Ixion Biotechnology report in the October 2001 issue of the Journal of Urology that the bacterium Oxalobacter forimgenes, an inhabitant of healthy gut flora, can help to prevent the formation of calcium oxalate, a compound involved in the formation of one type of kidney stone. The bacteria degrade dietary oxalate that ends up in the urine to bind with calcium, forming calcium oxalate crystals that become stones.
Twenty-six male rats were given a diet containing ammonium oxalate to elevate oxalic acid in the urine. They were then administered one of four regimens consisting of progressively higher amounts of the probiotic Oxalobacter formigenes for two weeks, and followed for changes in the amount of oxalate in their urine. A control group received a normal, unsupplemented diet. The rats receiving the O formigenes experienced a decline in urinary oxalate within two days of receiving the probiotic supplement, with the decline in oxalate proportional to the amount of probiotic received. The urinary oxalate in the rats receiving the highest levels of the probiotic returned to almost normal. No signs of toxicity or any other abnormalities were observed.
Future research will test orally administered Oxalobacter formigenes in humans.
Dr. Ammon B. Peck, professor of pathology, immunology and laboratory medicine at the University of Florida's College of Medicine commented, "Outside of attempts to change people's dietary habits, which are not very successful on a long-term basis, there has been a lack of successful treatment for lowering oxalate levels. This particular treatment is such a simple process, and if its safety and efficacy holds up in humans, it certainly will be a major step forward for individuals suffering from this disease. We're very optimistic that this will be something that we can bring to the public fairly soon."
Estrogen fails to protect against stroke recurrence or death
In another blow to the belief that estrogen replacement therapy benefits women's vascular systems and lengthens lifespan, a randomized, double-blind placebo-controlled study of women who had been diagnosed with ischemic stroke or transient ischemic attack within the previous ninety days has shown that estrogen replacement not only fails to prevent second strokes but makes them more dangerous. The National Institute of Neurological Disorders and Stroke-sponsored Women's Estrogen for Stroke Trial, or WEST, tested the standard oral replacement dose of 1 milligram estradiol against a placebo in 664 postmenopausal women for an average of 2.8 years. Treatment regimens were discontinued if a stroke occurred. Although both regimens experienced close to the same number of strokes and fatalities, the women receiving estrogen were more likely to have a second stroke sooner, and were more likely to experience neurologic impairment or death as a result. Women who received hormone replacement were also more likely to experience gynecologic complications.
Older studies had indicated a protective effect of estrogen against stroke, heart disease and death, but this newest study, published in the October 25, 2001 issue of the New England Journal of Medicine, as well as results from the Heart and Estrogen/Progestin Replacement Study, which examined the effect of estrogen on heart disease, have failed to demonstrate any preventive benefits of estrogen in these areas. Benefits attributed to estrogen in earlier studies may have been due to other factors.
National Institute of Neurological Disorders and Stroke Associate Director for Clinical Trials, John R Marler MD, stated, "The good news is that we have taken a lot of guesswork out of treating women with strokes. The benefits from estrogen that we hoped for are not there to balance the risks."
The researchers conclude that estrogen should not be prescribed in hope of preventing a second stroke or delaying death in postmenopausal women.
Another soy component shows cancer preventive benefits
Isoflavones such as genistein are the components of soy that have been the object of most of the recent attention, due to research revealing their cancer-fighting abilities. In a study published in the October 15 2001 issue of Cancer Research, researchers at the University of California, Berkeley demonstrated that lunasin, a peptide consisting of forty-three amino acids found in soybeans, prevents skin cancer in mice and in normal cell cultures. Previous work done by the researchers showed that a gene for lunasin, when injected into cultured cancer cells, arrested cell division.
The researchers applied several different doses of lunasin to the skin of groups of healthy mice over a nineteen week period and exposed them to carcinogens. A control group received no lunasin. The group of mice who received the highest level of lunasin developed 70% less tumors than controls. The researchers believe that lunasin selectively induces apoptosis, or programmed cell death, in cells undergoing transformation by preventing a process known as histone acetylation, which is linked to cancer development.
Lead researcher and nutritional sciences professor at the College of Natural Resources at the University of California, Berkeley, Ben O de Lumen, commented, "In the high dose group, some mice did develop some tumors, but there were fewer tumors per mouse and there was a two-week delay in their appearance compared with the control group . . . The chemical changes that occur in normal cells before and during cancer formation signal lunasin. We believe lunasin is like a watchdog; it's out there sniffing. When it sees a normal cell transforming, it gets in there and attacks the cell."
Vitamin C supplements significantly associated with lower gastric cancer risk
Cancers of the stomach and esophagus have been rapidly rising for the past three decades. In the attempt to find out why, a National Cancer Institute sponsored study conducted by researchers at Yale University School of Medicine discovered that vitamin C, vitamin B6, folate, beta-carotene and fiber intake are all associated with lower rates of stomach and esophageal cancer, and that vitamin C supplements are significantly associated with lowered risk. Conversely, animal protein, dietary cholesterol and vitamin B12 intake were associated with an increased risk of this type of cancer. However, vitamin B12 is naturally associated with many animal foods.
The population-based study, published in the October 2001 issue of the journal Cancer Epidemiology, Biomarkers and Prevention, examined data obtained by interview of 1,095 patients who had confirmed esophageal adenocarcinoma, adenocarcinoma of the gastric cardia, esophageal squamous cell carcinoma, and noncardia gastric adenocarcinoma, as well as 687 individuals who did not have cancer, who served as controls. Study participants were recruited from Washington, Connecticut and New Jersey. Data obtained during the interviews regarding nutrient intake was correlated with cancer incidence. A separate analysis found a link between obesity and this group of cancers.
Lead study author and associate professor in the Department of Epidemiology and Public Health at Yale School of Medicine, Susan Mayne, stated, "We found that many animal-based nutrients found in foods of animal origin are strongly associated with risk of developing these types of cancers and we were able to identify nutrients that presumably would be protective. We also found that regular users of vitamin C supplements were at significantly lower risk of stomach cancer. Our results suggest that prevention strategies for these cancers should emphasize increased consumption of plant foods, decreased consumption of foods of animal origin with the possible exception of dairy products, and control of obesity."
Zinc prevents esophageal cancer in rats
In a study published in the October 17 2001 issue of the Journal of the National Cancer Institute, zinc-deficient rats administered the carcinogen N-nitrosomethylbenzylamine (NMBA) were protected from esophageal tumor development when zinc was later given. Zinc deficiency is known to increase esophageal cell proliferation and the incidence of esophageal tumors induced by this carcinogen.
Five groups of rats were fed a zinc deficient diet for five weeks followed by treatment with NMBA. Four of the five groups were then fed zinc-replenished diets at one, 24, 72 and 432 hours following NMBA administration. At twenty-four hours to two weeks, the esophagi of the mice were examined for the incidence of cell proliferation or presence of apoptosis, the programmed destruction of unwanted cells. The incidence of tumor development was determined after fifteen weeks.
Ninety-three percent of the rats who did not receive zinc replenishment developed esophageal tumors. Zinc replenishment begun one hour after NMBA was given reduced the incidence of tumors to only 8% of the animals. Zinc replenishment given later was still effective, with 14% of those receiving it after 24 hours, 19% of those receiving zinc after 72 hours, and 48% of those receiving the mineral after 432 hours developing tumors. Twenty-four and 30 hours after zinc was replenished, the esophagi of the rats had an increase in apoptotic cells and double the expression of Bax protein, which stimulates apoptosis. Zinc replenishment within an hour of NMBA administration lowered epithelial thickness from 10-20 layers to 3-5 layers.
The researchers concluded that zinc's ability to induce apoptosis in the esophagus is responsible for preventing esophageal cancer in this group of animals.
Cooling protects revived patients but must be initiated rapidly
Mild to moderate hypothermia has been demonstrated in animals to protect the brain from ischemic injury that results from impairment in blood flow to the organ following cardiac arrest, or cessation of heartbeat. To test the safety and feasibility of hypothermia in humans, researchers funded by the National Institutes of Health lowered the body temperatures of patients who had experienced cardiac arrest outside of the hospital. Following advanced cardiac life support and subsequent sedation, the patients' temperatures were lowered to 33 degrees Celsius, or 91.4 degrees Fahrenheit, for twenty-four hours by use of external cooling blankets, after which the patients were rewarmed to normal body temperature. The rationale of the procedure is to lower the brain's oxygen requirement, thereby reducing inflammation and the release of chemicals that destroy brain cells. The study was published in the October 9 2001 issue of Circulation: Journal of the American Heart Association.
Four of the nine patients who were enrolled survived, and three of the survivors experienced none of the common neurologic problems that result from cardiac arrest. The remaining survivor was discharged from the hospital with memory problems.
Antioxidants and zinc save eyesight in macular degeneration
A study funded by the National Institutes of Health' National Eye Institute, published in the October 2001 issue of Archives of Neurology showed that antioxidants and the mineral zinc can prevent some of the loss of vision caused by age-related macular degeneration, or AMD. Macular degeneration is a leading cause of loss of sight in older individuals.
The study enrolled 3,640 participants at eleven centers in the United States for an average of 6.3 years. The participants were 55 to 80 years of age and were classified according as having no disease, early, intermediate or advanced macular degeneration as determined by the presence of yellow deposits under the retina called drusen. In addition to drusen, advanced macular degeneration is characterized by the breakdown of cells and in the central retinal or leaking blood vessels under the retina.
Participants received nutritional supplementation consisting of the antioxidants beta-carotene, vitamin C and vitamin E; 80 milligrams zinc plus 2 milligrams copper, the antioxidant vitamins plus zinc and copper, or a placebo. The researchers found that the antioxidant-zinc combination lowered the risk of progression to advanced macular degeneration by 25% and the risk of vision loss by 19% in those considered at high risk (categorized as having intermediate AMD or advanced AMD in one eye).
National Eye Institute Director Paul A. Sieving, M.D., Ph.D., commented, "This is an exciting discovery because, for people at high risk for developing advanced AMD, these nutrients are the first effective treatment to slow the progression of the disease. The nutrients are not a cure for AMD, nor will they restore vision already lost from the disease. But they will play a key role in helping people at high risk for developing advanced AMD keep their vision."
Oil of oregano fights bacterial infections
The findings of two studies presented at the annual meeting of the American College of Nutrition held this month in Orlando, Florida, revealed that oil of oregano is as effective as pharmaceutical antibiotics at killing bacteria. The news comes at a welcome time due to the emergence of antibiotic-resistant bacteria attributed to overprescribing of these drugs.
Research led by Harry G. Preuss, MD, MACN, CNS, professor of physiology and biophysics at Georgetown University Medical Center in Washington DC, tested the effects of the herb on the common bacteria staphylococcus, which is becoming more drug-resistant, and is the culprit in many infections. In one in vitro study, oregano oil was compared to the drugs streptomycin, vancomycin and penicillin, and was found to inhibit staphylococcus growth as effectively as the pharmaceutical antibiotics. A second study involved eighteen staphylococcus-infected mice, of whom six received oil of oregano and six received a substance known as carvacrol, believed to be oregano oil's active ingredient against bacteria. The carvacrol used in the study was derived from olive oil, not oregano oil. The remaining six mice received olive oil. After thirty days, half of the mice receiving oregano oil were alive, but none of the carvacrol treated mice lived longer than twenty-one days. The mice in the group receiving olive oil did not survive beyond three days. The study was repeated with the same results, which demonstrates that other ingredients in oil of oregano are responsible for its antibiotic effect.
Dr Preuss stated, "While this investigation was performed only in test tubes and on a small number of mice, the preliminary results are promising and warrant further study. The ability of oils from various spices to kill infectious organisms has been recognized since antiquity. Natural oils may turn out to be valuable adjuvants or even replacements for many antigermicidals under a variety of conditions."
Tannins from green tea and other plants protect against stroke damage
Researchers from the University of California and Veterans Affairs Medical Center in San Francisco have discovered that a tannin derived from green tea known as gallotannnin, and another tannin, nobotannin B, prevent stroke damage to brain cells in culture. The study, published in the October 9 2001 edition of Proceedings of the National Academy of Sciences, examined the effects of the two compounds on two types of cultured mouse brain cells exposed to hydrogen peroxide, NMDA or MNNG, substances capable of inducing DNA damage.
In one significant finding, tannins added to cells treated with hydrogen peroxide prevented 80% from dying, whereas without them, 30% survived. The tannins were found to inhibit PARG, an enzyme involved in the poly(ADP-ribose) polymerase 1 (PARP1)-mediated cell death pathway that depletes NAD, which is activated during ischemia and other conditions that lead to massive DNA damage. Because of this inhibitory action, the tannins may be able to protect brain cells from stroke damage. Researchers are planning on developing smaller versions of the molecule that can more readily pass the blood-brain barrier.
Normally PARP and PARG work together to mark cells that have damaged DNA so that the cell's DNA repair mechanisms can locate and repair the damage. But following a stroke this mechanism becomes overactive, and by depleting the cell's energy production system, causes the cell to die. Acting chief of neurology at san Francisco Veterans Affairs Medical Center and lead study author Raymond Swanson MD commented, "By inhibiting PARG we can protect brain cells from the type of cell death that happens during a stroke. This same death mechanism is seen in several other disorders, such as diabetes, inflammation, and heart attack . . . In our studies, PARG inhibitors were at least as effective at preventing cell death as PARP inhibitors, and they appeared to be more potent as well."
Tocotrienols reduce atherosclerotic lesions
Tocotrienols are antioxidant nutrients similar to tocopherols, or vitamin E, but slightly different in structure. There are four tocotrienols corresponding to the four tocopherols: alpha, beta, gamma and delta. Acting on the previous discovery by study author Asaf A Quereshi of two new tocotrienols from rice bran which are showing superior abilities compared with known tocotrienols and vitamin E in combating cholesterol, oxidation, inflammation, thrombosis and cancer, researchers at UCLA and the University of Illinois, Chicago have found that these tocotrienols inhibit atherosclerosis in mice.
The researchers used an apolipoprotein E deficient mouse model that develops hyperlipidemia and atherosclerosis even when fed a low fat diet. These mice were fed a low fat diet supplemented with alpha-tocopherol, a tocotrienol-rich fraction or with didesmethyl tocotrienol from rice bran, one of the newly discovered tocotrienols. Two similar strains of mice who were not apolipoprotein E deficient were fed low fat or high fat diets supplemented with one of the three compounds, or a nonsupplemented control diet.
In one strain of non-apolipoprotein E deficient mice fed a high fat diet supplemented with vitamin E, the tocotrienol fraction, or the new tocotrienol for twenty four weeks, a reduction in the size of atherosclerotic lesions occurred compared to mice fed the control diet, with didesmethyl tocotrienol responsible for the greatest reduction, that of 57%. The other strain of mice receiving the same regimens for eighteen weeks experienced reductions to a lesser degree. Low fat diets did not result in atherosclerosis in these strains. The apolipoprotein E-deficient mouse model supplemented with the tocotrienol-rich fraction for fourteen weeks experienced a 42% reduction in atherosclerotic lesion size, and the didesmethyl tocotrienol supplemented group experienced a 47% reduction compared to controls. Alpha-tocopherol only provided an 11% reduction in lesion size.
Low PSA range still not safe
Prostate specific antigen, or PSA is a protease secreted by the epithelial cells of the prostate gland, an elevation of which can be suggestive of the presence of prostate cancer. Prostate specific antigen readings of 4.0 nanograms per milliliter or lower are currently considered normal. Although PSA is an important marker, there are other markers, and a high PSA reading is not necessarily diagnostic of prostate cancer. In order to determine the incidence and pathological features of prostate cancer diagnosed when PSA ranges from 1 to 3 ng/mL, of which little is currently known, Swiss researchers investigated men enrolled in the European Randomized Study of Screening for Prostate Cancer who had PSA levels in this range and who had a free to total PSA ratio of .20 or less. One hundred-sixty eight volunteers met inclusion criteria, and 158 underwent ultrasound guided biopsy of the prostate in order to further evaluate their condition.
Biopsies revealed the presence of prostate cancer in over 10% of the men. In this study, patient age, prostate volume, PSA, free to total PSA ratio and PSA density were not associated with prostate cancer diagnosis as opposed to benign prostatic hypertrophy. Fourteen of the seventeen patients with positive biopsies underwent surgery, and eleven were found to have locally advanced cancers, not confined to the prostate, which is more difficult to treat.
This study suggests that PSA may not be able to characterize tumor aggressiveness and that more tests, such as free to total PSA ratio, are needed for early patients with low PSA levels to rule out prostate cancer. The researchers state that with a longer living population, the window of opportunity for detection of curable cancer may change, to that found with lower PSA levels.
Lower antioxidant vitamin status linked with greater atherosclerosis in men
In a study conducted in the UK, it was found that antioxidant nutrients beta-carotene, vitamin C and vitamin E when concentrated in higher levels in the blood are associated in older men with less thickening of the intima-media of the arteries, a measure of atherosclerosis. Researchers examined data collected from 468 men and women aged sixty-six to seventy-five in Sheffield, England. Participants were asked about occupation, smoking habits, vitamin and medication use and cardiovascular disease history . Blood pressure, weight and height were measured and blood samples analyzed for plasma beta-carotene, vitamin C, vitamin E, fibrinogen and cholesterol. Electrocardiograms and ultrasound examination of the carotid arteries were conducted, and average intima media thickness and degree of stenosis determined.
When the results were examined, several differences between male and female participants emerged. While age, systolic blood pressure, pulse pressure and the presence of hypertension were all associated with increased thickness of the intima-media in both sexes, men in the study were found to have positive associations with smoking, total and LDL cholesterol as well. Intima-media thickness in men was inversely correlated with serum concentrations of beta-carotene and vitamins C and E. However, among the women, users of vitamin E supplements had a smaller mean intima-media thickness and less stenosis than those who did not use supplements.
In conclusion, the researchers observed that older men with higher blood levels of beta-carotene, vitamin C and vitamin E have less thickening of arterial walls and little or no plaque in their carotid arteries, and they suggest that more emphasis be given to monitoring the effects of these nutrients on the initiation of atherosclerosis.
The study was published in the September 2001 issue of the American Journal of Clinical Nutrition.
Antioxidants protect kidneys from high cholesterol
In a study published in the September 2001 issue of Journal of the American Society for Nephrology, Mayo Clinic researchers found that supplementation with vitamins C and E protected the kidneys of pigs from the effects of a high cholesterol diet. High cholesterol levels are known to impair the ability of the blood vessels to dilate in response to endothelium-dependent vasodilators, such as nitric oxide, which can impair blood flow in the kidney. The researchers sought to determine if the increased formation of lipid peroxides caused by hypercholesterolemia is responsible for this impairment.
Pigs were divided into four groups who were fed a normal diet, a high cholesterol diet, a normal diet combined with 100 international units per kilogram body weight vitamin E and 1000 milligrams vitamin C or a high cholesterol antioxidant-supplemented diet. Serum cholesterol levels rose in both groups fed high cholesterol diets, but in the high cholesterol group supplemented with antioxidants the oxidation of LDL cholesterol significantly decreased while rising in the other group. Blood flow in the kidney was diminished in nonsupplemented high cholesterol fed pigs, but pigs fed vitamin C and E with the high cholesterol diet experienced no change.
The researchers concluded that dietary intervention with vitamins C and E normalize endothelium-dependent relaxation of the renal artery, impairment of which has been consistently demonstrated with high cholesterol which can lead to chronic progressive renal injury. This was attributed to the preservation of endogenous nitric oxide activity through its protection from oxidative stress, and decreasing oxidation of LDL cholesterol although the authors did not rule out the possibility of increased cyclic GMP generation. Therefore, these antioxidant vitamins may have a role in protecting the kidney from the effects of high cholesterol.