The researchers focused a powerful drug directly on tumors in rabbits using drug-coated nanoparticles. They found that a drug dose 1,000 times lower than used previously for this purpose markedly slowed tumor growth.

"Many chemotherapeutic drugs have unwanted side effects, and we’ve shown that our nanoparticle technology has the potential to increase drug effectiveness and decrease drug dose to alleviate harmful side effects," says lead author Patrick M. Winter, Ph.D., research assistant professor of medicine and biomedical engineering.

The nanoparticles are extremely tiny beads of an inert, oily compound that can be coated with a wide variety of active substances. In an article published online in The FASEB Journal, the researchers describe a significant reduction of tumor growth in rabbits that were treated with nanoparticles coated with a fungal toxin called fumagillin. Human clinical trials have shown that fumagillin can be an effective cancer treatment in combination with other anticancer drugs.

In addition to fumagillin, the nanoparticles’ surfaces held molecules designed to stick to proteins found primarily on the cells of growing blood vessels. So the nanoparticles latched on to sites of blood vessel proliferation and released their fumagillin load into blood vessel cells. Fumagillin blocks multiplication of blood vessel cells, so it inhibited tumors from expanding their blood supply and slowed their growth.

Human trials have also shown that fumagillin can have neurotoxic side effects at the high doses required when given by standard methods. But the fumagillin nanoparticles were effective in very low doses because they concentrate where tumors create new blood vessels. The rabbits that received fumagillin nanoparticles showed no adverse side effects.

Senior author Gregory M. Lanza, M.D., Ph.D., associate professor of medicine and of biomedical engineering, and Samuel A. Wickline, M.D., professor of medicine, of physics and of biomedical engineering, are co-inventors of the nanoparticle technology. The nanoparticles measure only about 200 nanometers across, or 500 times smaller than the width of a human hair. Their cores are composed mostly of perfluorocarbon, a safe compound used in artificial blood.

The nanoparticles can be adapted to many different medical applications. In addition to carrying drugs to targeted locations, they can be manufactured to highlight specific targets in magnetic resonance imaging (MRI), nuclear imaging, CT scanning and ultrasound imaging.

In this study, researchers loaded blood-vessel-targeted nanoparticles with MRI contrast agent and were able to make detailed maps of tumor blood vessel growth using standard MRI equipment. The MRI scans showed that blood vessel formation tended to concentrate in limited areas on the surface at one side of tumors instead of dispersing uniformly, which was a surprise.

"Using the blood-vessel targeted nanoparticles, we get a far more complete view of tumor biology than we would get with any other technique," Winter says. "If you followed a tumor over a period of time with the nanoparticles and MRI scans, you would have a much better understanding of the tumor’s reaction to treatment."

The researchers say they believe nanoparticle technology will be very useful for monitoring cancer treatment results in both the short and long term.

"It gives you a way of determining whether you should continue treatment, change the dose or even try a different treatment altogether," Lanza says.

Prior work has shown that the nanoparticles can be loaded with many kinds of drugs. The researchers used fumagillin nanoparticles in these experiments to demonstrate the feasibility of this approach, but they plan further investigations with other versions of the nanoparticles.

"What this report clearly demonstrates is that our nanoparticles can carry chemotherapeutic drugs specifically to tumors and have an effect at the tumor site," Lanza says. "Sometimes when I give presentations about our nanotechnology, people react as if it was science fiction or at best a technology of the distant future. But we’ve shown that the technology is ready for medical applications now."

The nanoparticles will be tested this year in preliminary human clinical trials to determine the optimal method for using them as imaging agents. These studies will lay essential groundwork for using the nanoparticles as therapeutic agents.

Journal reference: Winter PM, Schmieder, AH, Caruthers SD, Keene JL, Zhang H, Wickline SA, Lanza GM. Minute dosages of "v"3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits. The FASEB Journal. March 24, 2008 (advance online publication).

The nanotechnology is owned by Barnes-Jewish Hospital and Washington University and licensed to Kereos Inc, a St. Louis-based company. Gregory M. Lanza and Samuel A. Wickline are scientific cofounders of Kereos.

Funding from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute for Biomedical Imaging and Bioengineering, Philips Medical Systems and Philips Research supported this research.

In research published in the Sept 21 issue of Circulation, the researchers show for the first time that circulating mononuclear cells — the body’s monocytes (the largest type of white blood cell) and lymphocytes — exist in a proinflammatory state in obese persons known to be at increased risk of developing diabetes, heart disease or both.

“These cells are creating a lot of nuisance in the obese,” said Paresh Dandona, M.D., Ph.D., head of UB’s Division of Endocrinology, Diabetes and Metabolism and senior author on the study. “They enter the artery and set up atherosclerosis. They activate fat cells to produce more proinflammatory factors. They interfere with insulin signaling, causing insulin resistance. They even enter the brain.”

Husam Ghanim, Ph.D., research associate, is first author on the study.

The good news, said Dandona, is that, based on these findings, the status of mononuclear cells from one blood sample could serve as an easy early-warning system for the risk of developing insulin resistance and circulatory problems.

The research was conducted using fasting blood samples from 16 normal-weight subjects with an average body mass index (BMI) of 22.6 and from 16 obese subjects with an average BMI of 40. All participants had similar glucose levels and were taking no anti-inflammatory medication. The research was conducted at the Diabetes-Endocrinology Center of Western New York located in Kaleida Health’s Milliard Fillmore-Gates Hospital.

Mononuclear cells were isolated, and proinflammatory and anti-inflammatory factors within the nucleus and the cell were assayed. The researchers also calculated an insulin-resistance index for each participant, using a standard formula.

Results showed that measures of proinflammatory factors were significantly higher in blood samples from obese subjects than the average weight subjects, while levels of factors that normally inhibit inflammation were significantly lower.

“This proinflammatory state may contribute to insulin resistance,” said Dandona, “because the cytokines produced may interfere with insulin action.” The index of insulin resistance in the obese subjects was nearly three times higher, on average, than that of the normal subjects, findings showed.

To remedy the inflammation, persons must either change their diet or take medication or both, Dandona said. His laboratory currently is conducting studies with obese subjects to determine how much these remedies are able to reduce cellular inflammation.

In addition to Dandona, UB Distinguished Professor in the Department of Medicine, UB School of Medicine and Biomedical Sciences, and Ghanim, researchers involved in the study, all from the Division of Endocrinology, Diabetes and Metabolism, were Ahmad Aljada, Ph.D., Deborah Hofmeyer, Tufail Syed, M.D., and Priya Mohanty, M.D.

Black raspberries show promise for preventing cancer of the esophagus, colon

Using animal models (rodents) of cancer development, researchers at Ohio State University showed that animals whose diets were supplemented with black raspberries had a 60 percent reduction in tumors of the esophagus and up to an 80 percent reduction in colon tumors. Clinical trials are now underway to determine whether the berries will prevent the development of esophageal and colon cancer in humans, says study leader Gary D. Stoner, Ph.D., a researcher and professor of internal medicine at the university. 

Blueberries contain chemical that may help prevent colon cancer

A compound found in blueberries shows promise in animal studies of preventing colon cancer, according to a joint study by scientists at Rutgers University and the U.S. Department of Agriculture. The compound, pterostilbene, is a potent antioxidant that could be developed into a pill with the potential for fewer side effects than some commercial drugs that are currently used to prevent the disease, according to study leader Bandaru Reddy, Ph.D., a professor in the Department of Chemical Biology at the university. 

Grape seed compounds may prevent skin cancer by boosting immune system

Chemicals obtained from grape seed extract show promise in animal studies as a way to prevent sunlight-induced skin cancer when used as a dietary supplement, according to researchers at the University of Alabama in Birmingham. In studies using mouse models of ultraviolet-light-induced (non-melanoma) skin cancer, mice that were fed diets supplemented with the grape seed compounds, a group of antioxidants called proanthocyanidins, showed a reduction in tumor number (up to 65 percent fewer) and size (up to 78 percent smaller) in comparison to control animals that did not receive the compounds, the researchers say. The compounds appear to work by inhibiting suppression of the immune system caused by ultraviolet light exposure, says Santosh Katiyar, Ph.D., an associate professor in the university’s department of dermatology. 

Compound found in high-fiber foods shows promise against prostate cancer

A dietary component found in most whole grain foods, beans, nuts and other high-fiber items shows promise in animal studies as a potent weapon for preventing prostate cancer. The compound, inositol hexaphosphate (IP6), was fed to animal models of prostate cancer and resulted in up to a 66 percent reduction in tumor size in comparison to control animals that were given water instead, the researchers say. The compound, which is sold in stores as a dietary supplement, adds to a growing number of products — including lycopene, milk thistle extract, vitamin E and selenium — that also have shown promise against prostate cancer, says Rajesh Agarwal, Ph.D., a professor in the Department of Pharmaceutical Sciences at the University of Colorado Health Sciences Center in Denver. 

Drinking cloudy apple juice daily may help prevent colon cancer

Researchers in Germany say that drinking two to three glasses of cloudy apple juice (unfiltered) per day may help keep colon cancer at bay. In a ten-week study using a mouse model for colon cancer, animals that were fed either cloudy apple juice or a potent extract of the juice showed a 38 percent and 40 percent reduction (respectively) in benign tumors of the small intestine, an indicator of its potential to fight colon cancer, in comparison to control animals that were given water instead of juice, according to Clarissa Gerhäuser, Ph.D., a researcher with the German Cancer Research Center in Heidelberg. The anticancer effect is likely due to a potent class of antioxidants called procyanidins, the researcher says. A widely publicized recent study by a group of researchers in Poland found that cloudy apple juice also is richer in antioxidants — up to four times higher — than clear apple juice. 

The work by researchers at Columbia University Medical Center could potentially improve outcomes in diabetics who get stents, they say. Though drug-eluting stents reduce the chance coronary arteries will become blocked again, clogged stents are still more common in diabetic patients than in the general population. About 250,000 Americans with diabetes receive drug-eluting stents every year.

A hormone commonly associated with obesity – leptin – may be partly responsible, according to recently published research in the Proceedings of the National Academy of Sciences by Andrew Marks, M.D., chair of physiology & cellular biophysics and Clyde and Helen Wu Professor of Molecular Cardiology, and Steven Marx, M.D., associate professor of medicine and pharmacology. The study found that leptin, at the elevated concentrations frequently found in patients with diabetes, stimulates the growth of cells responsible for clogging the stents in mice, even in the presence of sirolimus, a drug used in many stents to prevent cell growth.

The same mouse study also identified a drug – a PI3kinase inhibitor – that counteracts the effect of leptin on cell growth. If added to current drug-eluting stents, such a drug may further reduce reclogging rates in patients with diabetes to the single digit rates seen in other patients. An improved stent could significantly reduce the numbers of patients who eventually need coronary bypass surgery after their stents become severely obstructed.

The heart research, published in the journal Nature Genetics, reveals how a gene called osteoglycin (Ogn), which had not previously been linked with heart function, plays a key role in regulating heart growth. The study suggests that the gene can behave abnormally in some people, and that this can lead to the heart becoming abnormally enlarged.

The researchers hope that through understanding how enlarged hearts are linked to the workings of genes like Ogn, they will be able to develop new treatments for the condition, which affects a large proportion of those with high blood pressure, obesity and diabetes.

Scientists believe that enlarged hearts are caused by a combination of genetic factors and external stimuli such as high blood pressure and obesity. However, the role played by genes has remained largely unknown.

The researchers, from Imperial College London, the Medical Research Council (MRC), and other international institutions, hope that their findings will provide new avenues for treating people who either have an enlarged heart or are at risk of developing one. At present enlarged hearts can only be treated by lowering blood pressure.

The study shows that Ogn regulates the growth of the heart’s main pumping chamber, its left ventricle. If the left ventricle thickens, this creates a condition known as elevated Left Ventricular Mass (LVM), a major contributing factor for common heart diseases. When the heart is enlarged it needs more oxygen and becomes stiff. This can cause shortness of breath or lead to a heart attack.

The researchers found that higher than normal levels of Ogn were associated with the heart becoming enlarged in rats and mice and in humans. Dr Stuart Cook, one of the corresponding authors of the study from the MRC Clinical Sciences Centre and the National Heart and Lung Institute at Imperial College London, said:

"Enlarged hearts are very common. A person whose heart is enlarged is more likely to suffer a heart attack or heart failure than someone whose heart is a normal size. We can’t currently treat the condition directly, so lowering a patient’s blood pressure is the only option we have. Now that we are unravelling how genes control heart growth, we can gain a better understanding of common forms of heart disease. This should lead to new and more effective ways of treating people."

The researchers first linked the Ogn gene with elevated LVM by looking at rat models and analysing how LVM related to the genetic makeup of rats with both elevated and normal LVM.

They then carried out the same analyses on samples from the human heart, volunteered by patients who had undergone cardiac surgery at Hammersmith Hospital, part of Imperial College Healthcare NHS Trust, and from a second group of patients from the Netherlands. These analyses showed that out of 22,000 possible genes, Ogn was the gene most strongly correlated with elevated LVM in humans.

Professor Tim Aitman, also a corresponding author of the study from the MRC Clinical Sciences Centre and Imperial College London, added: "This study shows how we can use the wealth of new genome technologies for analysing people’s genes to gain a much greater understanding of common human disorders. We already knew that enlarged hearts were linked with conditions such as high blood pressure and obesity but figuring out the genetic causes as well could be key to working out how to treat the condition."

In a parallel development today, Professor Aitman, working with colleagues including Professor Terry Cook from Imperial College London, has identified a gene which controls the activity of a group of cells thought to be responsible for potentially severe inflammation of the kidney. The gene, also revealed in a study in Nature Genetics, is known as Jund and it could offer a route for tackling the auto-immune destruction of kidney tissue which can occur in lupus patients, causing renal failure.

Jund regulates the activity of macrophages, cells which help us fight infection by eating up cellular debris and pathogens, and stimulating immune cells. The new research showed that when these cells are overactive, they can destroy healthy kidney tissue.

Professor Aitman, who led the Medical Research Council team, said: "We are hoping that this discovery will allow us to find a new and effective way of treating this potentially fatal form of kidney failure. By reducing the activity of the Jund gene, we were able to reduce activity of inflammatory cells that can become overactive in certain diseases of the kidney. Such a therapy would be of obvious benefit to patients suffering from auto-immune diseases such as lupus. This would allow them to avoid dialysis and maintain their quality of life."

The study was primarily funded by the British Heart Foundation and the UK Department of Health.

Previous studies have explored the correlates of visceral hypersensitivity among patients with IBS. To further evaluate somatic hyperalgesia among patients with IBS, the authors evaluated thermal pain sensitivity among patients with diarrhea-predominant IBS (D-IBS) vs constipation-predominant IBS (C-IBS) compared with healthy subjects.

A research led by G Nicholas Verne from United States addressed this issue. The article is to be published on July 14, 2009 in the World Journal of Gastroenterology. A total of 42 cases with D-IBS and 24 with C-IBS, and 52 control subjects were collected in the study. Their thermal pain hypersensitivity were examined Thermal stimuli were delivered using a Medoc Thermal Sensory Analyzer with a 3 cm × 3 cm surface area. Heat pain threshold (HPTh) and heat pain tolerance (HPTo) were assessed on the left ventral forearm and left calf using an ascending method of limits. The Functional Bowel Disease Severity Index (FBDSI) was also obtained for all subjects.

The research revealed controls were less sensitive than C-IBS and D-IBS with no differences between C-IBS and D-IBS for HPTh and HPTo. Thermal hyperalgesia was present in both groups of IBS patients relative to controls, with IBS patients reporting significantly lower pain threshold and pain tolerance at both test sites.

A unique finding of this study is that the authors detected a strong relationship between heat pain measures and Functional Bowel Disease Severity Index (FBDSI) scores. IBS patients with high FBDSI scores had the highest thermal pain sensitivity compared to those IBS patients with low to moderate FBDSI scores.

An article published in the March 26 issue of the New England Journal of Medicine shows that aggressive combination antiretroviral therapy — specifically including protease inhibitors — dramatically reduces death rates and opportunistic infections in HIV-infected patients.

The nationwide study described in the article found that the number HIV-related deaths decreased from almost 30 per 100 person-years in 1994 to about 9 per 100 person-years by mid-1997. At around the same time, prescription rates of combination antiretroviral therapy increased from 25 percent of patients seen in 1994 to 94 percent by June 1997, with dramatic increases noted in prescription of combination regimens including protease inhibitors from 2 percent in mid-1995 to 82 percent by June 1997.

Similarly, incidence of three major opportunistic infections, Pneumocystis carinii pneumonia, Mycobacterium avium complex and cytomegalovirus retinitis, declined from 22 cases per 100 person-years overall in 1994 to 3.7 cases for 100 person years by mid-1997.

"Changing patterns of antiretroviral treatment have reduced the morbidity and mortality of HIV-infected patients," said infectious disease specialist Frank J. Palella, M.D., of Northwestern University Medical School.

"Specifically, combination antiretroviral therapy accounted for the largest proportion of such reductions," he said.

Reductions in death and disease were clearly linked to the increasing use of combination antiretroviral therapy, with the most dramatic decline coinciding with growing use of protease inhibitors, Palella said.

"Our data suggest that intensive combination therapy including protease inhibitors should be considered the standard of care for patients with advanced HIV infection," he said.

Palella was lead author on the study, conducted in collaboration with researchers from the HIV Outpatient Study, a nationwide consortium of nine HIV clinics and research centers.

Another of the study's striking findings was that patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those on Medicare/Medicaid. However, Palella noted that use of protease inhibitors in the period from 1994 to mid-1997 had increased markedly for both those with private and publicly funded health care.

Protease inhibitor use did not differ significantly when patients were grouped by gender, race or age, although injection drug users were slightly less likely to receive protease inhibitors. Further, the large declines in mortality rates were seen regardless of gender, race, age or HIV transmission risk category.

The researchers analyzed data over a 42-month period from each of approximately 1,250 HIV-infected patients in each of four levels of increasing intensity of prescribed antiretroviral therapy: no antiretroviral therapy; single therapy; combination antiretroviral therapy not including a protease inhibitor; and combination therapy with a protease inhibitor. Death rates and incidence of opportunistic infection were compared by antiretroviral level, drugs prescribed to prevent opportunisitic infection, patient demographics (i.e., gender, age, ethnicity and mode of HIV acquisition), and CD4 cell count (a measure of drugs' efficacy) at first study visit, as well as method of payment (i.e., private insurance, Medicare/Medicaid, self-pay and Ryan White Care Act prescription programs). Death rates and protease inhibitor prescription rates were then analyzed by source of payment.

Palella's co-researchers on this study were Kathleen M. Delancy and Diane J. Aschman, Health Research Network of Apache Medical Systems, Inc., Chicago; Scott Holmberg, M.D., Anne C. Moorman and Glen A. Satten, Centers for Disease Control and Prevention, Atlanta, Ga.; Mark O. Loveless, M.D., Oregon Health Sciences University, Portland, Ore.; Jack Fuhrer, M.D., State University of New York, Stony Brook, N.Y.; and other HIV Outpatient Study (HOPS) Investigators.

An important component is the psoriasin protein

(S100A7), which are abundant in psoriasis-affected skin but rarely in normal skin. The same protein is also assumed to be a factor in the development of breast cancer. The research team, led by associate professor Charlotta Enerbäck, have now illustrated that, in a study on cultured skin cells, the interaction between psoriasin, oxygen free radicals and vascular endothelial growth factors (VEGF) leads to significantly increased cell division and growth of new blood vessels (angiogenesis). When we blocked the formation of psoriasin, the expression of VEGF also decreased.

Published in the journal Breast Cancer Research and Treatment, the results open new possibilities for the effective treatment of this crippling disease.

"We want to examine the ability of psoriasin as a target for therapy. By inhibiting psoriasin, we believe we can reduce vascular formation and thus the proliferation of the disease’s magnitude and intensity," says Charlotta Enerbäck.

Previous studies in mice have shown that angiogenesis inhibitors reduce not only neovascularization but also inflammation and excessive cell division. Attempts to inhibit the growth factor VEGF have resulted in unwanted side effects because it exists in normal tissue where it contributes to wound healing.

"Since psoriasin expresses itself specifically only in the diseased psoriatic skin, we expect that inhibitors against this are highly selective and effective against the disease, and that the risk for side effects is minimal," says Charlotta Enerbäck.

Presently, palliative treatments with vitamin D, cortisone, light and low doses of chemotherapy are used. More recently, some "biological," antibody-based drugs arrived on the market, however they are very expensive and not free from side effects.

"Recent clinical studies and trials in glaucoma have advanced knowledge on risk factors for the disease. A recurring finding from these investigations is the importance of intraocular pressure for both the development of the disease in glaucoma suspects and progression in patients with established glaucoma," the authors write as background information in the article. "Evidence pertaining to risk factors and the effect of intraocular pressure reduction is derived almost exclusively from event-based or binary (progression vs. no progression) outcomes. In practical terms, it may be more beneficial to determine the effect of a risk factor or its modification on the rate of change such that the clinician can gauge the likelihood of lifetime visual disability with consideration of factors such as age, stage of the disease and life expectancy."

Balwantray C. Chauhan, Ph.D., of Dalhousie University, Halifax, Nova Scotia, Canada, and colleagues in the Canadian Glaucoma Study Group studied 216 patients with open-angle glaucoma, documenting several demographic, systemic and ocular parameters at the beginning of the study. The patients were all followed up with a standardized protocol for controlling intraocular pressure (targeting a reduction of 30 percent or greater) and then were re-examined every four months. Those who had confirmed progression of glaucoma as assessed by changes in their visual field received an additional 20 percent or greater reduction in intraocular pressure under the treatment protocol.

A total of 153 patients (70.8 percent) did not reach this end point of visual field deterioration during the study, 45 (20.1 percent) had one end point, 16 (7.4 percent) had two end points and two (.9 percent) had three end points. Having an abnormal level of anticardiolipin antibodies and being older were associated with a more rapid rate of visual change, but being female and having a higher follow-up intraocular pressure were not.

Patients who reached one end point and had an additional reduction in intraocular pressure experienced a slowing of their rate of visual field change. The magnitude of this amelioration may not have been clinically meaningful for some patients, but over 20 years, the difference would be significant. "In younger patients with more advanced damage, this difference is likely to be important," the authors write. However, there was no demonstrable effect of further reductions in intraocular pressure for patients with two or more end points.

This work was supported by the E.A. Baker Foundation, Canadian National Institute for the Blind, by the Glaucoma Research Society of Canada and by unrestricted grants from Allergan Canada, Merck Frosst Canada and Pfizer Canada.

This study is the first to examine the impact of safety-net burden status on access to curative-intent surgery for lung cancer patients nationwide. Researchers led by Katherine S. Virgo, Ph.D., used the National Cancer Database (NCDB) to review the treatment of more than 50,000 patients diagnosed with non-small cell lung cancer who were treated at American College of Surgeons Commission on Cancer accredited facilities throughout the United States. They found that 67.1 percent of patients treated at high safety-net burden hospitals underwent surgery intended to cure their disease, compared to 77.1 percent of those at low safety-net burden centers (odds ratio 0.69; 95% CI, 0.62-0.77).

"This study adds to the growing literature about the ability of the so-called safety-net to catch patients in need of care," said Dr. Virgo. "It demonstrates that access to high quality lung cancer care is less than optimal at high-safety net burden facilities."

The authors say while the reasons for the disparities are not fully understood, it appears that reimbursement issues may play a role. Some care centers likely lack full and unrestricted availability and/or participation of specialists, including thoracic surgeons, because treating uninsured and Medicaid-insured patients is less lucrative and/or hospital compensation is insufficient. Addressing the problem may require innovative solutions to ensure quality cancer care by strengthening the safety net to ensure needy patients receive appropriate care, including securing additional funding for safety-net facilities.