Researchers at the University of Connecticut have found a new way to identify protein mutations in cancer cells. The novel method is being used to develop personalized vaccines to treat patients with ovarian cancer.

"This has the potential to dramatically change how we treat cancer," says Dr. Pramod Srivastava, director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health and one of the principal investigators on the study. "This research will serve as the basis for the first ever genomics-driven personalized medicine clinical trial in immunotherapy of ovarian cancer, and will begin at UConn Health this fall," Srivastava says.

UConn bioinformatics engineer Ion Mandoiu, associate professor of computer science and engineering, collaborated as the other principal investigator for the study, which has been in development for the past four years. The results appear online in the 22 September issue of the Journal of Experimental Medicine.

Dr. Angela Kueck, a gynecological oncologist at UConn Health, will run the initial clinical study, once it is approved by the FDA. The research team will sequence DNA from the tumors of 15 to 20 women with ovarian cancer, and use that information to make a personalized vaccine for each woman.

The researchers focused their clinical trial on patients with ovarian cancer because the disease usually responds well to surgery and chemotherapy in the short term, but often returns lethally within a year or two. That gives researchers the perfect window to prepare and administer the new therapeutic vaccines, and also means they may be able to tell within two years or so whether the vaccine made a difference. If the personalized vaccines prove to be safe and feasible, they'll design a Phase II trial to test its clinical effectiveness by determining whether they prolong patients' lives.

Identifying tiny differences

In order for the immune system to attack cancers, it first has to recognize them. Every cell in the body has a sequence of proteins on its exterior that acts like an ID card or secret handshake, confirming that it's one of the good guys. These protein sequences, called epitopes, are what the immune system 'sees' when it looks at a cell. Cancerous cells have epitopes, too. Since cancer cells originate from the body itself, their epitopes are very similar to those of healthy cells, and the immune system doesn't recognize them as bad actors that must be destroyed.

But just as even the best spy occasionally slips up on the details, cancer cell epitopes have tiny differences or mistakes that could give them away, if only the immune system knew what to look for.

"We want to break the immune system's ignorance," Srivastava says. For example, there could be 1,000 subtle changes in the cancer cell epitopes, but only 10 are "real," meaning significant to the immune system. To find the real, important differences, Mandoiu, the bioinformatics engineer, took DNA sequences from skin tumors in mice and compared them with DNA from the mice's healthy tissue.

Previous researchers had done this but looked at how strongly the immune system cells bound to the cancer's epitopes. This works when making vaccines against viruses, but not for cancers. Instead, Srivastava's team came up with a novel measure: they looked at how different the cancer epitopes were from the mice's normal epitopes. And it worked. When mice were inoculated with vaccines made of the cancer epitopes differing the most from normal tissue, they were very resistant to skin cancer.

Theoretically, this approach could work for other cancers, although the research has yet to be done.

Researchers in cancer biology, immunology, and computational bioinformatics had to work together to discover these connections. This type of collaboration is the engine driving UConn's personalized medicine and genomics research, according to UConn's vice president for research, Jeffrey Seemann.

"This research is a great example of how diverse disciplines create synergy under the umbrella of genomics," Seemann says. "UConn aims to capitalize on such synergies to make progress in many areas that tap into the genomics realm."

UConn researchers have applied for two patents for their new technique, and a Connecticut start-up company, Accuragen Inc., in which Srivastava has a financial interest, has obtained an option to license the patents.

Creating a safe, effective cancer vaccine is one of the major long-term goals of personalized medicine. Using a different approach than the one described in this paper, Srivastava's research has already created a vaccine against kidney cancer, which is in clinical use and commercially available in Russia.

"It is known that patients have genetic sequences that make them better candidates for some drugs than others. And we can figure that out much more easily now than five years ago," Srivastava says. The novelty of Srivastava's approach in this new research is that it results in a drug specifically designed for a single person. If the approach proves safe and effective, it would be the ultimate in individualized medicine.

offee and diabetes are two of the most commonly covered topics in current medical news. The latest research looks in detail at some of coffee's ingredients and their potential effects on diabetes.

The prevalence of coffee and diabetes in modern media makes a great deal of sense: almost 1 in 10 Americans are diabetic, and more than half of American adults drink coffee daily.

The US spends roughly $40 billion on coffee per year, and in 2012, the total estimated cost of diagnosed diabetes in America was $245 billion.

Any links between these two unlikely bedfellows are likely to be chased down with vigor.

Recent research published in the American Chemical Society's Journal of Natural Products gives us a glimpse into the potential benefits of some of coffee's natural compounds in the management of type 2 diabetes.
Type 2 diabetes

Individuals with type 2 diabetes have a resistance to insulin. Insulin normally helps control the amount of glucose in the blood. If levels are high, it instructs the liver and muscles to absorb more.

Diabetes causes the body to stop reacting to insulin as it should. Insulin is released, but the liver and muscle cells no longer absorb the excess glucose. In the early phases of the disease, an increased amount of insulin is produced in an effort to convince the body to take on more glucose.

As the disease progresses, insulin-producing cells in the pancreas slowly die off through overuse.

The health implications of diabetes can be dire: damage to large blood vessels in the heart, brain and legs. Also, damage to smaller blood vessels can cause problems in the kidneys, eyes, feet and nerves.
The chemistry of coffee

All in all, there are more than 1,000 distinct chemical compounds in coffee. This impressive recipe includes quinic acid, 3,5-dicaffeoylquinic acid, acetylmethylcarbinol, dimethyl disulfide, putrescine, niacin, trigonelline, theophylline and our old friend and foe, caffeine.

Each of coffee's ingredients has the potential to affect human biology. More than likely, the majority of compounds, in the tiny amounts they are present in coffee, will not have a great effect on the body.

Having said that, there is no reason not to study each of these molecules in an effort to get to grips with the myriad of effects that coffee appears to exert on us.
Coffee and diabetes

Research into coffee and its ability to prevent or slow the onset of type 2 diabetes has garnered a fair amount of attention. A recent review of the literature concluded that habitual coffee drinking does seem to lower the risk of type 2 diabetes.

The next challenge is to tease apart the many components of coffee to pinpoint the active ingredients. As the bewildering list of chemicals above infers, this may be a gargantuan task.

Recent research conducted by Søren Gregersen and colleagues at the Department of Endocrinology and Internal Medicine at Aarhus University Hospital in Denmark may have narrowed the search.

Gregersen and his team looked at the effect of a number of coffee's constituents on rat cells in vitro. Most of the compounds did not have significant effects, but cafestol and caffeic acid threw out some intriguing results.

Taking a class of drugs commonly used to reduce acid in the stomach is linked to a higher risk of developing chronic kidney disease, compared with not taking them.
Stomach and esophagus
Over 15 million Americans used prescription PPIs - drugs that reduce stomach acid - in 2013, at a cost of over $10 billion.

This was the finding of a new study led by the Johns Hopkins University in Baltimore, MD, and published in JAMA Internal Medicine.

However, the authors also point out that finding a link between use of proton pump inhibitors (PPIs) and chronic kidney disease does not prove the drugs actually cause the disease - that is for further studies to establish.

It could be, they suggest, that the participants who were prescribed PPIs may have been at higher risk of chronic kidney disease for reasons unrelated to their PPI use.

However, the researchers also note that previous studies have linked use of PPIs to a form of kidney inflammation called acute interstitial nephritis.

PPIs are among the most commonly used drugs worldwide. They are used to relieve symptoms of acid reflux and gastroesophageal reflux disease (GERD). They are also prescribed for treating peptic or stomach ulcers and damage to the lower esophagus caused by acid reflux.

PPIs work by reducing the amount of stomach acid made by cells in the lining of the stomach. They are not the same as antacids, which work by neutralizing excess acid after it has entered the stomach.

There are many types and brands of PPI; examples include omeprazole (brand name Prilosec, also available without a prescription), esomeprazole (Nexium) and lansoprazole (Prevacid). The side effects vary from drug to drug.

In an accompanying editorial article - where they summarize recent evidence on the adverse effects of taking PPIs - Drs. Adam Jacob Schoenfeld and Deborah Grad, of the University of California-San Francisco, note that:

"A large number of patients are taking PPIs for no clear reason - often remote symptoms of dyspepsia or 'heartburn' that have since resolved."
10-year risk of kidney disease higher for PPI users

For their study, the Johns Hopkins researchers and their colleagues first analyzed data on 10,482 participants followed up for a median of nearly 14 years in the Atherosclerosis Risk in Communities (ARIC) study.

Fast facts about acid reflux

    Acid reflux, or gastroesophageal reflux (GER), happens when stomach contents come back up into the esophagus
    It is felt as heartburn when stomach acid touches the lining of the esophagus
    A more serious, persistent form - gastroesophageal reflux disease (GERD) - affects about 20% of the US population.



They then replicated the results in a bigger cohort of 248,751 participants followed up for a median of 6 years - these participants were members of the Geisinger Health System in Pennsylvania.

They found that at the beginning of the monitoring period, PPI users in both groups were more likely to have a higher body mass index (BMI) and to be taking aspirin, statins or drugs to control high blood pressure.

In the ARIC group, 56 of 332 participants using PPIs developed chronic kidney disease, compared with 1,382 of 10,160 non-users. These figures translate to 14.2 and 10.7 per 1,000-person years, respectively. Participants were classed as a PPI user if they were taking the drugs at the start of the follow-up.

Further analysis of these ARIC figures revealed that the 10-year absolute risk of developing chronic kidney disease in the PPI users was 11.8%, compared with 8.5% if they had not used PPIs.

When they repeated this same analysis in the Geisinger cohort, the researchers found 1,921 of 16,900 PPI users and 28,226 of 231,851 of non-users developed chronic kidney disease, which translates to 20.1 and 18.3 per 1,000 person-years, respectively.

Again, further analysis of the larger cohort showed PPI use was associated with higher risk of disease. The 10-year absolute risk of developing chronic kidney disease among the PPI users was 15.6%, compared with 13.9% had they not used the drugs.

Commenting on their own findings, the authors emphasize the point that their study "is observational and does not provide evidence of causality," but should the link between PPI use and chronic kidney disease prove to be causal, then it could have important implications for public health, given the widespread use of the drugs.

Over 15 million Americans used prescription PPIs in 2013 at a cost of over $10 billion, they note, and conclude:

    "Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs."

In 2010, Medical News Today reported how a study by researchers from Seoul National University Hospital in South Korea, published in the Canadian Medical Association Journal, also found that use of PPIs and another class of acid reflux drug called histamine2 receptor antagonists may be linked to higher risk of pneumonia.