A Case Western Reserve University School of Medicine study in the November 22 issue of Journal of Biological Chemistry, explains how vitamin A is generated from beta carotene, its dietary precursors. The discovery sheds new light into how beta carotene’s enzymes are utilized differently contributing to the vitamin’s production. This insight will help guide solutions for vitamin A deficiency, a global public health problem affecting more than half of all countries, according to the World Health Organization.

The study, named a Paper of the Week, led by Johannes von Lintig, PhD, associate professor of pharmacology, demonstrates that beta-carotene is converted to Vitamin A and not other metabolites, which some theorized were toxic compounds.

Vitamin A deficiency is especially prevalent in developing countries of Asia, due to largely rice-based diets which lack beta-carotene, a member of the micronutrient carotenoid family. The deficiency mainly affects pregnant women and children and leads to blindness and increases morbidity.

Understanding how vitamin A is produced in the body is essential to effective public health interventions. Efforts are underway by humanitarian groups to supplement young children and fortify foods, for example in the form of “golden rice,” rice genetically modified to contain beta-carotene. The von Lintig Laboratory’s discovery validates the benefits of fortifying foods to combat the worldwide deficiency problem. Some reports indicate the problem exists in areas of the U.S. where access to fresh fruits and vegetables is scarce.



The research team provided evidence that BCO1 directly converts beta-carotene to vitamin A. However, they discovered the second enzyme, BCO2, is also significant. It helps prepare carotenoids, other than beta-carotene, for vitamin A production. Specifically, BCO2 removes the part of the carotenoid that cannot be utilized for vitamin A production. The remaining portion of the carotenoid is then further processed by BCO1 to generate vitamin A.

“Our study shows that beta-carotene’s second enzyme does not produce a toxic compound, as had been proposed by some researchers. Rather, the enzyme aids in the metabolizing of carotenoids, aside from beta-carotene, to become vitamin A,” said von Lintig and concluded “that beta-carotene is an important and safe precursor for vitamin A in our diet. Our findings also suggest that golden rice plants are likely very safe for consumption.”

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.

Vitamin D deficiency increases the risk of poor brain function after sudden cardiac arrest by seven-fold, according to research presented at Acute Cardiovascular Care 2014 by Dr Jin Wi from Korea. Vitamin D deficiency also led to a higher chance of dying after sudden cardiac arrest.

Acute Cardiovascular Care is the annual meeting of the Acute Cardiovascular Care Association (ACCA) of the European Society of Cardiology (ESC) and takes place 18-20 October in Geneva, Switzerland.

Dr Wi said: "In patients resuscitated after sudden cardiac arrest, recovery of neurological function is very important, as well as survival. Vitamin D deficiency has been reported to be related to the risk of having various cardiovascular diseases, including sudden cardiac arrest. We investigated the association of vitamin D deficiency with neurologic outcome after sudden cardiac arrest, a topic on which there is no information so far."

The researchers prospectively analysed clinical data from all unconscious patients resuscitated from sudden cardiac arrest of presumed cardiac cause at Severance Cardiovascular Hospital in Seoul, Korea. Neurologic outcome was assessed by the Cerebral Performance Category (CPC) score at 6 months after discharge.1 Good neurologic outcome was defined as a CPC score of 1 or 2, whereas poor neurological outcome was defined as a CPC score of 3 to 5. Vitamin D deficiency was defined as 25-hydroxyvitamin D less than 10 ng/mL.

The study included 53 patients. Bystander cardiopulmonary resuscitation (CPR) was performed in 41 patients (77%). The first monitored heart rhythm was shockable in 36 patients (68%) and non-shockable in 17 patients (32%). The average vitamin D level was 10.3 ng/mL and 31 patients (59%) were deficient.

Patients with a poor neurological outcome had a significantly lower vitamin D level (7.9 ng/mL) compared to those with a good neurological outcome (12.4 ng/mL) (p=0.002). The researchers found that 65% of patients with vitamin D deficiency had a poor neurological outcome at 6 months after discharge compared to 23% of patients with healthy vitamin D levels. They also found that 29% of patients with vitamin D deficiency had died at 6 months compared to none of the patients with good vitamin D levels (p=0.007).


Dr Wi said: "Patients with vitamin D deficiency were more likely to have a poor neurological outcome or die after sudden cardiac arrest than those who were not deficient. Nearly one-third of the patients who were deficient in vitamin D had died 6 months after their cardiac arrest, whereas all patients with sufficient vitamin D levels were still alive."

The researchers conducted a multivariate logistic analysis to assess the impact of a number of factors on neurological outcome after sudden cardiac arrest. They found that vitamin D deficiency independently predicted poor neurological outcome with an odds ratio of 7.13.

Dr Wi said: "Vitamin D deficiency increased the risk of poor neurological outcome after sudden cardiac arrest by 7-fold. The only factors that had a greater impact on poor neurological outcome were the absence of bystander CPR or having a first monitored heart rhythm that was non-shockable."

He added: "Our findings suggest that vitamin D deficiency should be avoided, especially in people with a high risk of sudden cardiac arrest. People are at higher risk if they have a personal or family history of heart disease including heart rhythm disorders, congenital heart defects and cardiac arrest. Other risk factors for cardiac arrest include smoking, obesity, diabetes, a sedentary lifestyle, high blood pressure and high cholesterol, and drinking too much alcohol."

Dr Wi continued: "Vitamin D is found in oily fish, such as salmon, sardines, and mackerel, eggs, fortified fat spreads, fortified breakfast cereals and powdered milk. Most of our vitamin D stores are made by the body when our skin reacts to sunlight."

He concluded: "A large randomised clinical trial is needed to find out whether supplements of vitamin D can protect high risk groups from having a sudden cardiac arrest.