Monthly Archives: July 2014

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Molly Hammell had her head way beyond the clouds when she met Victor Ambros. At the time, she was a graduate student studying how models of dark matter and dark energy contribute to the distribution of galaxies seen in the sky. Through friends, she met Ambros and asked him about his work in molecular biology.

An amateur astronomer who took photographs of the night sky with a small telescope in his backyard, Ambros brought his family to public observations sessions Hammell ran at the Dartmouth College observatory. Speaking with Ambros helped give her the “biology bug,” she said.

Instead of looking at the remnants of dead stars like Cassiopeia A, which exploded around 1670, Hammell decided to focus her attention on events happening inside cells. Hammell handled the transition from astrophysics to biology incredibly well, said Ambros.

“In less than two years in my lab, [her] breadth and depth of biological knowledge had become comparable to that of any other postdoc at the same stage,” Ambros, the co-director of the RNA Therapeutics Institute at the University of Massachusetts Medical School, said.

She also shared her skill sets with the lab. Her lab meeting presentations were “exceptionally lucid and especially appreciated … as she could often make it almost effortless for the rest of us to understand what had been for us unfamiliar mathematical concepts,” Ambros said.

Now an assistant professor of genomics at Cold Spring Harbor Laboratory, Hammell studies transposons, or jumping genes. These bits of DNA can cut themselves out of one place in the genome and insert themselves into another spot. Another type of transposon makes an RNA copy of itself and then uses that copy to insert new DNA in another spot.

Transposons transcripts can become misregulated in neurodegenerative diseases, including amyotrophic lateral sclerosis, or Lou Gehrig’s disease, and frontotemporal lobar degeneration.

Her work with transposons has not only generated results, but has also distinguished her as a Rita Allen Scholar, an honor she received at the beginning of July. The award supports promising early career investigators and provides up to $110,000 annually for five years.

Hammell and her collaborators “have made one of the first connections between transposon activity and the function of a protein associated with neurodegenerative disease,” Ambros said.

“The possibility that transposon activation could contribute to the causes and/or progression of neurodegenerative disease is an extraordinarily important question.”

Hammell said she has looked for clues about the link between transposons and these diseases. It’s unclear yet whether the transposons are a causal factor in these diseases or whether they are a byproduct. Working with others at Cold Spring Harbor Laboratory, including Joshua Dubnau and Marja Timmermans, Hammell is hoping the team can gain a better understanding of the way transposons affect neurodegenerative diseases.

In one line of experiments, the researchers are looking to take animal models of these diseases and inhibit transposon activity. “If we can slow down or stop the symptoms in those models, that would be a fabulous clue,” she said.

Hammell is using computational analysis to differentiate between the effects of a protein called TDP-43 that is implicated in these diseases and the transposons themselves. Studies at Cold Spring Harbor Laboratory indicate that TDP-43 might normally keep transposons in check. If TDP-43, however, doesn’t work the way it should, these transposons can become more active, which may lead to diseases.

Some transposons, Hammell said, are closely related to retroviruses in the way they are copied in the cell. Drugs like AZT that is used as a treatment for AIDS might also be effective in controlling transposon activity in patients with ALS and other neurodegenerative diseases.

Hammell lives in lab-provided housing with her 10-year-old daughter Anna and her 4-year-old son Max in a converted firehouse on the shores of the harbor. The previous exit door for fire engines is now a huge glass window overlooking Cold Spring Harbor.

As for her work, Hammell appreciates the opportunity to contribute to research that may help people suffering with disease. Hammell’s grandmother succumbed to Alzheimer’s disease when she was a postdoctoral student. “If the work I do helps understand the progression of that disease,” she said, “that would make my family proud.”

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Niacin raises HDL, but potentially without clinical benefit

Niacin has recently become a highly contested drug. In my last article, “Reducing triglycerides,” I mentioned that niacin has powerful effects to treat elevated triglycerides, but that the clinical benefit of this effect is questionable.  Here, I will expand on issues related to niacin.

What is niacin? It is a B vitamin, specifically B3.  It is one of the few supplements that is regulated by the FDA in higher doses as a medication.  It is also known as nicotinic acid and is a coenzyme involved in oxidation-reduction, where electrons are exchanged.  These reactions provide a source of energy  for organisms (1).

Just like with triglycerides, niacin seems to have a powerful effect on HDL  “good” cholesterol, by raising HDL levels as much 30-35 percent (2). While this is an impressive number, once again, it has become debatable whether this raising of HDL is clinically beneficial.

In several recent trials, niacin showed unexpectedly disappointing results in reducing the potential for cardiovascular disease and events. It also demonstrated significant side effects.  In other words, this is not a harmless drug.

Interestingly, as the benefit of niacin for cardiovascular disease has been debated, the number of scripts has increased almost threefold, or 200 percent, in the seven years from 2002 to 2009, according to IMS data for both the U.S. and Canada (3). The majority of the scripts were for extended-release niacin (Niaspan). The rest were mainly for Simcor (simvastatin-niacin combination) and Advicor (lovastatin-niacin combination).

Let’s look at the evidence.

Is raising HDL beneficial or not?

The paradigm has always been that higher HDL is better, but this may not be the case. It is not the first time that HDL’s protectiveness has been debated. An observational study showed that those who have genetically high levels of HDL may not benefit any more than those with normal levels (4). I wrote about this in a separate article entitled “New cholesterol guidelines released,” which can be found on

In a recent randomized controlled trial, the HPS2-THRIVE study, the results showed an increase of 6 mg/dL in HDL levels and a decrease of 10 mg/dL in LDL, “bad” cholesterol, when extended-release niacin plus laropiprant was added to statin therapy (5). This is considered by some to be a relatively small change. Also, there was no reduction in vascular events seen with the combination, even though there was improvement in both HDL and LDL when compared to the placebo.

Laropiprant is a drug used to help reduce the flushing with niacin. The dose used was 2 g of extended-release niacin and 40 mg of laropiprant. The demographics included a patient population that had vascular disease, and therefore was at greater risk of vascular events, such as non-fatal heart attacks, strokes, arterial revascularization and mortality from cardiovascular disease. There were over 25,000 patients involved in the study, and its duration was 3.9 years. LDL was already low in the participants at the start of the trial.

To make matters worse, the serious side effects were greater with the extended-release niacin compared to the placebo. There was a greater propensity toward diabetes — 32 percent relative increase — as well as exacerbation of diabetes — 55 percent increase in impaired sugar or glucose control — in patients who already had the disease. There were also increases in ulcers and diarrhea by 28 percent; muscle damage and gout by 26 percent; rashes and ulcerations by 67 percent; gastrointestinal bleeding or other bleeds by 38 percent; and infection rates by 22 percent. Using niacin to raise HDL may be ineffective, at least in vascular patients — those with atherosclerosis — who already have low LDL. It does not foretell what happens in patients with high LDL at the start.

Other studies have shown questionable efficacy and increased adverse events with niacin use in raising HDL levels to limit cardiovascular events. In the AIM-HIGH study, similarly disappointing results were seen. When extended-release niacin was added to patients with stable coronary artery disease, high triglycerides and low HDL who were already on statins, there was no clinical change in cardiovascular events (6).

Also, there were more serious adverse effects seen in the niacin group compared to the placebo group in a post-hoc analysis (7). These side effects included gastrointestinal disorders, infection, and infestations. However, there was no difference in bleed or hemorrhage, though the absolute number was small.

In yet another study, this a meta-analysis of 39 studies, including HPS2-THRIVE and AIM-HIGH, both mentioned previously, comparing the benefits of niacin, cholesteryl ester transfer protein inhibitors, and fibrates, the results showed that even though these drugs may raise HDL levels, there was no improvement in terms of cardiovascular endpoints when added to statin therapy (8). There were about 117,000 patients involved in the meta-analysis. The drugs and drug classes, niacin, CETP and fibrates, did not demonstrate any reduction in all-cause mortality or coronary heart disease mortality, nor did they reduce heart attacks or stroke risk. These drugs were added to statins as adjunct therapy.

Possible HDL explanation

Investigating a theory as to why raising HDL may not be effective when using niacin, a small study looked at cholesterol efflux capacity — the ability of HDL to garner cholesterol from macrophages, a type of white blood cells, compared to the HDL inflammatory index (9). The results showed that cholesterol efflux capacity may be a better indicator for vascular disease than HDL levels. There was an increase in HDL-C, where C stands for cholesterol, but no change in HDL inflammatory index, nor cholesterol efflux capacity, when niacin was used.

In conclusion, if you are on niacin to raise HDL levels and are already on a statin, you may want to talk to your physician about the evidence that refutes the clinical benefits in reducing cardiovascular events. The European Union has recently banned the use of niacin-laropiprant combination (10). Niacin alone does not seem to be harmless either. Whether HDL is as important as we thought is now in debate. Know that a change in a biomarker, such as HDL levels, is not synonymous with better clinical outcomes. This disappointing clinical result also holds true for niacin’s effects on triglycerides.

This article is only addressing niacin in regard to HDL and the cholesterol profile in general, not other roles for the drug. Of course, never discontinue your medication without first discussing it with your doctor.


(1) “Present Knowledge in Nutrition,” 10th ed. 2012;293-306. (2) Arch Intern Med. 1994;154:1586-1595. (3) JAMA Intern Med. 2013;173:1379-1381. (4) Lancet online. 2012 May 17. (5) New Engl J Med. 2014;371:203-212. (6) New Engl J Med. 2011;365:2255-2267. (7) New Engl J Med. 2014;371:288-290. (8) BMJ 2014;349:g4379. (9) J Am Coll Cardiol. 2013;62:1909-1910. (10) European Medicines Agency 2013 Jan. 18.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management.  For further information, go to and/or consult your personal physician.

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Ralph James has surpassed Derek Jeter. Working with a team of scientists at Brookhaven National Laboratory, James, a prolific scientific innovator, has now won the prestigious R and D 100 Award, described as the “Oscars of Invention,” six times, topping the retiring Yankee shortstop’s five World Series rings.

James, who is a senior scientist and group leader in the Nonproliferation and National Security Department at BNL, has led a group that has developed and improved a wide range of technologies that have applications in everything from detecting signature radiation from weapons to finding more efficient ways to detect tumors inside the human body.

The R and D 100 Awards have been given out annually by R and D magazine since the 1960s and include inventions like the halogen lamp and HDTV. James credited colleagues, including Aleksey Bolotnikov, with collaborating to produce the latest award.
BNL and James’ department have benefited from the scientist’s awards and from his vision for a department that has been able to recruit talented scientists.

“James creates conditions where we can attract the best people from all over the world,” said Bolotnikov, who is originally from Russia and who has colleagues from China and India. “All these awards convince our sponsors that we propose good ideas.”

Bolotnikov called James “visionary,” “an expert manager” and a “supporter of good ideas.” Bolotnikov, who shared in three of the R and D 100 awards, said he is “glad [James] directed me in the right direction.”

The latest award involves improving the performance of detectors produced from lower-quality and cheaper crystals, making them more effective at looking for the signature of a particular kind of radiation.

James helped develop cadmium zinc telluride, or CZT, crystals, which enable scientists, medical researchers, and homeland security experts to collect information about a radiation source at room temperature.

Prior to the creation of CZT, scientists used germanium to detect radiation. The biggest problem with germanium, which is, as James said, “the most pure material that exists today,” is that it had to be cooled to minus 200 degrees Celsius or minus 328 degrees Fahrenheit. These germanium detectors, which are still used in some places today, needed several hours to cool down and required considerable maintenance.

The discovery of CZT, however, enabled technicians to get specific isotope information at room temperature. Isotopes are variations of the same element with different number of neutrons. Uranium, for example, has several isotopes, including the more common Uranium 238. The lighter U 235, which occurs in natural uranium but at a very low concentration, however, can be used in nuclear reactions when it is enriched and is an isotope officials from Homeland Security, among other organizations, monitor closely.

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Early in his career, Zach Foda, who graduated from Ward Melville High School in 2005, has done something his father, Hussein Foda, an award-winning pulmonologist and medical researcher, hasn’t accomplished in a medical and research career that spans over three decades.

An M.D.-Ph.D. candidate at Stony Brook, the younger Foda recently participated in a research project on diabetes that was published in the prestigious journal Nature. The study, led by David Liu, a Harvard professor of chemistry and chemical biology, found a new possible treatment approach for diabetes, inhibiting something called the insulin-degrading enzyme.

“The Journal Nature is one of the very highest-impact journals in the country and actually in the world,” said the pulmonologist father, who is a professor of medicine in the pulmonology critical care division at Stony Brook. Everything after this, he laughed, may be “downhill.” As a member of Markus Seeliger’s lab in the Department of Pharmacology, Zach Foda helped determine the three-dimensional structure of the inhibitor compound and showed how it was bound to the insulin-degrading enzyme.

Over 20 million people in the United States live with type II diabetes, a problem in which the body can’t make enough of the hormone insulin. The IDE removes insulin from the blood. People with diabetes typically inject insulin, take medicine to increase their sensitivity to the hormone or take other drugs to increase the insulin their bodies produce. Inhibiting the effect of this enzyme may enable insulin to remain active in the blood for a longer time.

Testing their compound in mice, Liu and his Harvard colleagues showed that the inhibitor increased insulin levels, which in turn lowered blood sugar. While this study is encouraging, scientists caution it could be some time before this approach goes through all of the screening steps to become an approved treatment for diabetes.

Seeliger and Foda became involved in this collaboration at the request of Liu. An expert in determining the structure of molecules, Seeliger studies the structure of inhibitors of enzymes called protein kinases, some of which are involved in cancer.

When Liu reached out to Seeliger in the fall of 2011, the Stony Brook researcher didn’t hesitate to join the latest collaboration. Liu is “a total rock star in the field,” Seeliger offered. “I was delighted when he contacted me out of the blue initially. It was a no-brainer to say, ‘Sure, we’d be interested.’” Liu praised his Stony Brook collaborator. Seeliger is “a highly talented, dedicated and scholarly biochemist and structural biologist,” Liu offered in an email. “He is a superb collaborator and an asset to our community.”

While Seeliger contributed an important element to the diabetes study, he focuses more of his work on other areas, including studying the structural nature of kinases and the drugs used to affect them. Kinases are “important drug targets,” Seeliger said.

“There are a lot of potential compounds out there that could become drugs for kinases, but most of them don’t work well enough. We want to help understand why they don’t work.”

Kinases are signaling molecules inside the cell. If they send an incorrect signal, a cell could die or develop cancer, Seeliger explained. The problem in targeting these kinases is that there are many similar signaling molecules and it’s “difficult to turn off one without turning another one off. We need a high specificity of kinase inhibitors.”

The “Holy Grail” for Seeliger in his research would be to find out how a drug binds to a receptor, and not just what the final configuration of the drug and the receptor are. Seeliger, who considers himself a visual person, said he is humbled by people who bake professionally. Being able to manipulate yeast, flour and other ingredients to create a moist and spongy bread is something that “impresses me.”

Seeliger, who lives in Stony Brook, is married to Jessica Seeliger, an assistant professor who is also in the pharmacology department at Stony Brook. The couple enjoy going to the beach and visiting Stony Brook Village. Seeliger is a scuba diver who has explored the waters around Long Island.

Seeliger credits Foda with doing much of the hands-on and computational work on the structural part of the diabetes study.

Foda recently married equine veterinarian Kiara Barr and is going back and forth between Long Island and Westchester, where his wife will work with and show horses until she moves to the University of Pennsylvania next year.

The elder Foda said he is “very excited” for his son’s early success and, as someone who chose to combine medicine and research, is also pleased with his son’s career choice. “I’m very proud of him.”

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Low carbohydrate intake may trump calorie restriction

Triglycerides is a term that most of us recognize. This substance is part of the lipid (cholesterol) profile. However, this may be the extent of our understanding. Compared to the other substances, HDL (“good” cholesterol) and LDL (“bad” cholesterol), triglycerides are not covered much in the lay press and medical research tends to be less robust than for the other components. If I were to use a baseball analogy, triglycerides are the Mets, who get far less attention than their crosstown rivals, the Yankees.

But are triglycerides any less important? It is unclear whether a high triglyceride level is a biomarker for cardiovascular disease – heart disease and stroke – or an independent risk in its own right (1) (2). This debate has been going on for over 30 years. However, this does not mean it is any less important.

What are triglycerides? The most rudimentary explanation is that they are a kind of fat in the blood. Alcohol, sugars and excess calorie consumption may be converted into triglycerides.

Risk factors for high triglycerides include obesity, smoking, a high carbohydrate diet, uncontrolled diabetes, hypothyroidism (underactive thyroid), cirrhosis (liver disease), excessive alcohol consumption and some medications (3).

What levels are normal and what are considered elevated? According to the American Heart Association, optimal levels are <100 mg/dL; however, less than 150 mg/dL is considered within normal range. Borderline triglycerides are 150-199 mg/dL, high levels are 200-499 mg/dL and very high are >500 mg/dL (3).

While medicines that focus on triglycerides, fibrates and niacin, have the ability to lower them significantly, it is questionable whether this reduction results in clinical benefits, like reducing the risk of cardiovascular events. The ACCORD Study, a randomized controlled trial, questioned the effectiveness of medication; when these therapies were added to statins in type 2 diabetes patients, they did not further reduce the risk of cardiovascular disease and events (4). Instead, it seems that lifestyle modifications may be the best way to control triglyceride levels.

Let’s look at the evidence.

Exercise – timing and intensity

If you need a reason to exercise, here is really good one. I frequently see questions pertaining to optimal exercise timing and intensity. Most of the answers are vague, and the research is not specific. However, hold on to your hats, because a recent study may give the timing and intensity answer, at least in terms of triglycerides.

Study results showed that walking a modest distance with alacrity and light weight training approximately an hour after eating (postprandial) reduced triglyceride levels by 72 percent (5). However, if patients did the same workout prior to eating, then postprandial triglycerides were reduced by 25 percent. This is still good, but not as impressive. Participants walked a modest distance of just over one mile (2 kilometers). This was a small pilot study of 10 young healthy adults for a very short duration. The results are intriguing nonetheless, since there are few data that give specifics on optimal amount and timing of exercise.

Exercise trumps calorie restriction

There is good news for those who want to lower their triglycerides: calorie restriction may not the best answer. In other words, you don’t have to torture yourself by cutting calories down to some ridiculously low level to get an effect. We probably should be looking at exercise and carbohydrate intake instead.

In a well-controlled trial, results showed that those who walked and maintained 60 percent of their maximum heart rate, which is a modest level, showed an almost one-third reduction in triglycerides compared to the control group (maintain caloric intake and no exercise expenditure) (6). Those who restricted their calorie intake saw no difference compared to the control. This was a small study of 11 young adult women.

Thus, calorie restriction was trumped by exercise as a way to potentially reduce triglyceride levels.

Carbohydrate reduction not calorie restriction

In addition, when calorie restriction was compared to carbohydrate reduction, results showed that carbohydrate reduction was more effective at lowering triglycerides (7). In this small but well-designed study, patients with nonalcoholic fatty liver disease were randomized to either a lower calorie (1200-1500 kcal/day) or lower carbohydrate (20 g/day) diet. Both groups significantly reduced triglycerides, but the lower carbohydrate group reduced triglycerides by 55 percent versus 28 percent for the lower calorie group. The reason for this difference may have to do with oxidation in the liver and the body as a whole. Both groups lost similar amounts of weight, so weight could not be considered a confounding or complicating factor. However, the weakness of this study was its duration of only two weeks.

Fasting versus nonfasting blood tests

The paradigm has been that, when cholesterol levels are drawn, fasting levels provide a more accurate reading. Except this may not be true.

In a new analysis, fasting may not be necessary when it comes to cholesterol levels. NHANES III data suggests that nonfasting and fasting levels yield similar results related to all-cause mortality and cardiovascular mortality risk. The LDL levels were similarly predictive regardless of whether a patient had fasted or not. The researchers used 4,299 pairs of fasting and nonfasting cholesterol levels. The duration of follow-up was strong, with a mean of 14 years (8).

Why is this relevant? Triglycerides are an intricate part of a cholesterol profile. With regards to stroke risk assessment, nonfasting triglycerides possibly may be more valuable than fasting. In a study involving 13,596 participants, results showed that, as nonfasting triglycerides rose, the risk of stroke also rose significantly (9). Compared to those who had levels below 89 mg/dL (the control), those with 89-176 mg/dL had a 1.3-fold increased risk of cardiovascular events, whereas those within the range of 177-265 mg/dL had a twofold increase, and women in the highest group (>443 mg/dL) had an almost fourfold increase. The results were similar for men, but not quite as robust at the higher end with a threefold increase.

The benefit of nonfasting is that it is more realistic and, according to the authors, also involves remnants of VLDL and chylomicrons, other components of the cholesterol profile that interact with triglycerides and may affect the inner part (endothelium) of the arteries.

What have we learned? Triglycerides need to be discussed, just as we review HDL and LDL levels regularly. Elevated triglycerides may result in heart disease or stroke. The higher the levels, the more likely there will be increased risk of mortality – both all-cause and cardiovascular. Therefore, we ideally should reduce levels to less than 100 mg/dL.

Lifestyle modifications using carbohydrate restriction and modest levels of exercise after a meal may be the way to go to the best results, though the studies are small and need more research. Nonfasting levels may be as important as fasting levels when it comes to triglycerides and the cholesterol profile as a whole; they potentially give a more realistic view of cardiovascular risk, since we don’t live in a vacuum and fast all day.


(1) Circulation. 2011;123:2292-2333. (2) N Engl J Med. 1980;302:1383–1389. (3) (4) N Engl J Med. 2010;362:1563-1574. (5) Med Sci Sports Exerc. 2013;45(2):245-252. (6) Med Sci Sports Exerc. 2013;45(3):455-461. (7) Am J Clin Nutr. 2011;93(5):1048-1052. (8) Circulation Online. 2014 July 11. (9) JAMA 2008;300:2142-2152.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website or consult your personal physician.

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Life depends on taking a set of instructions and copying them over and over. That’s how the code that builds everything from aardvarks to kangaroos to zebras works. Inside each cell, a set of blueprints provides a twisting, ladder-like key that enables plants, animals and yeast to survive, grow and produce the next generation.

While the way that code is copied in creatures like bacteria is well known, the key structural changes that lead from the beginning of the copying process to a full-fledged new set of instructions for so-called eukaryotic organisms, or those with a true nucleus, remains a mystery for organisms like fruit flies, elephants, kangaroos and humans.

“In eukaryotes, the machine performs a similar function” as it does for bacteria, said Huilin Li, a biophysicist at Brookhaven National Laboratory and a professor of biochemistry and cell biology at Stony Brook, “but it’s more complicated. When it’s larger, it’s difficult to deal with and it’s difficult to study its structure.”

The concept of replication, or copying, is known. Li is studying the steps to get from the beginning of a copy to another model with the same important genetic information embedded in it. “Life has evolved this powerful copy machine and we want to know how the copy machine is assembled from scratch and how it works,” said Li.

Li likens his work to studying a car. “If you never saw a car and you suddenly see it running, you would wonder how it can move,” he said. Many of the protein complexes he studies can literally be called nanomachines, he said. Seeing the structure will help determine the function, he said. Quoting Albert Einstein, Li said, “If I can’t picture it, I can’t understand it.”

Li uses an electron microscope to magnify these parts up to a few million times. When he takes a picture, he explained, he controls the number of electrons to keep what he is looking at intact. Because he can’t use that many electrons, however, the picture is not fully exposed, leaving the image blurry or noisy. He takes many of these pictures and uses a computer to average them to get a sharper image.

Li’s work with electron microscopy has “definitely made a splash,” said Christian Speck, a nonclinical lecturer in the Faculty of Medicine at the Institute of Clinical Science at the Imperial College in London, who has collaborated with Li for over a decade. “I still remember when we saw the first structure of a large replication complex in 2004, we all realized that [Li’s] approach was a game changer. We had to think about DNA replication from a completely different perspective, as we could see for the first time the proteins that we have been working on for such a long time.”

Over the years, Li has determined the structure of a genetic machine called the Origin Recognition Complex. The ORC, which is comprised of six proteins, finds the special stretches of DNA, called replication origins, in the sea of a genome. Like a car that consumes gas, the ORC burns a form of chemical energy called adenosine triphosphate.
The ORC recruits a secondary machine, called a helicase, that splits up the DNA. “We recently captured a picture of the recruitment process,” said Li.

Working with Speck, who was at Cold Spring Harbor Laboratory when he started collaborating with Li, the tandem figured out the structure of this 14-protein, two-machine system. When these machines aren’t closely regulated, they can overduplicate DNA, leading to uncontrolled cell growth and proliferation. “A hallmark of cancer is the regulation of replication,” Li said. “They don’t stop replicating” when normal cells would.

Li is also trying to understand how a protein machine called proteasome helps the tuberculosis-causing bacterium, Mycobacterium tuberculosis, survive inside the host immune system.

Li and his wife, Hong Wang, who works in the microbiology and immunology department at Stony Brook, live in Miller Place. They have two sons, Paul, who finished his first year at the University of Miami and Calvin, who just completed his junior year at Miller Place High School.

Li grew up in China and came to the United States in 1994. He enjoys walking in the Pine Barrens at the Rocky Point Preserve.

In his approach to his work, he has a “deep appreciation of what’s under the surface,” he said. “As a scientist, part of the job is learning and, for that, it is really a privilege.”

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Lipoic acid may be effective in diabetes, multiple sclerosis and Alzheimer’s disease

Lipoic acid, also known as alpha lipoic acid and thioctic acid, is a noteworthy supplement. I am not a big believer in lots of supplements for several reasons: diet contributes thousands of more nutrients that work symbiotically; in the United States, supplements are not regulated by the FDA, thus there is no official oversight; and research tends to be scant and not well controlled.

So why would I write about lipoic acid? It is a supplement that has scientific data available from randomized controlled trials, which are the gold standard of studies. In Europe, lipoic acid is classified as a drug, unlike the U.S., where it is a supplement (1).

Lipoic acid is an antioxidant, helping to prevent free radical damage to cells and tissues, but also is a chelating agent, potentially removing heavy metals from the body. Lipoic acid is involved in generating energy for cells; it is an important cofactor for the mitochondria, the cell’s powerhouse. It may also boost glutathione production, a powerful antioxidant in the liver (1). We produce small amounts of lipoic acid in our bodies naturally. Lipoic acid may be important in chronic diseases, including Alzheimer’s, multiple sclerosis and diabetic peripheral neuropathy.

Let’s look at the evidence.

Diabetic peripheral neuropathy

Diabetic peripheral neuropathy, or diabetic neuropathy, involves oxidative stress and occurs in up to half the population with diabetes. One in five patients, when diagnosed, will already have peripheral neuropathy. The most common type is distal symmetric polyneuropathy — damage to nerves on both sides of the body in similar locations. It causes burning pain, numbness, weakness and pins and needles in the extremities (2).

The best studies with lipoic acid focus on peripheral neuropathy with diabetes. In a double-blinded, randomized controlled trial (SYDNEY I), results showed that the total treatment score had improved significantly more for those receiving 600 mg of lipoic acid by intravenous therapy compared to the placebo group (3). Also, individual symptoms of numbness, burning pain and prickling significantly improved in the group treated with lipoic acid compared to placebo.

The study involved 120 diabetes patients with stage 2 neuropathy. Its weakness was its duration. It was a very short trial, about three weeks. The author concluded that this therapy would be a good adjunct for those suffering diabetic neuropathy.

In a follow-up to this study (SYDNEY II), the design and the results were the same (4). In other words, in a second double-blinded, placebo-controlled trial, the lipoic acid treatment group showed significantly better results than the placebo group. There were 180 patients with a similarly short duration of five weeks.

Why include this study? There were several important differences. One was that lipoic acid was given in oral supplements, rather than intravenously. Thus, this is a more practical approach. Another difference is that there were three doses tested for lipoic acid: 600 mg, 1200 mg and 1800 mg. Interestingly, all of them had similar efficacy. However, the higher doses had more side effects of nausea, vomiting and vertigo, again without increased effectiveness. This suggests that an oral dose of 600 mg of lipoic acid may help treat diabetic peripheral neuropathy.

Dementia and Alzheimer’s

In a recent randomized, placebo-controlled trial involving Alzheimer’s patients, results were significantly better for lipoic acid (600 mg oral dose) in combination with fish oil, compared to fish oil alone or to placebo (5). The amount of fish oil used was 3 grams daily containing 675 mg of docosahexaenoic acid and 975 mg of eicosapentaenoic acid of the triglyceride formulation. The duration of this pilot study was 12 months with 39 patients, and the primary endpoint was a change in an oxidative stress biomarker, which did not show statistical significance. However, and very importantly, the secondary endpoint was significant: slowing the progression of cognitive and functional decline with the combination of fish oil and lipoic acid. Mini-mental status and instrumental activities of daily living declined less in the combination treatment group. This was encouraging, although we need larger trials.

However, another study showed 900 mg lipoic acid in combination with 800 IU daily of vitamin E (alpha tocopherol strain) and 500 mg of vitamin C actually mildly reduced an oxidative stress biomarker, but had a negative impact on Alzheimer’s disease by increasing cognitive decline on a mini-mental status exam (6). What we don’t know is whether the combination of supplements in this study produced the disappointing effects or if an individual supplement were the cause. It is unclear since the supplements were tested in combination. The study duration was 16 weeks and involved 78 moderate to severe Alzheimer’s patients.

Multiple sclerosis

In a study involving rats, giving them high doses of lipoic acid resulted in slowing of the progression of multiple sclerosis-type disease (7). The mechanism by which this may have occurred involved blocking the number of inflammatory white blood cells allowed to enter the cerebrospinal fluid in the brain and spinal cord by reducing the enzymatic activity of factors such as matrix metalloproteinases.

I know this sounds confusing, but the important point is that this may relate to a human trial with 30 patients that showed reduction in the enzyme MMP (8). Thus, it could potentially slow the progression of multiple sclerosis. This is purely connecting the dots. We need a large-scale trial that looks at clinical outcomes of progression in MS, not just enzyme levels. The oral dose used in this study was 1200 mg to 2400 mg of lipoic acid per day.

Interestingly, the 1200 mg dose used in the human trial was comparable to the high dose that showed slowed progression in the rat study (9). This only whets the appetite and suggests potential.

So, we have lots of data. What do we know? In diabetic neuropathy, 600 mg of oral lipoic acid may be beneficial. However, in Alzheimer’s the jury is still out, although 600 mg of lipoic acid in combination with fish oil has potential to slow the cognitive decline in Alzheimer’s disease. It also may have a role in MS with an oral dose of 1200 mg, though this is early data.

Always discuss the options with your physician before taking a supplement; in the wrong combinations and doses, supplements potentially may be harmful. The good news is that it has a relatively clean safety profile. If you do take lipoic acid, know that food interferes with its absorption, so it should be taken on an empty stomach (1).


(1) (2) emedicine. (3) Diabetes Care. 2003;26:770-776. (4) Diabetes Care. 2006;29:2365-2370. (5) J Alzheimers Dis. 2014;38:111-120. (6) Arch Neurol. 2012;69:836-841. (7) J Neuroimmunol. 2002;131:104-114. (8) Mult Scler. 2005;11:159-165. (9) Mult Scler. 2010;16:387-397.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website or consult your personal physician.

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By Linda M. Toga, Esq.

The Facts: My sister died recently. In her Will she left 50% of her estate to friends and 50% of her estate to a charity. I feel she should have left her estate to her family.

The Question: As her sibling, can I contest the probate of her Will?

The Answer: Whether you can contest the probate of your sister’s will depends on whether you have “standing.” For purposes of this article, standing is defined as a legally protectable right or interest in your sister’s estate. The law provides that an individual has standing to contest the probate of a Will if that individual would inherit from the estate if the person who died had died without a Will. In other words, you can contest your sister’s Will if you would inherit from her estate if she had died intestate.

To determine if you have standing to raise objections to the probate of the Will, you need to look at the relationships between your sister and the people who survived your sister. You then need to look at the intestacy statute. If your sister was survived by a spouse, children/grandchildren (known as her “issue”) or a parent, the intestacy statute provides that they would be in line ahead of you to inherit her estate. As a result, you would not have standing to contest her Will. However, if your sister was not survived by a spouse, issue or a parent, you and your siblings and/or the children of any predeceased siblings would be in line to inherit her estate. Under those circumstances, you would have standing to contest the probate of your sister’s Will. If you were successful, your sister’s estate would be divided between you and your siblings and/or their issue in accordance with the intestacy statute.

Even if you have standing to contest your sister’s Will, you must have valid grounds for objecting to its probate. While space limitations preclude me from going into detail about what constitutes valid grounds for contesting a Will, suffice to say that the fact that you may feel that your sister should have left her estate to her family does not constitute grounds for a Will contest.

If you believe a Will contest is in order, I suggest you consult an attorney with experience in estate administration who can advise you as to the legal grounds necessary for contesting a Will and assist you in your efforts to overturn your sister’s Will.

Linda M. Toga, Esq. provides legal services in the areas of litigation, estate planning and real estate from her East Setauket office.

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Defeating a deadly enemy requires preventing that killer from traveling to key areas and wreaking irreversible damage. Stony Brook’s Jian Cao, an associate professor in the Department of Medicine, is seeking ways to prevent the enemy, in this case cancer, from making its deadly journey through the body.

Recognized for ground-breaking work he did in Japan, Cao has focused on understanding how to stop a tissue-degrading enzyme called matrix mettalloproteinases, or MMP.

“Understanding the scientific basis for metastasis has been the most challenging aspect of cancer research,” said Stanley Zucker, a professor emeritus in the Department of Medicine at Stony Brook who has collaborated with Cao for close to two decades. “No one has yet figured out a treatment that specifically interferes with the metastatic process.”

Cao, who was born in China and trained with a renowned Japanese biologist, Motoharu Seiki, explained that scientists have focused their attention on disrupting the catalytic site, the place where the MMP breaks apart cell-cell adhesion molecules.

Clinical trials of an inhibitor or blocker for that site failed because of a lack of selectivity. He now focuses on a different area, called a hemopexin domain, that is required for enhanced cell migration. He has developed inhibitors targeting different MMPs.

“We have identified the region that is required for MMP-mediated cell migration, then, we developed inhibitors to target this region,” he said. “We found or developed regions that specifically interfere” with their signaling pathway that leads to enhanced cell migration.

He uses a small protein and synthetic compounds that don’t destroy the enzyme, but rather render it ineffective in spreading cancer.

There are 25 forms of MMP. For breast cancer, for example, MMP-14 activates MMP-2, which activates MMP-9. Based on other research, all these MMP’s play an important role in breast cancer metastasis, Cao said. “We identified regions that are required for enhanced cell migration that are specific and selective for each MMP,” he said.

Cao said his work has generated attention from pharmaceutical companies that are hoping to develop treatments for metastatic forms of cancer. A company reached out to him recently because they “want to collaborate to license our inhibitors,” he said.

Cao’s scientific peers lauded his results and his approach. “Many top investigators in the field consider Dr. Cao to be the best scientist to have entered the rapidly expanding field of MMPs in the past 20 years,” said Zucker. “Dr. Cao gained worldwide recognition for his research contributions to Dr. Seiki’s laboratory in Japan.”

In addition to working with these MMP inhibitors, Cao also has a three-dimensional drug screening test. Cao looks to see whether drugs that might be approved for other uses might have anti-cancer properties. The National Institute of Health’s National Center for Advanced Translational Sciences created a program aimed at repurposing old drugs for new uses. He has seen some benefit from a psychiatric drug that can interfere with cell migration and can inhibit cancer invasion.

At the recent 2014 Gloria and Mark Snyder Symposium for Cancer Medicine, Cao presented his research on a gene he cloned, called CeMIP, that is normally expressed in the central nervous system.

After analyzing thousands of patients, he found that people who have a high level of this gene have a shorter survival period with breast cancer. Those with less of this gene survive longer.
Knocking out this gene in highly aggressive breast cancer in animal models causes cancers to become less invasive.

He is studying a promoter region of this gene that selectively hits the on switch. He hopes to develop a compound that interferes with the CeMIP protein.

A resident of South Setauket, Cao lives with his wife, Qiang Zhao, who is also a scientist working on cancer at Stony Brook, and their 16-year-old son Kevin.

His work often includes going to the lab seven days a week. Cao is “the hardest working scientist I’ve ever encountered,” said Zucker.

“His productivity is outstanding in terms of publication and new research grants.”

Cao believes he is on the right track to develop possible treatments to battle cancer as it spreads. “If you can stop the invasion,” he said, “you can prevent metastasis.”