Phase 3 study: Canagliflozin improved beta cell function.

An SGLT2 inhibitor recently approved by the FDA may improve measures of beta cell function in addition to glycemic control in patients already taking metformin plus sulfonylurea, according to phase 3 study results presented here at the AACE Annual Scientific and Clinical Congress.

“Despite the fact it doesn’t act directly on the beta cells, there is a lot of evidence from previous studies that SGLT2 inhibitors can improve beta-cell function,” David Polidori, PhD, of Janssen Research & Development, LLC, said here during a presentation.

Polidori and colleagues conducted a 26-week, randomized, double blind, placebo controlled study to evaluate canagliflozin (Invokana, Janssen) 100-mg and 300-mg compared with placebo as an add on to metformin plus sulfonylurea in patients with type 2 diabetes (n=469; mean age, 57 years). The mean baseline HbA1c level was 8.1%, BMI was 33 kg/m², and duration of diabetes was 9.6 years, according to data.

Of the 469 patients, 168 were administered a meal tolerance test at baseline and week 26. Their plasma glucose and serum C-peptide levels were measured seven times over a 3-hour period.

Polidori reported that at week 26, canagliflozin 100 mg significantly reduced HbA1c by –0.71% and 300 mg  by –0.92% compared with placebo (P<.001).

Further data indicate that the insulin secretion rates (ISR) vs. glucose relationship did not change with placebo. However, the relationship shifted upwards in both canagliflozin doses, Polidori said. This indicated an increase in ISR at each plasma glucose concentration, according to data.

Measures of beta cell function, including the ratio of C-peptide to glucose, were approximately 20% higher than baseline levels in both canagliflozin groups (P=.051 for 100 mg and P=.056 for 300 mg) but remained relatively unchanged in the placebo group. Mean beta cell glucose sensitivity was also increased by about 20% in both canagliflozin groups (P=.14 for 100 mg andP=.22 for 300 mg).

Additionally, mean ISR at 9 mM of glucose increased by about 50% to 60% in both canagliflozin groups (P=.02 for 100 mg and P=.007 for 300 mg), but remained relatively unchanged in the placebo group.

“Consistent with what we’ve seen in patients at earlier stages of diabetes and in some of the animal studies, both doses of canagliflozin improved the measures of beta cell function that we looked at in the meal tolerance test in these more advanced patients who were already inadequately controlled on dual therapy. This is promising,” Polidori said. “This is 26-week data and we’re certainly interested to see longer term data to see if this type of treatment can better prolong beta cell function and hopefully slow the rate of progression of type 2 diabetes.” – by Samantha Costa

Source: Endocrine Today

 

 

New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia .

Abstract

Purpose The occurrence of ≥ two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes.

Patients and Methods Four unrelated patients were investigated, with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. The prolyl hydroxylation and stability of the mutant HIF2α protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2α was performed on formalin-fixed, paraffin-embedded tumor tissue.

Results Patients were found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2Amutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2α interaction with the prolyl hydroxylase domain 2–containing protein, decreasing the hydroxylation of HIF2α, and reducing HIF2α affinity for the von Hippel–Lindau protein and its degradation. An increase in the half-life of HIF2α was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.

Conclusion Our findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology.

 

Source: JCO

 

Scientists find mutation driving pediatric brain tumors.

A type of low-grade but sometimes lethal brain tumor in children has been found, in many cases, to contain an unusual mutation that may help to classify, diagnose and guide the treatment of the tumors, report scientists at Dana-Farber Cancer Institute.

The researchers led a study of pediatric low-grade gliomas, samples of which were collected through an international consortium organized by brain tumor specialists at Dana-Farber/Children’s Hospital Cancer Center. Their findings are being published online by the Proceedings of the National Academy of Sciences (PNAS) the week of April 29.

Low-grade gliomas are the most common type of pediatric brain tumors, diagnosed in about 1,000 young patients annually in the United States. There are about 30 distinct types of these tumors, which arise from specialized cells called glia in the brain. Low-grade gliomas are generally slow-growing, said Keith Ligon, MD, PhD, a senior author of the study, but they behave unpredictably and can be life-threatening.

The investigators focused on diffuse low-grade gliomas, so-called because they lack a tumor mass but spread throughout the brain. As a result, diffuse gliomas often recur after surgery and are more likely to evolve into lethal glioblastomas than are non-diffuse low-grade tumors. “Many of these patients do well, but it’s hard to generalize, as the tumors are difficult to diagnose and study because without better tools pathologists can’t name them consistently,” explained Ligon, who in addition to being a researcher is also a neuropathologist. The research was undertaken in hopes of identifying a common genetic alteration that could be used to better define and design treatments for them.

The researchers analyzed DNA from 45 tissue samples collected from seven institutions in collaboration with Rameen Beroukhim, MD, PhD, a Dana-Farber genome biologist and co- senior author of the study. They looked for mutations caused by extra or missing copies of DNA code in the tumor genomes.

One alteration stood out: a gene called MYBL1, a transcription factor important for controlling other genes, was rearranged and missing a part of its genetic message in nearly 30 percent of the diffuse tumors categorized as grade 2 in terms of aggressiveness. The scientists went on to show that the mutated version of MYBL1 can cause tumors in mice. Previously MYBL1 was not known to cause cancer, but a closely related gene, MYB, is one of the oldest “proto-oncogenes” — a normal gene that can become a cancer-causing gene.

“The creation of these truncated genes, reminiscent in structure of the viral oncogene, is a potential driver for this type of tumor,” said Lori Ramkissoon, PhD, co-first author along with Peleg Horowitz, MD, PhD, a neurosurgery resident, both of Dana-Farber. “It gives us something to follow up on and investigate the function of this gene. It may lead to a specific test for diagnosing these tumors, and we will also try to determine whether patients who have this mutation do better or worse than those lacking the mutation.”

The paper’s other authors include investigators and clinicians from Dana-Farber; the Broad Institute; Brigham and Women’s Hospital; Boston Children’s Hospital; Stanford University School of Medicine; Children’s Cancer Hospital, Cairo, Egypt; University of Texas South Western Medical Center, Dallas; Hospital for Sick Children, Toronto; Children’s National Medical Center, Washington; Johns Hopkins University School of Medicine; and the University of Calgary.

Source: Dana-Farber/Children’s Hospital Cancer Center

 

Aspiration Pneumonia Risks Premature Death in Alzheimer’s.

The risk of dying of aspiration pneumonia among people with Alzheimer’s disease and related dementias (ADRD) is higher for men than women and, in the United States, is higher for younger elderly compared with those 85 years or older, according to a survey of death certificates.

Presenting his analysis here at the Alzheimer’s Disease International (ADI) 28th International Conference, Tsung-Hsueh Lu, MD, PhD, from the Department of Public Health at National Cheng Kung University Hospital in Tainan, Taiwan, told delegates that death certificates list a disease or condition directly leading to death and then other antecedent conditions as contributing causes, but often those latter causes are lost in analyses.

For example, a death certificate may list sepsis as the direct cause, but if aspiration pneumonia and Alzheimer’s disease are listed as antecedent causes, only sepsis may be considered for purposes of vital statistics. So he and a colleague looked for occurrences of listings of aspiration pneumonia, which can be a preventable cause of premature death, with ADRD.

Between 2002 and 2009, 6% of death certificates in the United States and 3.6% of those in Taiwan that listed ADRD as a cause of death also listed aspiration pneumonia.

Men in the United States were at a 78% greater risk for aspiration pneumonia if they had ADRD than were women (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.776 – 1.80). Similarly, men in Taiwan were 71% more likely than women there to die with aspiration pneumonia with ADRD (OR, 1.71; 95% CI, 1.36 – 2.14).

Compared with people aged 65 to 74 years in the United States, residents with ADRD had a decreasing risk for aspiration pneumonia as they aged (at 75 to 84 years: OR, 0.92 [95% CI, 0.90 - 0.94]; at ≥85 years: OR, 0.84 [95% CI, 0.82 - 0.86]). An interesting finding that Dr. Lu could not explain was that Taiwan residents trended in the direction of a nonsignificant increased risk with age.

In both countries, the proportion of people dying with aspiration pneumonia and ADRD decreased during the study period, from 6.9% in 2002 to 2003 to 5.0% in 2008 to 2009 in the United States (OR, 0.72 [95% CI, 0.70 - 0.73] for later period vs earlier) and (nonsignificantly) from 3.9% to 3.5% in Taiwan for the same periods (OR, 0.86 [95% CI, 0.63 - 1.17]).

Dr. Lu cautioned that aspiration pneumonia may be underreported as a cause of death, so the true figures may be even higher than that found from death certificates. And in the United States, different states may have different systems for determining and reporting the causes of deaths.

Preventing Premature Death

Aspiration of food is a major cause of pneumonia, but the risk can be reduced. “Speech therapists should be consulted to evaluate the swallowing ability in such a patient, training of the swallowing, or preparing of food to prevent this premature death,” Dr. Lu advised.

Session moderator David Troxel, MPH, a long-term care consultant and writer in the field of dementia in Sacramento, California, commented to Medscape Medical News that swallowing issues and food aspiration are recognized as big problems among elderly patients with dementia.

“Where I’d say we aren’t doing a good job is I think that families don’t know to go to a speech pathologist. Doctors may not think about referring to a speech pathologist who can maybe help with that and assess [the patient],” he said. “Certainly in home settings I doubt families know much about how to prepare foods or go to different kinds of puréed foods.”

He said he believes families are not getting much support in this area, so problems persist. He suggests that professionals in the elder care field talk to physicians about recognizing problems contributing to aspiration, about referring to speech pathologists, and “to really do more education with the families about different dos and don’ts about food.”

Source: medscape.com

 

Beam of Hope.

 

Beth colorfully compares her first proton therapy treatment session to watching a scene from a science fiction movie unfold around her. Although the pristine white walls and state-of-the-art equipment conjure up images from the future, the technology will soon be a reality on the St. Jude Children’s Research Hospital campus. The hospital is currently building the world’s only proton center dedicated solely to the treatment of children.

Part of a $198 million project to enhance the hospital’s clinical and laboratory facilities, the St. Jude Red Frog Events Proton Therapy Center is slated to open in 2015.

The new center will greatly enhance the hospital’s ability to conduct research optimizing the use of proton therapy in children.

“This facility will enable us to complete important trials while providing the support that only St. Jude can provide to patients,” says Larry Kun, MD, chair of St. Jude Radiological Sciences.

What is proton therapy?

Proton therapy offers tremendous advantages compared to X-ray technology because it is more precise and may be used to deliver a potentially higher dose of radiation to the tumor with fewer side effects. By confining radiation exposure to the tumor itself, the pinpointed therapy reduces a person’s risk of experiencing toxic effects on major organs and of developing secondary cancers later in life.

“It’s exciting to hear that St. Jude is building its own proton therapy center,” adds Beth, who participated in a St. Jude protocol that involved traveling to Florida for treatment.

Beth was found to have a rare brain tumor known as craniopharyngioma when she was a college sophomore. After six weeks of daily proton therapy, which lasted from one to two hours each, Beth’s tumor is now smaller.

“St. Jude has given Beth hope, and that was more than any other therapy could offer,” says Beth’s mom.

Precise treatment

Beth’s doctor, Thomas Merchant, DO, PhD, division chief
of St. Jude Radiation Oncology, says proton therapy represents the next logical step for the hospital as it remains a world leader in the research and treatment of brain tumors and radiation therapy. Proton therapy can deliver high radiation doses directly to tumors while sparing normal tissues and reducing the side effects of traditional X-ray therapy. Proton therapy’s chief advantage is the ability to control its depth and intensity in tissue. The more precise the beam, the more targeted the therapy.

“It’s very important that we deliver precise treatment to children, and we’ve designed our facility in such a way that when it opens in 2015, it will have one of the narrowest beams in the United States,” says Merchant, who toured leading proton centers throughout the world in researching the project.

In addition to treating brain tumors, the new technology will also be used to treat Hodgkin lymphoma and other solid tumors such as Ewing sarcoma, neuroblastoma and retinoblastoma. Treatment sessions may range from 20 minutes to an hour.

“It’s been wonderful to be able to offer the treatment to our patients at the facility in Florida, but it’s a huge challenge for the families to have to uproot again,” says St. Jude social worker Melanie Russell. “When we have our own treatment facility here, it will be so much easier for our families.”

The new tower housing the facility will also include expanded surgical suites, an advanced Intensive Care Unit, the new Computational Biology department and a global education and collaboration center.

Source: http://www.stjude.org

Cholesterol Plays Key Role in Cell Signaling.

Are you still under the impression that cholesterol is a dietary villain and a primary cause of heart disease? And do you avoid eating healthy animal foods like eggs, butter and grass-fed beef because of “high-cholesterol” fears?

It’s time for these pervasive myths to be laid to rest, as when you understand the truth about how cholesterol works in your body you’ll realize it’s not an enemy to your health, but instead plays an essential role in keeping your body functioning optimally.

Cholesterol Crucial for Healthy Cell Functioning

Cholesterol has been demonized since the early 1950′s, following the popularization of Ancel Keys’ flawed research. As a result, people now spend tens of billions of dollars on cholesterol-reducing drugs each year, thinking they have to lower this “dangerous” molecule lest they keel over from a heart attack.

But cholesterol has many health benefits. Recent research revealed, for instance, that cholesterol plays a key role in regulating protein pathways involved in cell signaling and may also regulate other cellular processes.¹

It’s already known that cholesterol plays a critical role within your cell membranes, but this new research suggests cholesterol also interacts with proteins inside your cells, adding even more importance.

Your body is composed of trillions of cells that need to interact with each other. Cholesterol is one of the molecules that allow for these interactions to take place. For example, cholesterol is the precursor to bile acids, so without sufficient amounts of cholesterol, your digestive system can be adversely affected.

It also plays an essential role in your brain, which contains about 25 percent of the cholesterol in your body. It is critical for synapse formation, i.e. the connections between your neurons, which allow you to think, learn new things, and form memories.

In fact, there’s reason to believe that low-fat diets and/or cholesterol-lowering drugs may cause or contribute to Alzheimer’s disease. Low cholesterol levels have also been linked to violent behavior, due to adverse changes in brain chemistry, particularly a reduction in serotonin activity Furthermore, you need cholesterol to produce steroid hormones, including your sex hormones. Vitamin D is also synthesized from a close relative of cholesterol: 7-dehydrocholesterol.

Considering the fact that conventional medicine has been telling us that heart disease is due to elevated cholesterol and recommends lowering cholesterol levels as much as possible, it may come as a shock to learn that having too little cholesterol is actually a verifiable risk to your health. As Chris Masterjohn, who recently received his PhD in nutritional sciences from the University of Connecticut, explained, to get an idea of the importance of cholesterol you only need to look at what happens if you don’t have it…

“If we want to understand why cholesterol is really an incredibly important molecule and is really our friend rather than our enemy, I think what we should look at is the question, ‘What happens without cholesterol?’ he says.

…[L]ook at Smith-Lemli-Opitz syndrome or SLOS, which is a symptom of genetic deficiency in cholesterol. It’s when people can’t make enough cholesterol on their own. In order to actually have this full-blown syndrome, it’s a recessive trait, which means you need a defective gene for cholesterol synthesis from your father, and you need one from your mother as well. Now, the number of people who carry this defective gene in the population is about one to three percent of the population.

However, the number of babies who are born with Smith-Lemli-Opitz syndrome is far lower than we would expect. …It turns out that if [the fetus] has both of these genes and the unborn child can’t synthesize its own cholesterol, then this usually results in spontaneous abortion. So right away we see that cholesterol is needed for life itself…”

In those rare cases where a baby is born with Smith-Lemli-Opitz syndrome, the child is susceptible to and can present a wide range of defects, such as:

Autism or mental retardation	Failure to thrive	Physical defects in hands, feet and/or internal organs
Visual problems	Increased susceptibility to infection	Digestive problems

Heart Disease May Even be Caused by a Cholesterol Deficiency

According to Dr. Stephanie Seneff:

“Heart disease, I think, is a cholesterol deficiency problem, and in particular a cholesterol sulfate deficiency problem…”

Through her research, she has developed a theory in which the mechanism we call “cardiovascular disease” (of which arterial plaque is a hallmark) is actually your body’s way to compensate for not having enough cholesterol sulfate. She believes that cholesterol combines with sulfur to form cholesterol sulfate, and this cholesterol sulfate helps thin your blood by serving as a reservoir for the electron donations you receive when walking barefoot on the earth (also called grounding). She believes that, via this blood-thinning mechanism, cholesterol sulfate may provide natural protection against heart disease. In fact, she goes so far as to hypothesize that heart disease is likely the result of cholesterol deficiency — which of course is diametrically opposed to the conventional view.

Total Cholesterol Level is Not a Reliable Indicator of Your Heart Disease Risk

As the the leading causes of death in the United States, it’s important to monitor your risk factors for heart disease and make changes to your lifestyle accordingly. However, total cholesterol will tell you virtually nothing about your disease risk, unless it’s exceptionally elevated (above 330 or so, which would be suggestive of familial hypercholesterolemia, and is, in my view, about the only time a cholesterol-lowering drug would be appropriate). Two ratios that are far better indicators of heart disease risk are:

1. Your HDL/total cholesterol ratio: HDL percentage is a very potent indicator of your heart disease risk. Just divide your HDL level by your total cholesterol. This percentage should ideally be above 24 percent. Below 10 percent, it’s a significant indicator of risk for heart disease
2. Your triglyceride/HDL ratios: This percentage should ideally be below 2

Four additional risk factors for heart disease are:

1. Your fasting insulin level: Any meal or snack high in carbohydrates like fructose and refined grains generates a rapid rise in blood glucose and then insulin to compensate for the rise in blood sugar. The insulin released from eating too many carbs promotes fat and makes it more difficult for your body to shed excess weight, and excess fat, particularly around your belly, is one of the major contributors to heart disease.

Your fasting insulin level can be determined by a simple, inexpensive blood test. A normal fasting blood insulin level is below 5, but ideally you’ll want it below 3. If your insulin level is higher than 3 to 5, the most effective way to optimize it is to reduce or eliminate all forms of dietary sugar, particularly fructose, from your diet.

2. Your fasting blood sugar level: Studies have shown that people with a fasting blood sugar level of 100-125 mg/dl had a nearly 300 percent higher risk of having coronary heart disease than people with a level below 79 mg/dl.
3. Your waist circumference: Visceral fat, the type of fat that collects around your internal organs, is a well-recognized risk factor for heart disease. The simplest way to evaluate your risk here is by simply measuring your waist circumference. For further instructions, please see my previous article, Your Waist Size Can Be a Powerful Predictor of Hypertension and Other Chronic Diseases.
4. Your iron level: Iron can be a very potent cause of oxidative stress, so if you have excess iron levels you can damage your blood vessels and increase your risk of heart disease. Ideally, you should monitor your ferritin levels and make sure they are not much above 80 ng/ml. The simplest way to lower them if they are elevated is to donate your blood. If that is not possible you can have a therapeutic phlebotomy and that will effectively eliminate the excess iron from your body.

Do You Need to Monitor Your Dietary Cholesterol Intake?

About 80-90 percent of the cholesterol in your body is produced by your liver, which has led to the faulty assumption that cholesterol from dietary sources can, and should, be avoided. Dr. Seneff actually believes it’s difficult to get “too much” cholesterol in your diet, particularly in the standard American diet. But you may very well be getting too little, and that can cause serious problems. She points to the research by Weston A. Price, a dentist by profession who traveled all around the world studying the health effects of indigenous diets. Interestingly enough, many indigenous diets are shockingly high in dietary cholesterol based on today’s conventional medical standards.

Cholesterol-rich foods like caviar, liver and the adrenal glands of bears were highly valued in some cultures that also had very low rates of heart disease and other modern diseases.

Dr. Seneff believes, as do I, that placing an upper limit on dietary cholesterol, especially such a LOW upper limit as is now recommended, is likely causing far more harm than good. You can get an idea of what types of cholesterol-rich foods to include in your diet by following my nutrition plan. As Masterjohn further pointed out:²

“Since we cannot possibly eat enough cholesterol to use for our bodies’ daily functions, our bodies make their own. When we eat more foods rich in this compound, our bodies make less. If we deprive ourselves of foods high in cholesterol — such as eggs, butter, and liver — our body revs up its cholesterol synthesis. The end result is that, for most of us, eating foods high in cholesterol has very little impact on our blood cholesterol levels.

In seventy percent of the population, foods rich in cholesterol such as eggs cause only a subtle increase in cholesterol levels or none at all. In the other thirty percent, these foods do cause a rise in blood cholesterol levels. Despite this, research has never established any clear relationship between the consumption of dietary cholesterol and the risk for heart disease… Raising cholesterol levels is not necessarily a bad thing either.”

How to Optimize Your Cholesterol Levels Naturally

The goal of the guidelines below is not to lower your cholesterol as low as it can go, but rather to optimize your levels so they’re working in the proper balance with your body. Again, the majority of your cholesterol is produced by your liver, which is influenced by your insulin levels. Therefore, if you optimize your insulin level, you will automatically optimize your cholesterol. This is why my primary recommendations for safely regulating your cholesterol have to do with modifying your diet and lifestyle as follows:

• Reduce, with the plan of eliminating, grains and sugars in your diet. It is vitally important to eliminate gluten-containing grains and dangerous sugars especially fructose.
• Consume a good portion of your food raw.
• Make sure you are getting plenty of high-quality, animal-based omega 3 fats, such as krill oil. Research suggests that as little as 500 mg of krill per day may improve your total cholesterol and triglycerides and will likely increase your HDL cholesterol.
• Replace harmful vegetable oils and synthetic trans fats with healthful fats, such as olive oil, butter and coconut oil (remember olive oil should be used cold only, use coconut oil for cooking and baking).
• Include fermented foods in your daily diet. This will not only optimize your intestinal microflora, which will boost your overall immunity, it will also introduce beneficial bacteria into your mouth. Poor oral health is another powerful indicator of increased heart disease risk.
• Optimize your vitamin D levels, ideally through appropriate sun exposure as this will allow your body to also create vitamin D sulfate—another factor that may play a crucial role in preventing the formation of arterial plaque.
• Exercise regularly. Make sure you incorporate high-intensity interval exercises, which also optimize your human growth hormone (HGH) production.
• Avoid smoking or drinking alcohol excessively.
• Be sure to get plenty of high-quality, restorative sleep.

Source: Dr. Mercola

 

 

 

 

 

Association between low vitamin D, clinical outcomes varied.

Previous studies have suggested that low 25-hydroxyvitamin D concentration could be a modifiable risk factor associated with chronic disease. However, recent data derived from four cohort studies now suggest genetic variants might modify the association between low 25-hydroxyvitamin D and adverse health outcomes such as hip fractures, incident myocardial infarction, incident cancer or death from any cause.

Gregory P. Levin, PhD, of the University of Washington in Seattle, and colleagues examined 141 single nucleotide polymorphisms (SNPs) from a discovery cohort of 1,514 patients from the Cardiovascular Health Study (CHS). From 1992 to 1993, 2,312 patients underwent serum 25-(OH)D measurements and were followed for 11 years.

Besides the CHS, researchers used replication meta-analyses in the US Health, Aging, and Body Composition study (Health ABC; n=922) with follow-up in 1998-1999 through 2005. They also used the Italian Invecchiare in Chianti study (InCHIANTI; n=835) with follow-up in 1998-2000 through 2006; and the Swedish Uppsala Longitudinal Study of Adult Men (ULSAM; n=970) with follow-up in 1991-1995 through 2008.

Levin and colleagues found that interactions between 5 SNPs and low 25-(OH)D were identified in the CHS discovery cohort and one SNP associated with a variant in the VDR gene replicated from the Health ABC study.

Of the patients examined from the CHS, researchers discovered that low 25-(OH)D was linked to hip fractures, incident MI, incident cancer or death from any cause (composite outcomes) in patients with one minor allele at rs7968585 (HR=1.40; 95% CI, 1.12-1.74) and in patients with two minor alleles at rs7968585 (HR=1.82; 95% CI, 1.31-2.54). However, researchers wrote there was no evidence of an association in patients with no minor alleles (HR=0.93; 95% CI, 0.70-1.24).

“These results suggest that individuals with specific 25-(OH)D metabolism genotypes may be particularly susceptible to, or protected from, the potential adverse health effects of low vitamin D,” the researchers wrote.

Source: Endocrine Today.

Targeting cancers’ ‘addiction’ to cell-cycle proteins shuts down tumors in mice.

In what they say is a promising and highly selective treatment strategy, scientists at Dana-Farber Cancer Institute have safely shut down breast cancer and a form of leukemia in mice by targeting abnormal proteins to which the cancers are “addicted,” according to a new study.

Even though the investigators genetically silenced the proteins or blocked them with a drug in normal as well as cancerous tissues, the animals remained healthy, they report in the Oct. 16 issue of the journal Cancer Cell.

The experiments targeted two related proteins, cyclin D1 and cyclin D3, that control cells’ growth cycle. Many types of cancer have abnormal amounts of the proteins, spurring the cells to grow too rapidly and form tumors. Peter Sicinski, MD, PhD, the paper’s senior author, said that the new results show that the cancers’ addiction to these proteins is an Achilles’ heel that can be safely targeted with an inhibitor drug that halts cancer growth or causes cancer cells to die.

Based on the results, the Dana-Farber scientists are planning a clinical trial, using an experimental cyclin-inhibiting drug called PD0332991 that has already been tested in a form of lymphoma.

“It was impressive to find that you could target a single cyclin protein and completely clear the leukemia and the mouse remained healthy,” said Yoon Jong Choi, PhD, the study’s lead author. “We’re excited because we think this approach is very promising” as a potential treatment for some cancer types, she added.

Some of the experimental mice had been engineered to develop a type of breast cancer driven by the ErbB2 oncogene. Others were modified to develop a type of T-cell acute lymphoblastic leukemia (T-ALL) that is driven by an abnormal pathway known as Notch1. In one experiment, human T-ALL cells were infused into mice that then developed the disease.

Blocking cyclin D1 in the mice drove the breast cancer cells into a kind of permanent retirement called senescence, an irreversible halt to their growth cycle. Inhibiting cyclin D3 in the T-ALL leukemia mice caused the cancer cells to self-destruct — a programmed death process called apoptosis.

In addition to these tests with mouse cancers, the scientists found that the cyclin-D-inhibiting drug had similar effects on human blood cancer cells in the laboratory.

Cyclin proteins act as “checkpoint” guards to control cell’s cycle of rest, growth and division. The D-cyclins determine when a cell begins making DNA in preparation for dividing to form new cells. In many types of cancer, an excess of cyclins allows cells to grow too fast and form tumors. Abnormal cyclins D1, D2 and D3 are found in breast, lung, endometrial, pancreatic, and testicular cancers and in multiple myeloma and other blood cancers.

In a key report in Nature in 2001, Sicinski showed that mice engineered to lack cyclin D1 were resistant to developing breast cancer. It wasn’t known for many years, however, whether knocking out cyclin D1 could halt an established cancer, or if breast cancer needed the protein long-term.

Also unknown was whether normal cells could get along without cyclin D1: If not, treating cancer by targeting the protein might be too dangerous.

To test these questions, Choi and her Dana-Farber colleagues developed a strain of mice with cyclin D proteins that could be inactivated at any time by treating the mice with the drug tamoxifen.

“By generating these ‘conditional’ knockout mice, we could address these questions for the first time,” said Choi. The effect was global, affecting all the body cells, not just those that were cancerous. When the cyclin D proteins were turned off using this technique, the addicted cancer cells shut down while normal cells were unaffected.

The authors say the results show that blocking cyclin D “represents a highly selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.”

Other authors of the report include Xiaoyu Li, MD, PhD, a co-first author, and Harald von Boehmer, MD, PhD, of Dana-Farber, and Andrew L. Kung, MD, PhD, formerly at Dana-Farber and now at Columbia University.

Source: Dana-Farber cancer institute.

 

 

New EASD/ADA Position Paper Shifts Diabetes Treatment Goals?

A new position statement for the treatment of type 2 diabetes takes an approach much more focused on the individual patient compared with the “one number fits all” target of glycated hemoglobin (HbA1c) used up to now.

These new recommendations from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), announced here today in a news conference at the European Association for the Study of Diabetes (EASD) 48th Annual Meeting, put the patient’s condition, desires, abilities, and tolerances at the center of the decision-making process about the goals and methods of treatment. “Our recommendations are less prescriptive than and not as algorithmic as prior guidelines,” the authors write.

In light of the increasing complexity of glycemic management in type 2 diabetes and the wide array of antidiabetic agents now available, as well as uncertainties about the benefits of intensive glycemic control on macrovascular complications, a joint task force of the EASD and the ADA sought to develop recommendations for the treatment of nonpregnant patients with type 2 diabetes to help clinicians determine optimal therapies. Their aim was to take into account the benefits and risks of glycemic control, the efficacy and safety of the drugs used to achieve it, and each patient’s situation. The resulting guidelines are published simultaneously in Diabetes Care (2012;35:1364-1379) and Diabetologia (2012;55:1577-1596) by the EASD and the ADA and are available on the EASD Web site.

“What we’re trying to do is encourage people to really engage in a complex world with the patient, given the variety of choices,” said David Matthews, MD, DPhil, from the Oxford Centre for Diabetes, Endocrinology and Metabolism at Churchill Hospital and the National Institute for Health Research, Oxford Biomedical Research Centre, United Kingdom, and cochair of the Position Statement Writing Group of the EASD and ADA. “And the algorithmic approach, in our view, has finally had its day. We can’t do that anymore.”

Dr. Matthews said the EASD and ADA writing group decided not to issue guidelines but rather to take positions and issue recommendations. “Published guidelines tend to be algorithmic, yet few clinicians prescribe by algorithms…and so there’s a lot of lip service to explicit guidelines,” he said.

Furthermore, there’s a danger in guidelines in that some payers and regulatory bodies focus on them as an absolute measure of success or failure and pay accordingly, or not. So for this reason, the authors did not put a specific HbA1c number in their position statement, and in addition, they did not want to give the impression that it is all right for the number to drift upward if it is below a certain level.

On the other hand, a lower HbA1c value may not be best for some patients. “We’ve got trial data challenging the simplistic view of the lower-the-better approach to glycemic control…. That tells us we need to be careful about just using numbers, however important they may be, to treat patients,” Dr. Matthews said.

So the plan is to have the physician and patient combine the best available evidence with clinical expertise and patient preferences to determine the course of treatment, which may include lifestyle interventions such as physical activity, dietary advice, and oral or injectable antidiabetic drugs, including insulin.

Main Points to New Approach

The position statement lays out 7 key points:

• Individualized glycemic targets and glucose-lowering therapies
• Diet, exercise, and education as the foundation of the treatment program
• Use of metformin as the optimal first-line drug unless contraindicated
• After metformin, the use of 1 or 2 additional oral or injectable agents, with a goal of minimizing adverse effects if possible (despite limited data to guide specific therapy)
• Ultimately, insulin therapy alone or with other agents if needed to maintain blood glucose control
• Where possible, all treatment decisions should involve the patient, with a focus on “patient preferences, needs and values”
• A major focus on “comprehensive cardiovascular risk reduction”

The authors highlight several elements that need to be gauged for making decisions about the appropriate levels of effort to reach glycemic targets. Patient attitudes and expected efforts may range from highly motivated with good adherence and self-care abilities to poor motivation, nonadherence, and poor self-care abilities. The potential risks for hypoglycemia and other adverse effects are another element in decision-making.

The recommendations also focus on duration of disease, life expectancy, significant comorbidities, established vascular complications, and the patient’s resources and support system.

The authors make the point that although the recommendations focus on glycemic control, clinicians and patients should also pay attention to other risk factors, and specifically, “aggressive management of cardiovascular risk factors” in light of the increased risk for cardiovascular morbidity and mortality among patients with type 2 diabetes. Physicians should encourage as much physical activity as possible, aiming for a minimum of 150 min/week, consisting of aerobic, resistance, and flexibility training if possible.

If newly diagnosed patients are at or near the HbA1c target of less than 7.5% and they are highly motivated, they should be given a trial of lifestyle changes for 3 to 6 months with a goal of avoiding pharmacotherapy. But for patients with moderate hyperglycemia or for whom lifestyle changes are expected to be unsuccessful, antidiabetic drug therapy, usually with metformin, should be initiated. If lifestyle efforts are eventually successful, drug therapy may be modified or discontinued.

Information to Guide Pharmacotherapy

Many of the drugs to control blood glucose have similar efficacy, said Writing Group cochair Silvio Inzucchi, MD, professor of medicine, clinical director of the Section of Endocrinology, and director of the Yale Diabetes Center at the Yale School of Medicine in New Haven, Connecticut.

Based on an extensive review of more than 500 articles, “all of these drugs work more or less to the same extent,” he said. “In the grand scheme of things, when you’re talking about a patient taking a medication for years, perhaps decades, and being faced with side effects of medications, the differences in hemoglobin A1c may actually pale in comparison to how they experience that medication.”

To guide choices of glucose-lowering agents, the authors provide in tabular form summaries of the cellular mechanisms, physiological actions, advantages, disadvantages, and costs of classes of agents and drugs within the classes. They also show an algorithm for escalating treatment, starting with lifestyle changes and progressing to initial drug monotherapy, 2- and then 3-drug therapy, and finally to basal and then more complex insulin strategies.

The recommendations end with considerations of the effects of age, weight, sex/racial/ethnic/genetic differences, the comorbidities of coronary artery disease, heart failure, chronic kidney disease, liver dysfunction, and concerns about hypoglycemia. The authors also point out several areas where data are insufficient and therefore where research efforts should be aimed.

When asked if the new recommendations are feasible given the time allotted to seeing a patient, Andreas Pfeiffer, MD, DrMed, chief of the Department of Clinical Nutrition at the German Institute of Human Nutrition Potsdam-Rehbruecke in Nuthetal, Germany, and professor of internal medicine and director of the Department of Endocrinology, Diabetes and Nutrition at Charité Universitaetsmedizin Berlin, Germany, was cautious in his answer.

“If you calculate the time a doctor has per patient, it’s something like 7 minutes or so, and most patients are used to the physician telling him what he’s supposed to do,” Dr. Pfeiffer said. “In some ways it’s unrealistic” for a physician to explore a patient’s desires, capabilities, tolerances, and social support systems in that amount of time. On the other hand, patients return to the doctor several times over the course of a year, so there are more chances to expand the discussion.

But Dr. Pfeiffer worries whether diabetes specialists may become lax if they are not trying to treat to a specific goal. “Diabetologists have average HbA1c’s in Germany of around 7%, which is pretty good, actually…. And now if you relax the guidelines and say, ‘You don’t really have to care so much about it,’ so where do they go?” he wondered.

Source: Mescape.com

Diabetes Screening Fails to Reduce Mortality.

Screening and intervention for type 2 diabetes in a British population had no effect on all-cause mortality during a 10-year period, according to a study published online October 4 in The Lancet and presented that same day during the annual meeting of the European Association for the Study of Diabetes (EASD) in Berlin, Germany.

Rebecca K. Simmons, PhD, from the Medical Research Council (MRC) Epidemiology Unit in Cambridge, United Kingdom (UK), and colleagues conducted a randomized trial involving 33 general medical practices in eastern England. They first randomly assigned the practices to 1 of 3 groups: a control group that received no screening (n = 5 practices), screening followed by intensive diabetes care (n = 15), and screening followed by routine care (n = 13). One screening practice dropped out before screening began, which left the number of intensive care practices at 14.

The screening practices accounted for 16,047 patients and the nonscreening practices accounted for 4137 patients; the median patient age was 58 years (range, 40 – 69 years). Of the 20,184 total individuals in 32 practices, 15,089 (94%) were invited, on the basis of predefined criteria, to screening between January 2002 and March 2006; 11,737 (73%) of them participated in the screening; and diabetes was diagnosed in 466 (3% of those eligible).

During a median follow-up period of 9.6 years, 1532 patients died in the screening group (mortality hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.90 – 1.25; rate per 1000 person-years, 10.5; 95% CI, 9.99 – 11.04) and 377 died in the control group (rate per 1000 person-years 9.89; 95% CI, 8.94 – 10.94). Cancer was the most common cause of death in both groups.

“We noted no significant difference between groups in cardiovascular mortality, cancer mortality, or other causes of death,” the researchers write. Of the other causes of death listed, diabetes was cited in 75 of the screening cases and 16 in the control group.

“In this large, population-based UK sample, all-cause mortality over a median 9.6 years was not reduced by one round of screening for type 2 diabetes in people at high risk of prevalent undiagnosed diabetes,” they write.

The study population came from 1 of 2 phases of the ADDITION-Cambridge study of diabetes type 2 screening and intervention in British primary care clinics.

Limitations of the study include a possible lack of generalizability because the study was conducted in an area with above-average affluence, where disease risk may be lower than in other socioeconomic areas.

On the basis of this first-ever analysis of the effect of a population-based diabetes screening program, senior author Simon J. Griffin, DM, from the MRC’s Addenbrooke Hospital unit in Cambridge, UK, said in a statement, “It seems that the benefits of screening might be smaller than expected and restricted to individuals with detectable disease.  However, benefits to the population could be increased by including the detection and management of cardiovascular risk factors alongside the assessment of diabetes risk, performing repeated rounds of screening, and improving strategies to maximize the uptake of screening.”

In an accompanying commentary, Michael M Engelgau, MD, and Edward W. Gregg, PhD, from the Centers for Disease Control and Prevention in Atlanta, Georgia, write that the researchers “increase the doubt about the value of wide-scale screening for undiagnosed diabetes alone, and deserve credit for tackling the screening quandary head-on. Nevertheless, for any one study to address the diverse factors that affect screening policies — ranging from the magnitude of population burden of disease to the capacity and effectiveness of prevention approaches — is a tall order. Screening recommendations are therefore likely to be country-specific and context-specific for the foreseeable future.”

Countries with higher prevalences of undiagnosed diabetes and lower quality of care might see a higher magnitude of benefits from diabetes screening, the commentary authors write.

Asked to comment on the study, EASD session moderator Rury Holman, FMedSci, FRCP, director of the Diabetes Trials Unit and professor of diabetic medicine at Oxford University, United Kingdom, told Medscape Medical News, “The question they were asking in this study was if you take the trouble and expense to find people and declare they are at risk of diabetes and test, and then the community — the healthcare system — presumably treats them, you think they would do better. But in the time scale of this study, that wasn’t the case. It doesn’t mean that you couldn’t find them and put them in a special program, but if you put them into the normal health care system with an earlier label of diabetes than they would otherwise have, it doesn’t bring any clinical advantages. [The study] says that the incremental benefit of finding people a few years earlier is quite small.”

Source: Mescape.com