GENE RESPONSIBLE FOR TRAITS INVOLVED IN DIABETES DISCOVERED

A collaborative research team led by Medical College of Wisconsin (MCW) scientists has identified a new gene associated with fasting glucose and insulin levels in rats, mice and in humans. The findings are published in the September issue of Genetics.

Leah Solberg Woods, Ph.D., associate professor of pediatrics at MCW and a researcher in the Children's Hospital of Wisconsin Research Institute, led the study and is the corresponding author of the paper.

The authors of the paper identified a gene called Tpcn2 in which a variant was associated with fasting glucose levels in a rat model. Studies in Tpcn2 knockout mice also demonstrated the difference in fasting glucose levels as well as insulin response between the knockout animals and regular mice. Finally, Dr. Woods' team identified variants within Tpcn2 associated with fasting insulin in humans. Tpcn2 is a lysosomal calcium channel that likely plays a role in insulin signaling. Glucose tolerance, insulin resistance and beta cell dysfunction are key underlying causes of type 2 diabetes.

"Genome-wide association studies in humans have identified 60+ genes linked to type 2 diabetes; however, these genes explain only a small portion of heritability in diabetes studies. As we continue to identify genes and variants of interest, we will evaluate them in multiple models to understand the mechanism of disease," said Dr. Solberg Woods.

According to the American Diabetes Association, 29 million Americans have diabetes -- more than nine percent of the total population. It is the 7th leading cause of death, and experts estimate diabetes is an underreported cause of death because of the comorbidities and complications associated with the disease.

OPTIMAL PARTICLE SIZE FOR ANTICANCER NANOMEDICINES DISCOVERED

Nanomedicines consisting of nanoparticles for targeted drug delivery to specific tissues and cells offer new solutions for cancer diagnosis and therapy. Understanding the interdependency of physiochemical properties of nanomedicines, in correlation to their biological responses and functions, is crucial for their further development of as cancer-fighters.

"To develop next generation nanomedicines with superior anti-cancer attributes, we must understand the correlation between their physicochemical properties -- specifically, particle size -- and their interactions with biological systems," explains Jianjun Cheng, an associate professor of materials science and engineering at the University of Illinois at Urbana-Champaign. In a recent study, published in theProceedings of the National Academy of Sciences, Cheng and his collaborators systematically evaluated the size-dependent biological profiles of three monodisperse drug-silica nanoconjugates at 20, 50 and 200 nm.

"There has been a major push recently in the field to miniaturize nanoparticle size using novel chemistry and engineering design," Cheng added. "While most current approved anti-cancer nanomedicines' sizes range from 100-200 nm, recent studies showed that anti-cancer nanomedicines with smaller sizes -- specifically of 50 nm or smaller -- exhibited enhanced performance in vivo, such as greater tissue penetration and enhanced tumor inhibition."

"Over the last 2-3 decades, consensus has been reached that particle size plays a pivotal role in determining their biodistribution, tumor penetration, cellular internalization, clearance from blood plasma and tissues, as well as excretion from the body -- all of which impact the overall therapeutic efficacy against cancers," stated Li Tang, first author of this PNAS article. "Our studies show clear evidence that there is an optimal particle size for anti-cancer nanomedicines, resulting in the highest tumor retention.

Among the three nanoconjugates investigated, the 50 nm particle size provided the optimal combination of deep tumor tissue penetration, efficient cancer cell internalization, as well as slow tumor clearance, exhibits the highest efficacy against both primary and metastatic tumors in vivo.

To further develop insight into the size dependency of nanomedicines in tumor accumulation and retention, the researchers developed a mathematical model of the spatio-temporal distribution of nanoparticles within a spherically symmetric tumor. The results are extremely important to guide the future research in designing new nanomedicines for cancer treatment, Cheng noted. In addition, a new nanomedicine developed by the Illinois researchers -- with precisely engineered size at the optimal size range -- effectively inhibited a human breast cancer and prevented metastasis in animals, showing promise for the treatment of a variety of cancers in humans.

Cheng, a Willett Faculty Scholar at Illinois, is affiliated with the departments of Bioengineering and of Chemistry, the Beckman Institute for Advanced Science and Technology, the Micro and Nanotechnology Laboratory, the Institute of Genomic Biology, the Frederick Seitz Materials Research Laboratory, and University of Illinois Cancer Center.

Tang, who obtained his PhD degree from the University of Illinois with Jianjun Cheng, is currently a CRI Irvington postdoctoral fellow at the Massachusetts Institute of Technology. Collaborators and co-corresponding authors of the paper at Illinois include Timothy Fan, associate professor, veterinary clinical medicine; Andrew Ferguson, assistant professor, materials science and engineering; and William Helferich, professor, food science and human nutrition.

NEW GENE DISCOVERED THAT STOPS SPREAD OF CANCER

Scientists at the Salk Institute have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world's deadliest cancers.

By identifying the cause of this metastasis -- which often happens quickly in lung cancer and results in a bleak survival rate -- Salk scientists are able to explain why some tumors are more prone to spreading than others. The newly discovered pathway, detailed today in Molecular Cell, may also help researchers understand and treat the spread of melanoma and cervical cancers.

"Lung cancer, even when it's discovered early, is often able to metastasize almost immediately and take hold throughout the body," says Reuben J. Shaw, Salk professor of molecular and cell biology and a Howard Hughes Medical Institute early career scientist. "The reason behind why some tumors do that and others don't has not been very well understood. Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive."

Lung cancer, which also affects nonsmokers, is the leading cause of cancer-related deaths in the country (estimated to be nearly 160,000 this year). The United States spends more than $12 billion on lung cancer treatments, according to the National Cancer Institute. Nevertheless, the survival rate for lung cancer is dismal: 80 percent of patients die within five years of diagnosis largely due to the disease's aggressive tendency to spread throughout the body.

To become mobile, cancer cells override cellular machinery that typically keeps cells rooted within their respective locations. Deviously, cancer can switch on and off molecular anchors protruding from the cell membrane (called focal adhesion complexes), preparing the cell for migration. This allows cancer cells to begin the processes to traverse the body through the bloodstream and take up residence in new organs.

In addition to different cancers being able to manipulate these anchors, it was also known that about a fifth of lung cancer cases are missing an anti-cancer gene called LKB1 (also known as STK11). Cancers missing LKB1 are often aggressive, rapidly spreading through the body. However, no one knew how LKB1 and focal adhesions were connected.

Now, the Salk team has found the connection and a new target for therapy: a little-known gene called DIXDC1. The researchers discovered that DIXDC1 receives instructions from LKB1 to go to focal adhesions and change their size and number.

When DIXDC1 is "turned on," half a dozen or so focal adhesions grow large and sticky, anchoring cells to their spot. When DIXDC1 is blocked or inactivated, focal adhesions become small and numerous, resulting in hundreds of small "hands" that pull the cell forward in response to extracellular cues. That increased tendency to be mobile aids in the escape from, for example, the lungs and allows tumor cells to survive travel through the bloodstream and dock at organs throughout the body.

"The communication between LKB1 and DIXDC1 is responsible for a 'stay-put' signal in cells," says first author and Ph.D. graduate student Jonathan Goodwin. "DIXDC1, which no one knew much about, turns out to be inhibited in cancer and metastasis."

Tumors, Shaw and collaborators found in the new research, have two ways to turn off this "stay-put" signal. One is by inhibiting DIXDC1 directly. The other way is by deleting LKB1, which then never sends the signal to DIXDC1 to move to the focal adhesions to anchor the cell. Given this, the scientists wondered if reactivating DIXDC1 could halt a cancer's metastasis. The team took metastatic cells, which had low levels of DIXDC1, and overexpressed the gene. The addition of DIXDC1 did indeed blunt the ability of these cells to be metastatic in vitro and in vivo.

"It was very, very surprising that this gene would be so powerful," says Goodwin. "At the start of this study, we had no idea DIXDC1 would be involved in metastasis. There are dozens of proteins that LKB1 affects; for a single one to control so much of this phenotype was not expected."

Right now, there is no specific treatment for cancers harboring LKB1 or DIXDC1 alterations, but those with a deletion of either gene would likely see results from cancer drugs that target the focal adhesions, says Shaw.

"The good news is that this finding predicts that patients missing either gene should be sensitive to new therapies targeting focal adhesion enzymes, which are currently being tested in early-stage clinical trials," says Shaw, who is also a member of the Moores Cancer Center and an adjunct professor at the University of California, San Diego.

"By identifying this unexpected connection between DIXDC1 and LKB1 in certain tumors, we have expanded the potential patient population that may be good candidates for these therapies," adds Goodwin.

New Clue To Neuropathies Discovered

Today's post from medicalxpress.com (see link below) is one of those complex scientific explanations that may leave many people scratching their heads. To put it very simply, we have a gene in our system that normally prevents tumors forming and leading to cancer. If this gene is disrupted in any way, one of the side effects can be neuropathy. The gene plays an important role in the healthy growth of myelin, which forms the protective lining around nerves (a bit like insulation around an electrical wire). One of the main causes of neuropathy is damage to the myelin sheath, so making the link between the tumor suppressor gene (called Lkb1) and neuropathy, is not so difficult and it becomes clear that disruption to that gene can interfere with myelin production and lead to the nerve damage we're very aware of. This discovery is the sort of thing that goes over most of our heads but the more we can form a picture of what's happening in our nervous system, the better we can understand it and the easier it is for scientists to work on solutions.

Study identifies unexpected clue to peripheral neuropathies

Journal reference: Nature Communications

Provided by Cincinnati Children's Hospital Medical CenterSeptember 26, 2014

 
New research shows that disrupting the molecular function of a tumor suppressor causes improper formation of a protective insulating sheath on peripheral nerves – leading to neuropathy and muscle wasting in mice similar to that in human diabetes and neurodegeneration.

Scientists from Cincinnati Children's Hospital Medical Center report their findings online Sept. 26 in Nature Communications. The study suggests that normal molecular function of the tumor suppressor gene Lkb1 is essential to an important metabolic transition in cells as peripheral nerves (called axons) are coated with the protective myelin sheath by Schwann glia cells. 


(Tumor suppressor gene:

A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.) For information: Ed

"This study is just the tip of the iceberg and a fundamental discovery because of the unexpected finding that a well-known tumor suppressor gene has a novel and important role in myelinating glial cells," said Biplab Dasgupta PhD, principal investigator and a researcher at the Cincinnati Children's Cancer and Blood Diseases Institute (CBDI). "Additional study is needed, as the function of Lkb1 may have broader implications – not only in normal development, but also in metabolic reprogramming in human pathologies. This includes functional regeneration of axons after injury and demyelinating neuropathies."

The process of myelin sheath formation (called myelination) requires extraordinarily high levels of lipid (fat) synthesis because most of myelin is composed of lipids, according to Dasgupta. Lipids are made from citric acid which is produced in the powerhouse of cells called mitochondria. Success of this sheathing process depends on the cells shifting from a glycolytic to mitochondrial oxidative metabolism that generates citric acid, the authors report.

Dasgupta's research team used Lkb1 mutant mice in the current study. Because the mice did not express Lkb1 in myelin forming glial cells, this allowed scientists to analyze its role in glial cell metabolism and formation of the myelin sheath coating.

When the function of Lkb1 was disrupted in laboratory mice, it blocked the metabolic shift from glycolytic to mitochondrial metabolism, resulting in a thinner myelin sheath (hypomyelination) of the nerves. This caused muscle atrophy, hind limb dysfunction, peripheral neuropathy and even premature death of these mice, according to the authors.

Peripheral neuropathy involves damage to the peripheral nervous system – which transmits information from the brain and spinal cord (the central nervous system) to other parts of the body, according to the National Institute of Neurological Disorders and Stroke (NINDS). There are more than 100 types of peripheral neuropathy, and damage to the peripheral nervous system interferes with crucial messages from the brain to the rest of the body.

The scientists also reported that reducing Lkb1 in Schwann cells decreased the activity of critical metabolic enzyme citrate synthase that makes citric acid. Enhancing Lkb1 increased this activity.

They tested the effect of boosting citric acid levels in the Lbk1 mutant Schwann cells. This enhanced lipid production and partially reversed myelin sheath formation defects in Lbk1 mutant Schwann cells. Dasgupta said this further underscores the importance of Lbk1 and the production of citrate synthase.

Dasgupta and his colleagues are currently testing whether increasing the fat content in the Lbk1 mutant mice diet improves hypomyelination defects. The researchers emphasized the importance of additional research into the laboratory findings to extend their relevance more directly to human disease.

Journal reference: Nature Communications Provided by Cincinnati Children's Hospital Medical Center

http://medicalxpress.com/news/2014-09-unexpected-clue-peripheral-neuropathies.html