Metformin

Not Just For Diabetes.

In the last three years, researchers have shown that diabetic patients with head and neck cancer, may have better outcomes than non-diabetic patients when they are taking the drug metformin for their diabetes. In order to examine this relationship further and understand how metformin changes the biology of cancer cells, researchers at the Sidney Kimmel Cancer Center at Thomas Jefferson University tested tumour cells before and after metformin treatment in non-diabetic cancer patients. The pilot clinical trial results were published in the journal The Laryngoscope.

“This study is the first step in showing how metformin acts on head-and-neck tumours, and we are excited that it could eventually offer patients a method of improving their outcomes with few side effects,” says senior author Ubaldo Martinez-Outschoorn, M.D., Assistant Professor in the Department of Medical Oncology at Thomas Jefferson University and researcher at the Sidney Kimmel Cancer Center.

Dr. Martinez-Outschoorn and colleagues showed that metformin not only changes the pathways that cancer cells rely on to make fuel for growth, but also alters the cancer microenvironment, the cells that surround and support the tumour. “Because tumours need a lot of energy to grow quickly, throwing a wrench in their energy-production pathway makes this kind of cancer more susceptible to standard therapies,” says first author Joseph Curry, M.D., Associate Professor in the Department of Otolaryngology at Jefferson.

The researchers treated 39 patients with metformin and examined their tumour samples before and after metformin treatment. Patients received doses of metformin that were about half of what is given to diabetic patients for a short time-span.

The study looked at molecular markers of cell death, or apoptosis, and changes in metabolic pathways that might make the cancer more susceptible to standard therapy. The patients treated with metformin had a significant increase in tumour cell apoptosis. The cells surrounding the cancer, the so called cancer-supporting fibroblasts, also showed signs of deterioration, indicating that the cells were less capable of helping neighboring cancer cells grow and metastasize to other parts of the body.

Metformin is well-tolerated and has a long track record of being a safe medication, that is much less toxic that traditional cancer treatments. In this study, few patients had side effects from metformin and those that were reported were considered low grade such as gastrointestinal upset. No patients experienced high grade adverse events.

“This study demonstrates that metformin has effects on head-and-neck cancers, at safe doses, that are at or lower than what is given to diabetic patients and that it changes head-and-neck tumour biology in a way that likely makes the cancer easier to kill,” says co-author Madalina Tuluc, M.D., Ph.D., an Associate Professor and Director of Surgical Pathology in the Department of Pathology, Anatomy and Cell Biology at Jefferson. “Metformin disrupts the cancer’s most efficient method of generating fuel for its growth and shuts off the cancer’s support system.” In addition, other work suggests that metformin could have immunotherapeutic effects on tumours as well.

“The next step would be to test these doses of metformin in phase II clinical trials with a greater number of patients,” says Dr. Martinez-Outschoorn.

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Future Cameras

A team of physicists at the Australian National University (ANU) believe they are on the verge of making a reality of smartphone cameras so tiny they are near invisible, yet able to produce images in incredible detail and in three dimensions. .

The scientists have been able to create high-quality holographic images using a material they invented made from millions of tiny silicon pillars, each one 500 times thinner than a human hair.

Lead researcher on the project Sergey Kruk, said each pillar captured all the detail of light directed at it and could then reproduce it in 3D.

“If you compare that to conventional pictures or computer monitors, those produce only a portion of the information of light, basically just the intensity of light and in two dimensions only,” Dr Kruk said.

Dr Kruk said their invention was a major improvement on traditional camera and holographic technology.

“Conventional optical components like lenses and prisms, are bulky and heavyweight,” Dr Kruk said.

“But with our new material we can create components with the same functionality but that would be essentially flat and lightweight.”

He said he believed the possibilities could be endless.

“Starting from further shrinking down the sizes of cameras in consumer smart phones and all the way up to space technologies by reducing the size and weight of complex optical systems for satellites,” Dr Kruk said.

The team’s achievements have been published in the science journal Optica and was partly done in collaboration with the Oak Ridge National Laboratory in the United Sates and Nanjing University in China.

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Green Tea

A compound found in green tea could have lifesaving potential for patients with multiple myeloma and amyloidosis, who face often-fatal medical complications associated with bone-marrow disorders, according to a team of engineers at Washington University in St. Louis and their German collaborators.

Jan Bieschke, assistant professor of biomedical engineering at the School of Engineering & Applied Science, studies how proteins fold and shape themselves and how these processes can contribute to a variety of diseases. He says the compound epigallocatechine-3-gallate (EGCG), a polyphenol found in green tea leaves, may be of particular benefit to patients struggling with multiple myeloma and amyloidosis. These patients are susceptible to a frequently fatal condition called light chain amyloidosis, in which parts of the body’s own antibodies become misshapen and can accumulate in various organs, including the heart and kidneys.

“The idea here is twofold: We wanted to better understand how light chain amyloidosis works, and how the green tea compound affects this specific protein,” Bieschke said.

Bieschke’s team first isolated individual light chains from nine patients with bone marrow disorders that caused multiple myeloma or amyloidosis, then ran lab experiments to determine how the green tea compound affected the light chain protein.

Bieschke previously examined EGCG’s effect in both Parkinson’s and Alzheimer’s disease, and found it prevented dangerous buildups of protein present in both diseases. His team had a similar conclusion in this study: In bone marrow patients, the EGCG transformed light chain amyloid, preventing the misshapen form from replicating and accumulating dangerously.

“In the presence of green tea, the chains have a different internal structure,” Bieschke said. “The ECGC pulled the light chain into a different type of aggregate that wasn’t toxic and didn’t form fibril structures,” as happens to organs affected by amyloidosis.

While Bieschke is gaining a greater understanding at the intracellular processes involved, his partners at the University of Heidelberg are working in tandem with him, running clinical trials.

“My group is looking at the mechanism of the protein in a test tube; we are studying how it works on a foundational level. At the same time, clinical trials at the Amyloidosis Center in Heidelberg, with Alzheimer’s in Berlin and with Parkinson’s in China examine the process in people. We all want this compound to work in a patient.”

The research was published in the Journal of Biological Chemistry.

 

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Natural Sunscreens

The ideal sunscreen should block UVB and UVA radiation while being safe and stable. In the journal Angewandte Chemie, Spanish scientists have introduced a new family of UVA and UVB filters based on natural sunscreen substances found in algae and cyanobacteria. They are highly stable and enhance the effectivity of commercial sunscreens.

Commercial available sunscreen lotions can very effectively protect from dangerous radiation in the ultraviolet, but they need to be applied regularly and in high amounts to develop their full potential. One of the most critical issues is the limited stability of the UV filter molecules. Inspired by nature, Diego Sampedro and his colleagues from La Rioja University in Logrono and collaborators from Malaga University and Alcala University, Madrid, Spain, have screened a natural class of UV-protecting molecules for their possible use in skin protection. They adjusted the nature-given motif to the requirements of chemical synthesis and found that the molecules could indeed boost the sun protection factor of common formulations.

The natural sunscreen molecules are called microsporine-like amino acids (MAAs) and are widespread in the microbial world, most prominently in marine algae and cyanobacteria. MAAs are small molecules derived from amino acids, thermally stable, and they absorb light in the ultraviolet region, protecting the microbial DNA from radiation damage. Thus they are natural sunscreens, which inspired Sampedro and his colleagues to create new class of organic sunscreen compounds.

Theoretical calculations revealed what is chemically needed for a successful design. “We performed a computer calculation of several basic scaffolds to identify the simplest compound that fulfills the requisites for efficient sunscreens,” the authors write. The result of their search was a set of molecules which were readily synthesized, “avoiding the decorating substituents that come from the biosynthetic route.” Thus the small basic molecules can be tuned to give them more favorable properties.

The authors found that the synthesized compounds are characterized by excellent filter capacities in the relevant UV range. In addition they are photostable, much more than for example, oxybenzene which is a widely used sunscreen in commercial formulations. They do not react chemically and dissipate radiation as heat (but not to such an extent that the skin temperature would rise as well). And most importantly, when tested in real formulations, the sun protection factor (SPF) rose by a factor of more than two. Thus they could be promising targets for more stable, more efficient sunscreen lotions.

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EVAM

EVAM To Evade.

In Stockholm, ambulances will soon be piloting a system that interrupts whatever you’re listening to, be it CDs, Bluetooth or the radio and broadcasts a voice warning that an emergency vehicle is heading your way.

Developed by students at KTH Royal Institute of Technology in Stockholm, the solution involves a radio transmission from the emergency vehicle to nearby FM tuners that are equipped with Radio Data System (RDS).

The signal is sent over the FM band along with the transmission of a text message that appears in the tuner display, says Florian Curinga, one of three students at KTH who developed the solution called EVAM System.

Crashes involving motorists who didn’t hear sirens are becoming more common thanks to improvements in sound insulation, Curinga says.

“Often drivers have only a few seconds to react and give way to emergency vehicles,” says Curinga’s partner, Mikael Erneberg, who also studies industrial engineering at KTH. “The optimal warning time is at least 10 to 15 seconds.”

Stockholm will begin testing their system in a limited number of emergency vehicles beginning in Q1 2017. “We want to catch motorists’ attention at an early stage, and mitigate stress that impairs road safety,” Erneberg says.

As long as the tuner is turned on, a voice message will broadcast on the system. Unlike lights and sirens, the warning system anticipates how far in advance messages need to be heard depending on the speed of local traffic. On a highway, for example, the signal will broadcast earlier than in slow city traffic.

Curinga says that the EVAM System would reach two-thirds of all vehicles on the road, and it can also warn of accidents along the route.

“It fulfills three functions: improving accessibility for first responders, improving road safety and make the working environment in transport better for vulnerable professions,” he says.

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Bias Against Abuse

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a possible drug candidate that suppresses pain and itch in animal models. Their new approach also reduces the potential for drug abuse and avoids the most common side effects, sedation and anxiety, of drugs designed to target the nervous system’s kappa opioid receptors (KORs).

“The most significant aspect of the study is that we can preserve itch and pain treatment qualities in a KOR agonist that we developed, triazole 1.1, while avoiding the euphoria associated with narcotic opioids and the dysphoria associated with some other selective KOR agonists,” said TSRI Professor Laura Bohn, senior author of the new study.

The research was published in the journal Science Signaling.

KORs help regulate the release of the neurotransmitter dopamine. Drugs that target KORs have shown promise as therapeutic candidates because of their efficacy for treating chronic itch and relieving pain. Unlike opioid narcotics that target other opioid receptors, these compounds do not produce a “high” or increased risk of overdose; however they can deplete the body’s supply of dopamine and produce dysphoria and sedation, side effects that have limited their clinical development.

Bohn’s laboratory has pioneered the concept that KOR signaling can be fine-tuned to preferentially activate certain pathways over others so that the receptor signals through G proteins rather than through a protein called β-arrestin2.

In the new study, the researchers used rodent models to compare this kind of “biased” KOR agonist, called triazole 1.1 and a conventional KOR agonist.

They found that triazole 1.1 could indeed circumvent the two side effects of previously developed KOR compounds without decreasing dopamine levels, a property associated with dysphoria and sedation.

“This adds to the mounting evidence that shows analgesic effects can be separated from the sedative and dysphoric effects by altering how the agonist engages the receptor,” said TSRI Research Associate Tarsis Brust, first author of the study.

Bohn said the new findings clearly demonstrate that the strategy of developing biased KOR agonists offers a promising new way to treat pain and intractable itch without the potential for abuse.

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Clever Cocktail

A combination of a diabetes medication and an antihypertensive drug can effectively combat cancer cells. The team of researchers led by Prof. Michael Hall at the Biozentrum of the University of Basel has also reported that specific cancer cells respond to this combination of drugs. The results of the study have now been published in Science Advances.

Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. Besides its blood sugar lowering effect, it also displays anti-cancer properties. The usual therapeutic dose however, is too low to effectively fight cancer. The research team led by Prof. Michael Hall, at the Biozentrum of the University of Basel, has now made an unexpected discovery: The antihypertensive drug syrosingopine potentiates the anti-cancer efficacy of metformin. Apparently, this drug combination drives cancer cells to programmed “suicide.”

At higher doses, the antidiabetic drug inhibits the growth of cancer cells but could also induce unwanted side effects. Therefore, the researchers screened over a thousand drugs for whether they can enhance the anticancer action of metformin. A favourite emerged from this screening: Syrosingopine, an antihypertensive drug. As the study shows, the cocktail of these two drugs is effective in a wide range of cancers.

“For example, in samples from leukaemia patients, we demonstrated that almost all tumour cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” says the first author, Don Benjamin. “And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.”

In mice with malignant liver cancer, enlargement of the liver was reduced after the therapy. Also the number of tumour nodules was less, in some animals the tumours disappeared completely. A glance at the molecular processes in the tumour cells explains the drug combination’s efficacy: Metformin lowers not only the blood glucose level, but also blocks the respiratory chain in the energy factories of the cell, the mitochondria. The antihypertensive drug syrosingopine inhibits among other things, the degradation of sugars.

Thus, the drugs interrupt the vital processes which provide energy for the cell. Due to their increased metabolic activity and rapid growth, cancer cells have a particularly high energy consumption, which makes them extremely vulnerable when the energy supply is reduced.

By testing a range of other compounds with the same mode of action, the scientists could demonstrate that the inhibition of the respiratory chain in the mitochondria is a key mechanism. These also reduced cancer cell growth in combination with the antihypertensive drug.

“We have been able to show that the two known drugs lead to more profound effects on cancer cell proliferation than each drug alone,” explains Benjamin. “The data from this study support the development of combination approaches for the treatment of cancer patients.” This study may have implications for future clinical application of combination scenarios targeting the energy needs of tumour cells.

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