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December 11, 2014
Image Caption: After maturation, malaria parasites (yellow) are leaving an infected red blood cell and are efficiently blocked by nanomimics (blue). (Fig: Modified with permission from ACS).
Provided by University of Basel
Malaria parasites invade human red blood cells, they then disrupt them and infect others. Researchers at the University of Basel and the Swiss Tropical and Public Health Institute have now developed so-called nanomimics of host cell membranes that trick the parasites. This could lead to novel treatment and vaccination strategies in the fight against malaria and other infectious diseases. Their research results have been published in the scientific journal ACS Nano.
For many infectious diseases no vaccine currently exists. In addition, resistance against currently used drugs is spreading rapidly. To fight these diseases, innovative strategies using new mechanisms of action are needed. The malaria parasite Plasmodium falciparum that is transmitted by the Anopheles mosquito is such an example. Malaria is still responsible for more than 600,000 deaths annually, especially affecting children in Africa (WHO, 2012).
Artificial bubbles with receptors
Malaria parasites normally invade human red blood cells in which they hide and reproduce. They then make the host cell burst and infect new cells. Using nanomimics, this cycle can now be effectively disrupted: The egressing parasites now bind to the nanomimics instead of the red blood cells.
Researchers of groups led by Prof. Wolfgang Meier, Prof. Cornelia Palivan (both at the University of Basel) and Prof. Hans-Peter Beck (Swiss TPH) have successfully designed and tested host cell nanomimics. For this, they developed a simple procedure to produce polymer vesicles small artificial bubbles with host cell receptors on the surface. The preparation of such polymer vesicles with water-soluble host receptors was done by using a mixture of two different block copolymers. In aqueous solution, the nanomimics spontaneously form by self-assembly.
Blocking parasites efficiently
Usually, the malaria parasites destroy their host cells after 48 hours and then infect new red blood cells. At this stage, they have to bind specific host cell receptors. Nanomimics are now able to bind the egressing parasites, thus blocking the invasion of new cells. The parasites are no longer able to invade host cells, however, they are fully accessible to the immune system.
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Nanotechnology Against Malaria Parasites Could Lead To Treatment, Vaccination Strategies
COLLEGE PARK, Md., Dec. 11, 2014 /PRNewswire/ -- Recent efforts between the University of Maryland (UMD) and Bethesda-based Weinberg Medical Physics LLC (WMP) have led to a new technique to magnetically deliver drug-carrying particles to hard-to-reach targets. The method has the potential to transform the way deep-tissue tumors and other diseases are treated.
UMD Fischell Department of Bioengineering (BioE) alumnus Dr. Aleksandar Nacev and BioE and Institute for Systems Research Professor Benjamin Shapiro have teamed up with WMP to exploit fast pulsed magnetic fields to focus nano-therapeutic magnetic particles to deep targets.
For years, researchers have worked with magnetic nano-particles loaded with therapies such as drugs or genes to develop noninvasive techniques to direct therapies and diagnostics to targets in the body. Magnetic nanoparticle research garnered media attention in October, when Google X (Google's innovation lab dedicated to furthering major technological advancements) announced its interest in the use of magnetic nano-particles for diagnostic applications.
Instead of surgery or systemically administered treatments, such as chemotherapy, the use of magnetic particles as drug carriers could potentially allow clinicians to use external electromagnets to focus therapy to the precise locations of a disease within a patient. However, until now, particles could only be attracted to a magnet, and thus could not be concentrated to points away from the magnet face. As a result, in prior clinical trials magnets held outside the body had only been able to concentrate treatment to targets at or just below the skin surface.
"What we have shown experimentally is that by exploiting the physics of nanorods we can use fast pulsed magnetic fields to focus the particles to a deep target between the magnets," Shapiro said.
These pulsed magnetic fields allowed the team to reverse the usual behavior of magnetic nano-particles. Instead of a magnet attracting the particles, they showed that an initial magnetic pulse can orient the rod-shaped particles without pulling them, and then a subsequent pulse can push the particles before the particles can reorient. By repeating the pulses in sequence, the particles were focused to locations deep between the electromagnets.
"The Holy Grail of magnetic drug targeting is the dream of using magnets outside the body to minimally-invasively direct drug therapy to anywhere inside the body, for example, to inoperable deep tumors or to sections of the brain that have been damaged by trauma, vascular or degenerative diseases," said Dr. Irving Weinberg, a practicing physician and the President of WMP. "We have shown that fast pulsing of external electromagnetic fields may be able to achieve this goal."
The study, published this week in Nano Letters under the title "Dynamic Inversion Enables External Magnets to Concentrate Ferromagnetic Rods to a Central Target," shows that, with appropriate external magnetic pulses, ferromagnetic particles carrying drugs or molecules could be concentrated to arbitrary deep locations between magnets. Nacev, Weinberg, Shapiro and their fellow researchers are now working to demonstrate this method in vivo to prove its therapeutic potential, in a project funded by the National Cancer Institute (NCI) Small Business Innovation Research program and featured at the NCI-sponsored Investor Conference in San Francisco. Additionally, the research team recently launched IronFocus Medical, Inc., a startup company established to commercialize their invention. More information about IronFocus Medical, Inc. is available online at http://www.ironfocusmedical.com.
"This technology could enable a new therapeutic modality that combines the spatial precision of traditional image-guided radiation with the biochemical specificity of molecular medicine," said Dr. John R. Adler, Vice President and Chief of New Clinical Applications for Varian Medical Systems.
Full text of the Nano Letters paper is available online at http://dx.doi.org/10.1021/nl503654t with a video showing the magnetic focusing at http://ter.ps/magnetic.
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Run Deep: Pulsing Magnetic Fields Focus Nano-Particles to Deep Targets
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Newswise If seeing is believing, C.K. Choi has a passion for clarityin a very tiny world. The assistant professor of mechanical engineering's research lies at the micro-scale, in channels no thicker than a strand of hair.
Chois first visualization breakthrough came more than 10 years ago when his team, for the first time in the world, used a confocal microscope to observe velocity fields in a micro-channel, in a space with a diameter smaller than a pin.
His next pioneering move was an innovative use of a technology Choi describes as beautiful, the Total Internal Reflection Fluorescence Microscope. He integrated this system with other optical devices to help researchers literally see in the dark, creating fluorescent images clear enough to examine nanoparticles and proteins near the surface.
Choi sought practical applications for his optical devices and found them in biomedical engineering. Researchers were using electrical measurements to analyze physiological changes of cells inside blood vessels, but needed an optical way to verify the data. He proposed using indium tin oxide (ITO), a common coating used in modern electronics. His hunch worked: the ITO biosensor offered the perfect marriage of optical transparency and electrical conductivity, allowing both electrical measurements and visual observation simultaneously.
The ITO biosensor led to other inter-disciplinary workand a lot more questions. In the human body, cells are subjected to different environments: lung cells to the flow of oxygen, heart cells to pulses of blood, brain cells to electrical charges, etc. Given these radically different environments, Choi asked himself, If I grow cells outside their normal living conditions, will they really be the same type of cells? If companies test their drugs on cells grown here [in the static environment of the lab], will their results be accurate?
He knew that he couldnt mimic all the bodys natural conditions, but he could at least create a device that allowed medical researchers to examine their cell lines under appropriate flow conditions.
Actually very low flow conditions, as is the case with lung cells. In his search for a device that could create ultra-low flows, Choi realized that neither direct current (DC) nor syringe pumps could be used: most mechanical pumps cannot produce consistent flow in micro-channels, and DC can physiologically affect the cells being studied. Exposure to DC can alter the metabolism and nutrients, especially problematic for stem cells which are highly sensitive to environmental changes.
Choi and his collaborators proposed using diodes, which are cheap, reliable components, to drive the current in their electro-osmosis diode pumping device (EOS). It worked. The EOS creates low, consistent flows in a way that does not affect cell growth and contains optical elements to visually track the fluorescent particles.
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Black is one of the most respected managers in Major League Baseball, and by all rights he should be locked in for the long term. But he said this week as the Winter Meetings took place in the Padres' backyard that there has been no discussion with Preller about an extension.
"I'm comfortable with this. I'm comfortable managing," Black told a group of reporters during his media session on Wednesday. "I think those of us in this game realize at certain points contracts will be worked out if they're going to get worked out. I think we've seen over the years a lot of managers go into the last year, head coaches go into the last year of a contract and everything is fine. It's all good. I'm good with it."
This all depends on a person's temperament, and certainly these matters change from era to era.
After the 1985 season in San Diego, late Hall of Fame manager Dick Williams decided he didn't want to return to the Padres for the 1986 season with only one year left on his contract. By virtue of a .520 winning percentage, he raised the heretofore doormat Padres to respectability. They had four .500 or better seasons and won the 1984 National League pennant in Williams' four-year tenure. Prior to that, the Padres had only enjoyed one winning season in the first 13 years of the franchise's existence, 1978 under Roger Craig.
Williams wanted the security of a long-term contract, felt he deserved it and was very public about it. It never happened. There was a highly publicized summit after the 1985 season at owner Joan Kroc's La Jolla, Calif., mansion that included Williams, general manager Jack McKeon and club president Ballard Smith, then Kroc's son-in-law. When the smoke began billowing out of her chimney, reports varied. At first, Williams was out. Hours later, they all emerged smiling. Williams would honor his contract. There would not be an extension.
But when the club reported for Spring Training only months later in Yuma, Ariz., Williams was nowhere to be found. The club called a news conference back in San Diego and announced that Williams was resigning. He was replaced days later by Steve Boros.
There has been no such intrigue this offseason surrounding Black, who always seems to keep his composure through the good times and bad and will be there in Peoria, Ariz., when the Padres go to camp in February. He has a .476 winning percentage in eight seasons as manager, and that may be more a product of the Padres' historical whirling dervish approach to player and coaching personnel than anything else. For example, the Padres are on their seventh hitting coach since moving into spacious Petco Park in 2004. The new guy, Mark Kotsay, was a player on the team only two seasons ago.
Comparatively, Bochy, the man Black replaced, has a 20-year record of only 14 games over .500, largely because he was 24 games under .500 during his 12 years with the Padres, despite four division titles and the 1998 pennant. And Bochy has widely been touted now as a Hall of Fame manager after leading the Giants to three World Series titles in the past five seasons.
One wonders what Black might have accomplished with the same kind of Minor League system and continuity of management Bochy has had in his eight years with the Giants. Bochy has a .515 winning percentage in San Francisco with 50 more wins during the same period both men have been in their respective jobs.
But everyone has to keep moving forward. One can only look back for patterns and perspective.
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PUBLIC RELEASE DATE:
11-Dec-2014
Contact: Barbara Bachtler bachtler@mdc-berlin.de 49-309-406-3896 Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch
The Australian cancer researcher Dr. Jane Holland of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch was honored on the evening of December 10, 2014 with the Curt Meyer Memorial Prize. She received the prize, which is endowed with 10,000 euros, for her study on basal breast cancer, a particularly aggressive form of breast cancer, which was published online in the open access journal Cell Reports*. The study elucidated the main driver for the aggressiveness of this cancer subtype and at the same time identified targets for the development of new and more effective treatments. The prize was awarded to Dr. Holland, who is thirty-four years old and is originally from Adelaide, Australia, at a symposium in Berlin. Since 2007, she has been a member of the research group led by Professor Walter Birchmeier at the MDC.
Breast cancer is the most common cancer in women. The subtype basal breast cancer, also called estrogen receptor (ER)-negative breast cancer, is particularly aggressive. In contrast to estrogen-positive or progesterone-positive breast cancer, basal breast cancer is not controlled by these female sex hormones. This cancer subtype lacks hormone receptors, which is why in contrast to estrogen-positive or progesterone-positive breast cancer a "hormone withdrawal" (anti-hormone therapy) has no effect. In these types of breast cancer, doctors can suppress the cancer growth with anti-hormone therapies because the drugs block the receptors for estrogen or progesterone on the surface of cancer cells. Furthermore, breast cancer with receptors for the growth factor Her2 can be targeted with an antibody that occupies the Her2 receptors.
These therapies are not possible with the basal breast cancer subtype. In most cases the subtype neither has receptors for estrogen nor for progesterone nor Her2; it is therefore "triple negative". The only possible treatment is chemotherapy, which is why this cancer subtype is so difficult to treat.
Infamous "triple combination" - triple attack
Dr. Holland showed that an infamous "triple combination" is to blame for basal breast cancer growth. It is comprised of the two signaling pathways Wnt/beta-catenin and HGF/SF, which promote cancer cell growth, plus a system of signaling proteins (chemokines), which activate these signaling pathways. Jane Holland studied this chemokine system during her doctoral thesis at the University of Adelaide in Australia. Mice in which additionally the gene for the receptor CXCR4 of this chemokine system has been inactivated are immune to this cancer subtype.
In vitro and in vivo in mice, the researchers in Berlin-Buch tested various inhibitors that have already undergone clinical trials against other types of cancer but have not yet been used to treat breast cancer and also have not been approved. Ultimately, using combinations of various inhibitors, they were able to target all three attack points and succeeded in dramatically suppressing cancer growth in mice. Dr. Holland and Prof. Birchmeier explained: "A triple attack that blocks both the chemokine system and the two signaling pathways Wnt/beta-catenin and HGF/Met is the most effective." Therefore, Dr. Jane Holland together with clinicians from the Charit - Universittsmedizin Berlin wants to test these inhibitors in human breast cancer tissue in the laboratory.
Since 1988, the Curt Meyer Memorial Prize has been awarded by the Berlin Cancer Society to young scientists working in Berlin for "exceptionally outstanding" publications in the field of clinical, experimental and translational oncology. Prize recipients from the MDC and Charit in previous years were Dr. Dr. Sandrine Sander (MDC, 2013), the biologist Hua Jing (MDC) and the physician Dr. Julia Kase (Charit, 2012), the cancer researchers and clinicians Dr. Martin Janz and Dr. Stephan Mathas (MDC and Charit, 2008), Professor Clemens A. Schmitt (Charit, MDC Guest Group, 2006) and Professor Peter Daniel (MDC/Charit, 2000).
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Curt Meyer Memorial Prize for Dr. Jane Holland of the Max Delbrck Center DC
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