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Quinta-feira, 23.07.15

Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia

 

Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia

Published on July 22, 2015 at 5:18 AM 

Dartmouth researchers and their colleagues have carried out the first total syntheses of certain compounds involved in excessive cell death in leukemia.

The findings appear in the journal Angewandte Chemie International Edition. A PDF is available on request.

"We anticipate that these compounds will serve as useful tools for dissecting an important but as yet undefined step in the regulation of apoptosis," says senior author Jimmy Wu, an associate professor of chemistry at Dartmouth. "Studies to clarify the biological mechanism by which they operate are ongoing."

The researchers completed the total syntheses of several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily. These are structurally complex molecules that are capable of including apoptosis, or programmed cell death, in certain human leukemia cell lines faster than any other small molecule. The researchers also were able to synthesize some related structures that they predict might exist in nature but have not yet been found.

There have been only two reports that attempt to explain the biological mechanism of action of these molecules. But these are incomplete and more research is required to fully reveal how these compounds work. The Dartmouth-led team's synthetic efforts now provide a means to a steady supply of the active compounds for further study. Preliminary biological tests conducted by co-author Alan Eastman, a professor of pharmacology and toxicology at Dartmouth's Geisel School of Medicine, indicate that all the compounds, both naturally occurring and ones predicted to be exist in nature, are capable of inducing extremely rapid apoptosis in leukemia cells. The researchers are in the process of studying their biological mechanism of action.

"Insufficient apoptosis is strongly linked to cancer and autoimmune disorders," Wu says. "There are also numerous diseases associated with excessive cell death, such as AIDS, Alzheimer's, Huntington's, Parkingson's and ALS. A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics and other diseases attributed to abnormal apoptosis."

Source:

Dartmouth College

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por cyto às 22:57

Quinta-feira, 23.07.15

Researchers find easy way to produce carbon nanoparticles that can carry drugs to targeted tissues

 

Researchers find easy way to produce carbon nanoparticles that can carry drugs to targeted tissues

Published on June 19, 2015 at 3:57 AM ·

Researchers have found an easy way to produce carbon nanoparticles that are small enough to evade the body's immune system, reflect light in the near-infrared range for easy detection, and carry payloads of pharmaceutical drugs to targeted tissues.

Unlike other methods of making carbon nanoparticles - which require expensive equipment and purification processes that can take days - the new approach generates the particles in a few hours and uses only a handful of ingredients, including store-bought molasses.

The researchers, led by University of Illinois bioengineering professors Dipanjan Pan and Rohit Bhargava, report their findings in the journal Small.

"If you have a microwave and honey or molasses, you can pretty much make these particles at home," Pan said. "You just mix them together and cook it for a few minutes, and you get something that looks like char, but that is nanoparticles with high luminescence. This is one of the simplest systems that we can think of. It is safe and highly scalable for eventual clinical use."

These "next-generation" carbon spheres have several attractive properties, the researchers found. They naturally scatter light in a manner that makes them easy to differentiate from human tissues, eliminating the need for added dyes or fluorescing molecules to help detect them in the body.

The nanoparticles are coated with polymers that fine-tune their optical properties and their rate of degradation in the body. The polymers can be loaded with drugs that are gradually released.

The nanoparticles also can be made quite small, less than eight nanometers in diameter (a human hair is 80,000 to 100,000 nanometers thick).

"Our immune system fails to recognize anything under 10 nanometers," Pan said. "So, these tiny particles are kind of camouflaged, I would say; they are hiding from the human immune system."

The team tested the therapeutic potential of the nanoparticles by loading them with an anti-melanoma drug and mixing them in a topical solution that was applied to pig skin.

Bhargava's laboratory used vibrational spectroscopic techniques to identify the molecular structure of the nanoparticles and their cargo.

"Raman and infrared spectroscopy are the two tools that one uses to see molecular structure," Bhargava said. "We think we coated this particle with a specific polymer and with specific drug-loading - but did we really? We use spectroscopy to confirm the formulation as well as visualize the delivery of the particles and drug molecules."

The team found that the nanoparticles did not release the drug payload at room temperature, but at body temperature began to release the anti-cancer drug. The researchers also determined which topical applications penetrated the skin to a desired depth.

In further experiments, the researchers found they could alter the infusion of the particles into melanoma cells by adjusting the polymer coatings. Imaging confirmed that the infused cells began to swell, a sign of impending cell death.

"This is a versatile platform to carry a multitude of drugs - for melanoma, for other kinds of cancers and for other diseases," Bhargava said. "You can coat it with different polymers to give it a different optical response. You can load it with two drugs, or three, or four, so you can do multidrug therapy with the same particles."

"By using defined surface chemistry, we can change the properties of these particles," Pan said. "We can make them glow at a certain wavelength and also we can tune them to release the drugs in the presence of the cellular environment. That is, I think, the beauty of the work."

Source:

University of Illinois at Urbana-Champaign

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por cyto às 22:55

Quinta-feira, 23.07.15

Gold nanoparticles with functional surfaces regulate osteogenic differentiation of stem cells

 

Gold nanoparticles with functional surfaces regulate osteogenic differentiation of stem cells

Published on June 8, 2015 at 3:00 AM ·

Tissue Regeneration Materials Unit (Guoping Chen, Unit Director) at the International Center for Materials Nanoarchitectonics (MANA) (Masakazu Aono, Director General, MANA), NIMS (Sukekatsu Ushioda, President) successfully developed gold nanoparticles that have functional surfaces and act on osteogenic differentiation of stem cells.

In regenerative medicine, the technology to control stem cell functions such as differentiation and proliferation is indispensable. It has been reported that nanosized gold particles promote the differentiation of human mesenchymal stem cells into osteoblasts. Also, other studies suggested that various functional groups such as amino, carboxyl and hydroxyl groups promote or inhibit stem cell differentiation. Based on these reports, we assumed that gold nanoparticles with surface modified with functional groups is a promising candidate to control stem cell functions. However, specific effects of such particles on the differentiation of human mesenchymal stem cells was unknown.

We synthesized gold nanoparticles with surface modified with one of the following functional groups: a positively-charged amino group (-NH2), a negatively-charged carboxyl group (-COOH) or a neutral hydroxyl group (-OH), and identified how they affect the osteogenic differentiation of mesenchymal stem cells that were derived from human bone marrow. Among these three types of nanoparticles, those with the carboxyl groups were uptaken by cells and exhibited a strong bone differentiation-inhibitory effect compared to the other types of nanoparticles. Furthermore, we investigated the effect of gold nanoparticles with carboxyl groups on the gene expression profile of mesenchymal stem cell from human bone marrow. The results indicated that the nanoparticles inhibited several gene expressions related to osteogenic differentiation. Therefore, the influence of the gold nanoparticles on promoting or inhibiting osteogenic differentiation varied depending on the types of functional groups.

In view of regenerative medicine, it is essential to develop technology enabling controlling stem cell functions as well as safe and high-quality stem cells. In the present study, we attempted to control stem cell functions through material manipulation, and our findings will contribute to the creation of novel nanomaterials that facilitate the advancement of stem cell manipulation. We intend to build upon these results in our future endeavors in developing regenerative medicine.

Source:

International Center for Materials Nanoarchitectonics

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por cyto às 22:52

Quinta-feira, 23.07.15

Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use

 

Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use

Published on July 16, 2015 at 1:54 AM

In recent years, researchers have hotly pursued immunotherapy, a promising form of treatment that relies on harnessing and training the body's own immune system to better fight cancer and infection. Now, results of a study led by Johns Hopkins investigators suggests that a device composed of a magnetic column paired with custom-made magnetic nanoparticles may hold a key to bringing immunotherapy into widespread and successful clinical use. A summary of the research, conducted in mouse and human cells, appears online July 14 in the journal ACS Nano.

The Johns Hopkins team focused on training and rapidly multiplying immune system white blood cells known as T cells because of their potential as an effective weapon against cancer, according to Jonathan Schneck, M.D., Ph.D., a professor of pathology, medicine and oncology at the Johns Hopkins University School of Medicine's Institute for Cell Engineering. "The challenge has been to train these cells efficiently enough, and get them to divide fast enough, that we could use them as the basis of a therapy for cancer patients. We've taken a big step toward solving that problem," he says.

In a bid to simplify and streamline immune cellular therapies, Schneck, Karlo Perica, a recent M.D./Ph.D. graduate who worked in Schneck's lab, and others worked with artificial white blood cells. These so-called artificial antigen-presenting cells (aAPCs) were pioneered by Schneck's lab and have shown promise in activating laboratory animals' immune systems to attack cancer cells.

To do that, Perica explains, the aAPCs must interact with naive T cells already present in the body, awaiting instructions about which specific invader to target and battle. The aAPCs bind to specialized receptors on the T cells' surfaces and "present" them with distinctive proteins called antigens. This process activates the T cells to ward off a virus, bacteria or tumor, as well as to make more T cells.

In a previous study in mice, Schneck's team found that naive T-cells activated more effectively when multiple aAPCs bound to different receptors on the cells, and then were exposed to a magnetic field. The magnets brought the aAPCs and their receptors closer together, priming the T cells both to battle the target cancer and divide to form more activated cells.

But naive T cells are as rare in the blood as a "needle in a haystack," Perica says. Because the ultimate goal is to harvest a patient's T cells from a blood sample, then train them and expand their numbers before putting them back into the patient, Schneck's research team looked to magnets as a potential way to separate the naive T cells from others in the blood.

The team mixed blood plasma from mice and, separately, humans with magnetic aAPCs bearing antigens from tumors. They then ran the plasma through a magnetic column. The tumor-fighting T cells bound to aAPCs and stuck to the sides of the column, while other cells washed straight through and were discarded. The magnetic field of the column activated the T cells, which were then washed off into a nourishing broth, or culture, to grow and divide. After one week, their numbers had expanded by an estimated 5,000 to 10,000 times. Because numbers of these cells could be expanded quickly enough to be therapeutically useful, the approach could open the door to individualized immunotherapy treatments that rely on a patient's own cells, says Perica.

Schneck says that the use of naive T cells could make the new technique useful for more patients than another immunotherapy now being tested, which relies on other white blood cells called tumor-infiltrating lymphocytes. Those cells are already "trained" to fight cancer, and researchers have shown some success isolating some of the cells from tumors, inducing them to divide, and then transferring them back into patients. But, Schneck says, not all patients are eligible for this therapy, because not all have tumor-infiltrating lymphocytes. By contrast, all people have naive T cells, so patients with cancer could potentially benefit from the new approach whether or not they have tumor-infiltrating lymphocytes.

"The aAPCs and magnetic column together provide the foundation for simplifying and streamlining the process of generating tumor-specific T cells for use in immunotherapy," says Juan Carlos Varela, M.D., Ph.D., a former member of Schneck's laboratory who is now an assistant professor at the Medical University of South Carolina.

The researchers found that the technique also worked with a mixture of aAPCs bearing multiple antigens, which they say could help combat the problem of tumors mutating to evade the body's defenses. "We get multiple shots on the goal," Schneck says.

While the team initially tested the new method only on cancer antigens, Schneck says it could also potentially work for therapies against chronic infectious diseases, such as HIV. He says that if further testing goes well, clinical trials of the technique could begin within a year and a half.

Source:

Johns Hopkins Medicine

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por cyto às 22:49

Quinta-feira, 23.07.15

New UW-Madison study links two unrelated cancer treatments

 

New UW-Madison study links two unrelated cancer treatments

Published on July 14, 2015 at 5:10 AM 

A new study at the University of Wisconsin-Madison has linked two seemingly unrelated cancer treatments that are both now being tested in clinical trials.

One treatment is a vaccine that targets a structure on the outside of cancer cells, while the other is an altered enzyme that breaks apart RNA and causes the cell to commit suicide. The study was published July 13 in the new journal of the American Chemical Society: ACS Central Science.

The new understanding could help both approaches, says UW-Madison professor of biochemistry Ronald Raines, who has long studied ribonucleases -- enzymes that break apart RNA, a messenger with multiple roles inside the cell. In 1998, he discovered how to alter one ribonuclease to avoid its deactivation in the body. Soon thereafter, he found that the engineered ribonuclease was more toxic to cancer cells than to others.

Raines patented the advance through the Wisconsin Alumni Research Foundation and with UW-Madison chemist Laura Kiessling cofounded Quintessence Biosciences in Madison. They remain shareholders in the firm, which has licensed the patent from WARF and begun early-phase human trials with the ribonuclease at the UW Carbone Cancer Center and MD Anderson Cancer Center in Houston.

The current study began as an effort to figure out why the ribonuclease was selective for cancer cells. To identify which structure on the cell surface helped it enter the cell, Raines screened 264 structures using a specially designed chip. The winner was a carbohydrate called Globo H.

"We were surprised -- delighted -- to see that because we already knew that Globo H is an antigen that is abundant in many tumors," Raines says. Antigens are complex molecules with structures that are recognizable to proteins called antibodies. "Globo H is under development as the basis for a vaccine that will teach the immune system to recognize and kill cancer cells," he says.

Working with Samuel Danishefsky, who solved the difficult problem of synthesizing Globo H at the Memorial Sloan-Kettering Cancer Center in New York, Raines found that reducing the Globo H display on the surface made breast cancer cells less vulnerable to ribonucleases like those that Quintessence is testing. "This was exciting, as we now have a much clearer idea of how our drug candidate is working."

Biochemistry Professor John Markley aided the research with studies of the structure of the molecules in question.

The picture that emerges from the work is of ribonucleases patrolling our bodies, looking for telltales of cancer cells, Raines says. "We are working to demonstrate this surveillance more clearly in mice, but don't have direct evidence yet."

As other scientists test whether using a vaccine will start an immune attack on Globo H, Raines says, "we are probing a different type of immunity. This innate immunity does not involve the immune system. It's a way for our bodies to fight cancer without using white blood cells or antibodies, just an enzyme and a carbohydrate."

Source:

University of Wisconsin-Madison

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por cyto às 22:46

Quinta-feira, 23.07.15

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

 

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

Published on July 16, 2015 at 2:40 AM · 

Immunologists from Emory University have identified a distinct set of long-lived antibody-producing cells in the human bone marrow that function as an immune archive.

The cells keep a catalog of how an adult's immune system responded to infections decades ago in childhood encounters with measles or mumps viruses. The results, published Tuesday, July 14 in , could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

"If you're developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen," says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare's Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Co-senior author of the Immunity paper is Iñaki Sanz, MD, professor of medicine and pediatrics, chief of the Division of Rheumatology, Mason I. Lowance Chair of Allergy and Immunology and a Georgia Research Alliance Eminent Scholar. The research was started when Lee, Sanz and colleagues were investigators at the University of Rochester Medical Center, and continued when they arrived at Emory in 2012. The first author of the paper is Jessica Halliley, MS from Rochester.

As described in part of the Immunity paper, the researchers studied 11 older individuals (aged 43 to 70) who had not been immunized against measles or mumps, but who had antibodies in their blood indicating infection by those viruses in childhood. Measles and mumps vaccines first became available in the 1960s.

Antibodies in the blood have a half-life of just a few weeks, so researchers thought these individuals had long-lived plasma cells, or white blood cells secreting antibodies, dating from the childhood infection.

Examining bone marrow samples obtained from these volunteers, researchers divided plasma cells into four different groups based on the proteins found on their surfaces. Only one group ("subset D", CD19-, CD38high, CD138+) contained the cells that produce antibodies that react with measles or mumps virus.

"I like to call this group of cells the 'historical record' of infection or vaccination," Lee says.

In contrast, cells producing anti-influenza antibodies were found spread across three of the subsets. Because study participants were likely to have been exposed to influenza by annual vaccination or infection more recently than measles or mumps, the researchers inferred that cells specific to recent exposures can reside in multiple subsets while subset D represents the long-lived plasma cells.

In separate experiments, volunteers who were vaccinated against tetanus did have some plasma cells producing anti-tetanus antibodies within three weeks in several subsets, but over time tetanus-specific plasma cells were found in subset D.

The team proved that subset D cells were exclusively responsible for producing the measles- and mumps-specific antibodies in the blood of one of the older volunteers, through proteomics and RNA sequencing techniques.

Compared with other subsets, subset D cells are more quiescent: they displayed less signs of proliferation. In addition, subset D cells have a distinct "fried egg" appearance, containing bubble-like vacuoles or lipid droplets, which are rare in bone marrow cell samples, and a tighter, more condensed nucleus than other white blood cells.

Plasma cells differ from many other cells in the body in that they undergo changes in their DNA -- specifically, their antibody genes. In the patients the researchers examined, antibody genes from subset D are much more diverse than those from other plasma cells. Lee says this finding also reflects subset D's role as an archive, which does not devote too much cellular space to any one vaccination or infection.

Source:

Emory Health Sciences

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por cyto às 22:43


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