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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quarta-feira, 19.08.15

Oncolytic virotherapy lends benefits to melanoma patients

Oncolytic virotherapy lends benefits to melanoma patients

Published on August 19, 2015 at 6:12 AM

Recent study published online by Melanoma Research journal indicates that melanoma patients would significantly benefit from prolonging the survival with oncolytic viroherapy treatment (http://journals.lww.com/melanomaresearch/toc/publishahead).

The study  revealed that the early stage  melanoma patients treated with oncolytic medicine Rigvir were 4 to 6 times more likely to survive than those who following the current guidelines for the treatment of melanoma were only observed.

Oncolytic virotherapy

Melanoma is one of the fastest-growing cancers and has the highest mortality rate of skin cancers. More than half of melanoma patients experience progression of disease within next 3 years after diagnosis. Unfortunately, current clinical practice guidelines for early stage melanoma patients provide few, if any, recommendations for treatment after surgery.

Rigvir is a live nonpathogenic enterovirus, adapted and selected for melanoma that has not been genetically modified. Rigvir has oncotropic and oncolytic properties. Rigvir finds and infects tumour cells, a process called oncotropism. Then, Rigvir replicates in tumour cells and destroys them. This process is called oncolysis.

Both of these processes, oncotropism and oncolysis, are selective for tumour cells and normal healthy cells are minimally, if at all, affected. Moreover, Rigvir demonstrated an outstanding safety profile because there was no record of any untoward side effect from Rigvir treatment or its discontinuation.

Melanoma treatment using oncolytic virus is a cancer treatment option that has been observed for over a century and is presently being studied intensively. The effect of viruses on cancers, including melanoma, has been tested in clinical trials, however the effectivness of an approved and marketed virus has not yet  been shown in a clinical setting.

Rigvir is the first oncolytic virus in the world with anticancer and immunomodulating effects, which is registered for cancer virotherapy and introduced in medical practice. Rigvir was approved in 2004 in Latvia for melanoma therapy and since 2011 is fully reimbursed by government for skin melanoma patients here. Since 2015 Rigvir is included in the national guidelines for the skin cancer and melanoma treatment.

Source:

International Virotherapy Center

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por cyto às 12:10

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

Terça-feira, 21.07.15

TSRI study reveals alternative approach to current anti-HIV strategies

 

TSRI study reveals alternative approach to current anti-HIV strategies

Published on July 9, 2015 at 8:49 AM 

AIDS Study Points to ‘Functional Cure’

HIV-infected patients remain on antiretroviral therapy for life because the virus survives over the long-term in infected dormant cells. Interruption of current types of antiretroviral therapy results in a rebound of the virus and clinical progression to AIDS.

But now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that, unlike other antiretroviral therapies, a natural compound called Cortistatin A reduces residual levels of virus from these infected dormant cells, establishing a near-permanent state of latency and greatly diminishing the virus' capacity for reactivation.

"Our results highlight an alternative approach to current anti-HIV strategies," said Susana Valente, a TSRI associate professor who led the study. "Prior treatment with Cortistatin A significantly inhibits and delays viral rebound in the absence of any drug. Our results suggest current antiretroviral regimens could be supplemented with a Tat inhibitor such as Cortistatin A to achieve a functional HIV-1 cure, reducing levels of the virus and preventing reactivation from latent reservoirs."

The study was published this week in the journal mBio.

Cortistatin A was isolated from a marine sponge, Corticium simplex, in 2006, and in 2008, TSRI chemist Phil Baran won the global race to synthesize the compound. A configuration of the compound, didehydro-Cortistatin A, was shown in earlier studies to target the protein Tat, which exponentially increases viral production.

The new study shows that didehydro-Cortistatin A inhibits replication in HIV-infected cells by significantly reducing levels of viral messenger RNA - the blueprints for producing proteins and more infection.

"In latently infected primary T cells isolated from nine HIV-infected subjects being treated with antiretroviral drugs, didehydro-Cortistatin A reduced viral reactivation by an average of 92.3 percent," said Guillaume Mousseau, the first author of the study and a member of the Valente lab.

The results suggest an alternative to a widely studied strategy for latent HIV eradication known as "kick and kill," which tries to purge viral reservoirs by "kicking" them out of their latency with reversing agents and stopping new rounds of infection with an immunotherapy agent to boost the body's own immune system response while on antiretroviral treatment.

"In our proposed model, didehydro-Cortistatin A inhibits the viral transcriptional activator, Tat, far more completely, delaying or even halting viral replication, reactivation and replenishment of the latent viral reservoir," said Valente.

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por cyto às 18:25

Sábado, 04.07.15

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Published on July 3, 2015 at 5:17 AM 

Viruses need us. In order to multiply, viruses have to invade a host cell and copy their genetic information. To do so, viruses encode their own replication machinery or components that subvert the host replication machinery to their advantage.

Ebola virus and rabies virus, two of the most lethal pathogens known to humans, belong to an order of RNA viruses that share a common strategy for copying their genomes inside their hosts. Other relatives include Marburg virus, measles, mumps, respiratory syncytial virus and vesicular stomatitis virus (VSV). Scientists study VSV, which causes acute disease in livestock but typically does not lead to illness in people, as a model for viruses that are harmful to humans.

Now a team from Harvard Medical School, using electron cryomicroscopy (imaging frozen specimens to reduce damage from electron radiation), has for the first time revealed the structure of a VSV protein at the atomic level. Called polymerase protein L, it is required for viral replication in this group of RNA viruses. The findings are published in Cell.

"We now have a better understanding of how RNA synthesis works for these viruses," said Sean Whelan, HMS professor of microbiology and immunobiology and senior author of the paper. "I think if you were trying to develop a viral-specific target to block the replication of one of these viruses, having the structure of the polymerase protein would help."

Scientists already know how these RNA viruses infect cells. They start by delivering a large protein RNA complex, which is viral RNA enclosed in a protein coat. The protein that copies viral RNA is polymerase protein L, which conducts all the enzymatic activities needed to synthesize RNA and then add a cap structure to its end to ensure it doesn't get destroyed by the cell--and to ensure that it can be translated into protein.

While researchers have known the atomic structures of the protein that coats the viral RNA, there are no data on protein L's atomic structure.

Antiviral drugs that target polymerase molecules are based in part on knowing their structure. That approach has been successful against HIV and herpes and hepatitis C viruses. But for the class of viruses known as nonsegmented negative-strand RNA viruses, finding the structure of polymerase protein L has been challenging.

The "L" stands for large. Larger proteins are often difficult to produce and to purify, Whelan said. Protein L is also flexible, with many functional fragments that are hard to isolate. The viruses evolved to make only small quantities of this protein.

Five years ago, using a lower-resolution form of electron microscopy in which the protein is visualized in the presence of negative stain, Whelan's team was able to detect at low resolution a structure that looked like a doughnut with three globular domains. Those earlier studies were informative, but the approach could not provide the atomic level of resolution the team ultimately needed.

Advances in electron cryomicroscopy encouraged them to try again. A team from Whelan's lab, working with a group led by Stephen Harrison, Giovanni Armenise - Harvard Professor of Basic Biomedical Science at HMS and a Howard Hughes Medical Institute (HHMI) investigator, was able to collect data from their viral samples that gave them much greater resolution. They also were able to align the images they collected into a three-dimensional model of polymerase protein L.

Into the density map obtained from these studies, members of the team built an atomic model of the polypeptide chain of VSV L protein. Solving this puzzle was a significant challenge and also involved the team of Nikolaus Grigorieff at HHMI's Janelia campus.

The result? An atomic level model of polymerase protein L's structure for VSV, which will form the basis for understanding the L protein of the other viruses in the order.

"The Ebola protein will look the same, the rabies protein will look the same, the other L proteins will look the same," Whelan said. "There will be some subtle differences reflecting the precise nature of amino acids, but we know that they're functionally and structurally the same."

Knowing the structure means scientists can explore how RNA synthesis is working in these viruses.

"It begins to suggest ways that we can perhaps pull apart other proteins that have not been so easy to express, such as the L protein in Ebola," Whelan said. "It doesn't mean we're going to have inhibitors immediately, but this is an important step, I think, towards that longer-term goal."

Source:

Harvard Medical School

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por cyto às 11:37


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