PUBLIC RELEASE DATE:

16-Dec-2014

Contact: Barbara Bachtler bachtler@mdc-berlin.de 49-309-406-3896 Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch

Some neurons are more active than others, even when they are positioned right next to each other and are one and the same neuron type. Dr. Jean-Sbastien Jouhanneau and Dr. James Poulet of the Max Delbrck Center for Molecular Medicine (MDC) Berlin Buch have discovered the cause for this phenomenon. They found that the more active neurons in the somatosensory area of the brain respond to a broader receptive field and probably play a particularly important role in our sensory perception. The findings of the researchers, who also work at the NeuroCure Cluster of Excellence at Charit in Berlin, have now been published in the journal Neuron*.

Billions of neurons process signals in our brain. In the sensory part of our cerebral cortex, which is responsible for perceptions of the outside world, not all neurons are equally active: even neurons positioned directly next to each other can be differentially active. If there is input of a stimulus, some neurons respond more than their neighbors. Until now, the reason for this remained elusive. Are the more active neurons perhaps more strongly connected within the cortex? Or do they get more information from upstream areas of the brain?

To clarify this, the researchers stimulated the whiskers of mice and investigated how different neurons in the brain react. For this purpose, they measured the activity of two neurons simultaneously. The active cells are characterized by a high concentration of the protein cFos. Since this was coupled to the green fluorescent protein (GFP), the researchers were able to distinguish more active cells from less active ones.

First they stimulated only one central whisker. Surprisingly, no differences showed up between the two neurons. However, if the researchers stimulated many whiskers at the same time with a short airpuff, the response of the GFP-labeled neuron was significantly earlier and larger. Apparently, the more active neurons are distinguished by the fact that they respond to a wider receptive field. But where does this information come from?

Before we perceive a stimulus from our environment, it must pass through the thalamus in the brain. This area is therefore also called "the gateway to consciousness". In mice, the signals from the whiskers are processed in two areas of the thalamus, the so-called ventral posteromedial nucleus (VPM) and the area of the posteromedial nucleus (POm). Using optogenetic stimulation, the team led by James Poulet determined which of these two nuclei is responsible for the enhanced response of specific neurons. By means of light impulses in the brain, they could specifically activate the thalamic nuclei and thus selectively simulate a flow of information through one of the two nuclei.

If the scientists activated the VPM, both types of neurons showed an equally strong response. They behaved exactly as if only a single whisker was touched. This specific reaction is thus apparently mediated by the VPM. The POm, by contrast, elicited - just like the stimulation of several whiskers - a stronger and faster response of the GFP-labeled neurons.

The POm is known for covering a broad receptive field and for transmitting the signals to widely distributed areas in the cerebrum. According to current research, the most active neurons in the somatosensory (touch-sensitive) cortex are characterized by the fact that they not only get specific information from the VPM, but can also draw on the wide receptive field of the POm. This parallel processing of specific and large-scale stimulus information by separate groups of neurons could be a fundamental mechanism of sensory perception. The more active neurons may have a particularly important role in sensory perception.

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Broad receptive field responsible for differentiated neuronal activity

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Newswise New research from The Johns Hopkins University suggests that the amount of mitochondrial DNA (mtDNA) found in peoples blood directly relates to how frail they are medically. This DNA may prove to be a useful predictor of overall risk of frailty and death from any cause 10 to 15 years before symptoms appear.

The investigators say their findings contribute to the scientific understanding of aging and may lead to a test that could help identify at-risk individuals whose physical fitness can be improved with drugs or lifestyle changes. A summary of the research was published online Dec. 4 in the Journal of Molecular Medicine.

We dont know enough yet to say whether the relationship is one of correlation or causation, says Dan Arking, Ph.D., associate professor of genetic medicine. But either way, mitochondrial DNA could be a very useful biomarker in the field of aging.

Mitochondria are structures within cells often referred to as power houses because they generate most of cells energy. Unlike other cell structures, they contain their own DNA separate from that enclosed in the nucleus in the form of two to 10 small, circular chromosomes that code for 37 genes necessary for mitochondrial function. There are 10 to thousands of mitochondria per cell, depending on a cells energy needs.

Previous research from Arkings laboratory linked genetic differences in mtDNA to increased frailty and reduced muscle strength in older individuals. Medically speaking, frailty refers to a well-recognized collection of aging symptoms that include weakness, decreased energy, lower activity levels and weight loss. To further test this link, Arkings team analyzed the amount of mtDNA in blood samples collected for two large, human studies that began in the late 1980s and tracked individuals health outcomes for 10 to 20 years.

After calculating how much mtDNA each sample contained relative to the amount of nuclear DNA, the team looked at measures of frailty and health status gathered on the studies participants over time.

On average, Arking says, subjects who met the criteria for frailty had 9 percent less mtDNA than nonfrail participants. And, when grouped by amount of mtDNA, white participants in the bottom one-fifth of the study population were 31 percent more likely to be frail than participants in the top one-fifth.

It makes intuitive sense that decreased mtDNA is associated with bad health outcomes, says Arking. As we age, our energy reserves decrease, and we become more susceptible to all kinds of health problems and disease.

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Amount of Mitochondrial DNA Predicts Frailty and Mortality

PUBLIC RELEASE DATE:

15-Dec-2014

Contact: Terry Lynam tlynam@nshs.edu 516-465-2640 North Shore-Long Island Jewish (LIJ) Health System

MANHASSET, NY -- Molecular Medicine, a peer-reviewed biomedical journal published by the Feinstein Institute Press, published the results of a new study reporting clinically significant pain reduction in type 2 diabetic patients. In an exploratory study conducted by Araim Pharmaceuticals, a biotech company developing novel treatments for chronic diseases, investigators also observed improvements in metabolic control in patients administered ARA 290. ARA 290 is a peptide engineered to activate the innate repair receptor, a receptor discovered by Araim scientists, which is only expressed following tissue damage or stress.

In the initial study, patients were administered ARA 290, a novel, first-in-class drug, daily for 28 days, with the purpose of evaluating its efficacy in treating neuropathic pain, a common condition among diabetics. When ARA 290 is administered, the repair receptor is activated and subsequently turns off inflammation and turns on the body's natural repair system. The short half-life of ARA 290, coupled with the restricted expression of the innate repair receptor, functions as a dual safety system to avoid potential side effects.

"The results from this study indicate a major breakthrough in the treatment of diabetes," said Kevin J. Tracey, MD, president of the Feinstein Institute for Medical Research and Editor of Molecular Medicine. "Over the years, Molecular Medicine has prided itself on publishing groundbreaking papers with implications on the broader medical community, and we're proud to have a potential disease-modifying solution to diabetes featured in the current issue."

The clinically significant results and excellent safety profile support Araim's development strategy of two future studies in 2015. First, metabolic improvement will be studied in type 2 diabetics with moderate kidney damage. Second, neuropathic pain reduction will be assessed in a multi-center proof of concept trial in type 1 diabetics. Both phase 2 clinical trials will be conducted in the United Kingdom, and patients will be dosed daily for six months to allow time for adequate tissue repair.

"We're excited to be on the cusp of the first diabetic disease modifier that demonstrates the potential to repair the complications of diabetes systemically," said Anthony Cerami, PhD, CEO of Araim Pharmaceuticals." Dr. Cerami developed the HbA1c diagnostic test, the current gold standard for diagnosing diabetes.

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The research was supported in part by a grant from the Netherlands Institute for Regenerative Medicine. Read the full report in http://www.molmed.org.

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Study: Novel agent decreases neuropathic pain in patients with type 2 diabetes

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Newswise When someone you know is wearing an unfamiliar hat, you might not recognize them. Georgia Institute of Technology researchers are using just such a disguise to sneak biomaterials containing peptide signaling molecules into living animals.

When the disguised peptides are needed to launch biological processes, the researchers shine ultraviolet light onto the molecules through the skin, causing the hat structures to come off. That allows cells and other molecules to recognize and interact with the peptides on the surface of the material.

This light-activated triggering technique has been demonstrated in animal models, and if it can be made to work in humans, it could help provide more precise timing for processes essential to regenerative medicine, cancer treatment, immunology, stem cell growth, and a range of other areas. The research represents the first time biological signals presented on biomaterials have been activated by light through the skin of a living animal, and could provide a broader platform technology for launching and controlling biological processes in living animals.

Many biological processes involve complex cascades of reactions in which the timing must be very tightly controlled, said Andrs Garca, a Regents Professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech and principal investigator for the project. Until now, we havent had control over the sequence of events in the response to implanted materials. But with this technique, we can deliver a drug or particle with its signal in the off position, then use light to turn the signal on precisely when needed.

Supported by the National Science Foundation and the National Institutes of Health, the research is reported in the December issue of the journal Nature Materials. It resulted from collaboration between scientists from Georgia Tech and the Max-Planck Institute in Germany through the Materials World Network Program.

When biomaterials are introduced into the body, they normally stimulate an immune system response immediately. But the researchers used molecular cages like hats to cover binding sites on the peptides that are normally recognized by cell receptors, preventing recognition by the animals cells. The cages were designed to detach and reveal the peptides when they encounter specific wavelengths of light.

During the five-year project, the research team which included Ted Lee and Jose Garcia from Georgia Tech and Aranzazu del Campo from Max-Planck modified peptides that normally trigger cell adhesion to present the molecular cage in order to disguise them. They showed that disguised peptides introduced into animal models on biomaterials could trigger cell adhesion, inflammation, fibrous encapsulation, and vascularization responses when activated by light. They also showed that the location and timing of activation could be controlled inside the animal by simply shining light through the skin.

The work involved numerous controls to ensure that the triggering observed by the researchers was actually done by exposure of the peptides not the light, or the removal of the protective cage. The researchers also had to demonstrate that the hats were stable enough that they didnt come off spontaneously, but only when the link between the molecular cage and the peptide was severed by the ultraviolet light.

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Molecular "Hats" Allow in vivo Activation of Disguised Signaling Peptides

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By: Patricia R. Coffman

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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

PUBLIC RELEASE DATE:

9-Dec-2014

Contact: Barbara Bachtler bachtler@mdc-berlin.de 49-309-406-3896 Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch

Two researchers of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch will receive more than 3 million euros in research funding from the European Research Council (ERC) in Strasbourg. Cancer researcher Dr. Michela Di Virgilio and systems biologist Dr. Baris Tursun of the Berlin Institute for Medical Systems Biology (BIMSB) of the MDC will receive an ERC Starting Grant endowed with 1.9 million euros and 1.5 million euros respectively. They were selected from 3,273 applicants. The ERC grants are for a period of five years and will begin in spring 2015.

In her ERC project, Dr. Di Virgilio focuses on the repair of DNA double-strand breaks. These cytotoxic DNA lesions arise following exposure to ionizing radiation and several chemicals, but they also occur in B lymphocytes as intermediates of physiological processes essential for antibody production. Accurate repair of DNA double-strand breaks is therefore essential not only for the maintenance of our genome integrity but also for the establishment of a proper immune response. Dr. Di Virgilio will investigate the regulatory mechanisms that ensure efficient and accurate repair of these lesions in B lymphocytes. By elucidating the molecular mechanisms underlying DNA repair in B cells, Dr. Di Virgilio hopes to advance the understanding of the molecular basis of immunodeficiencies and cancer predisposition.

Dr. Di Virgilio began work in September this year as Helmholtz junior research group leader at the MDC, a research institution of the Helmholtz Association. She came from The Rockefeller University in New York City, USA, where she had worked as a postdoctoral fellow in the laboratory of the immunologist Professor Michel C. Nussenzweig. There she investigated repair mechanisms in B cells. In the field of DNA repair, her results are considered to be groundbreaking. She received her doctorate from the Universit degli Studi di Milano, Milan, Italy, for the work she performed at Columbia University in New York City in the laboratory of the geneticist and developmental biologist Professor Jean Gautier.

In his ERC project Dr. Tursun Baris wants to investigate how cells can be directly reprogrammed, thus circumventing the use of embryonic stem cells or induced pluripotent stem cells and generating tissues for the treatment of severe diseases in the future. However, to date, direct reprogramming is successful in only a few cells types, and it is not well understood why most cells are refractory to this process. Recently, his group identified factors which inhibit direct conversion of germ cells into neurons or muscle cells. In this project his group wants to further understand mechanisms which restrict direct reprogramming. For their investigations they use C. elegans, a roundworm widely used as a model system in genetics and systems biology. It was the first animal to have its genome completely sequenced. Also, its developmental program is understood at the single-cell level.

Baris Tursun joined the BIMSB at the MDC in February 2012 as Independent Junior Group leader, working on gene regulatory mechanisms of the direct conversion of cell types. He received his PhD at the Center for Molecular Neurobiology at the University of Hamburg, Germany, and then worked as a postdoctoral fellow and research scientist at Columbia University in the laboratory of Professor Oliver Hobert. In spring 2014, Baris Tursun co-organized the first European C. elegans conference, which took place at the MDC in Berlin.

Altogether thirteen researchers at the MDC have been awarded one of the highly endowed ERC grants. Besides Dr. Di Virgilio and Dr. Tursun they are: Professor Thomas Willnow and Dr. Oliver Daumke (both grants started in 2014), Dr. Zsuzsanna Izsvk (2013), Professor Gary Lewin, Professor Thomas Jentsch (MDC, Leibniz Institut fr Molekulare Pharmakologie, FMP), Professor Michael Gotthardt and Dr. Jan Siemens (now University of Heidelberg) (all in 2012), Dr. James Poulet and Professor Klaus Rajewsky (both in 2011), Dr. Matthew N. Poy (2010) and Dr. Francesca Spagnoli (2009).

Established in 2007 by the EU, the European Research Council is the first pan-European funding organization for cutting-edge research. Since 2007, the ERC has funded over 4,500 projects throughout Europe.

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ERC starting grants for two researchers of the Max Delbrck Center

PUBLIC RELEASE DATE:

9-Dec-2014

Contact: Kevin Stacey kevin_stacey@brown.edu 401-863-3766 Brown University @brownuniversity

PROVIDENCE, R.I. [Brown University] -- Harmful bacteria have evolved some ingenious mechanisms to resist antibiotics. One of those is the drug efflux pump -- proteins that stand guard along bacterial cell membranes, identifying antibacterial agents that pass through the membrane and swiftly ejecting them from the cell.

"These drug efflux pumps are extremely problematic," said Jason Sello, associate professor of chemistry at Brown University. "The drugs are pumped out of the bacteria and cannot reach the critical concentration for toxicity."

Sello and a team of researchers from Brown have come up with a new strategy that may help sneak drugs past the efflux guards. The new approach makes use of molecular fragments administered alongside antimicrobial agents. The efflux pumps are kept busy pumping out the fragments while the antimicrobial agents are able to stay inside the cell.

"We're basically using decoys," Sello said. "It's a relatively simple idea to solve a significant problem in medicine."

Sello and his colleagues describe the method and some preliminary lab results in a paper published in the journal ACS Infectious Diseases. The paper was co-authored by graduate students Corey Compton and Daniel Carney and undergraduate Patrice Groomes.

For the study, Sello and his team experimented with a promising new class of antimicrobial drug candidates called acyldepsipeptides or ADEPs. The compounds have been shown to be effective in killing many species of bacterial pathogens but are generally less effective against the bacterium that causes tuberculosis. It had been reported that the ADEP resistance of M. tuberculosis was due to the presence of one or perhaps more efflux pumps. Sello and his team were seeking a way to interfere with those pumps so that the ADEPs could be used for the treatment of tuberculosis.

"There are two scenarios for how an ADEP efflux pump could operate," Sello said. "The pump could either recognize the entire molecule or some portion of it. We thought, if the latter scenario is operative, then a molecule comprising the minimal portion of the ADEP that is recognized by the pump could competitively interfere with efflux of the ADEP."

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Molecular decoys help overcome drug resistance

Researchers in Hamilton have discovered how to turn back the clock on the body's metabolism, potentially paving the way for people to eat and burn calories like they did when they were teenagers.

They're calling it a possible solution to obesity and a preventativemeasure for diabetes, one that turns up the body's metabolic rate without the negative side effects of increasing the heart rate or blood pressure.

Published inNature MedicineMonday, researchers from McMaster University show that by inhibiting the hormone serotonin found in the gut of mice, the body's natural furnace, a lesser-known organ called brown adipose tissue, is more active and burns more calories.

Brown adipose tissue is found near the collar bone, and is also known as brown fat. It has no relation to white fat, the fat stores found all over the body, and was previously thought to only exist in rodents, hibernating animals and children, says the paper's co-authorGregory Steinberg, a professor of medicine at the Michael G. DeGroote School of Medicine.

Our results are quite striking and indicate that inhibiting the production of [serotonin] may be very effective for reversing obesity and related metabolic diseases including diabetes,"Steinberg said.

Brown fat plays an important role in burning calories and increasing a person's basal metabolic rate, the resting rate at which someone burns calories.

Researchers say a "western diet" high in fat also raises levels of the hormone serotonin, which inhibits brown fat activity, slowing downone's metabolism as they age.

"Too much of this serotonin acts like the parking brake on your brown fat, Steinberg explained. You can step on the gas of the brown fat, but it doesnt go anywhere.

By inhibiting the production of serotonin, Steinberg says they have releasedthat "parking break" on the brown fat. The implications, Steinberg said, could be both in reversing obesity, but also preventing diabetes by burning sugar in brown fat so the body does not have to produce insulin in the pancreasto regulate blood sugar.

"We're talking about intervening in the pre-diabetes stage or the early stages of diabetes to try and treat it," Steinberg said.

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Want to eat like a teenager again? McMaster scientists may have found a way

2014 Global Summit on Angelman Syndrome: Friday panels
Friday #39;s event schedule is as follows: 9:00 AM to 10:00 AM - New Animal Models in Angelman Syndrome - Featured Speakers: Dr. Jorge Piedrahita, Professor of Genomics, North Carolina State...

By: Foundation for Angelman Syndrome Therapeutics

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2014 Global Summit on Angelman Syndrome: Friday panels - Video

PUBLIC RELEASE DATE:

5-Dec-2014

Contact: Barbara Bachtler bachtler@mdc-berlin.de 49-309-406-3896 Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch

Chronic lymphocytic leukemia (CLL) is among the most frequent leukemias affecting adults in Western countries. It usually occurs in older patients, does not cause any symptoms for a long time and is often only discovered by accident. Despite treatment, relapses frequently occur. The immunologists Dr. Kristina Heinig and Dr. Uta Hpken (Max Delbrck Center for Molecular Medicine, MDC, Berlin-Buch) and the hematologist Dr. Armin Rehm (MDC and Charit - Universittsmedizin Berlin) have now discovered why this is so. In a mouse model they developed, the researchers demonstrated that crosstalk between the cancer cells and a group of stromal cells in the spleen is crucial for cancer growth. At the same time they were able to block the entry of cancer cells into the spleen as well as their proliferation and thus identified new targets for future therapies in humans (Cancer Discovery, doi: 10.1158/2159-8290.CD-14-0096).*

A high number of malignantly mutated B lymphocytes is characteristic for CLL. B cells are normally an important component of the immune system. They produce antibodies with which the body combats pathogens (foreign antigens) and pathogenically modified structures. They acquire their final functionality in the germinal centers of lymphoid organs such as the spleen.

For this purpose, the healthy B cells migrate into the B-cell zone (B-cell follicle) of the spleen and lodge there in the stromal cell niche. There they interact with follicular dendritic cells (FDC). Unlike the similarly named classical dendritic cells, the FDC are not blood cells but rather stromal cells that form a network in the center of the B cell follicle. This stromal cell network lures B cells into it and exposes them to foreign antigens, which the B cells recognize and require for their activation and maturation. Only then are they fit for their task as antibody-producing immune cells.

The B cells enter the "training center" of the lymphoid organs via the messenger molecules of the immune system, the chemokines. They guide the B lymphocytes, which have a receptor on their surface for these chemokines. Leukemia cells, as malignant immune cells, also have these homing receptors on their cell surface to which these chemokines bind, thus enabling them to establish themselves in the stromal cell niche.

In their research project, Dr. Hpken and Dr. Rehm started from the hypothesis that the processes which normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle the survival and growth of malignant B cells may depend on the contact of the leukemia cells with the FDC.

In CLL, despite chemotherapy or radiotherapy, a relapse with renewed leukemic proliferation in lymphoid tissues can occur because the FDC usually survive chemotherapy or radiotherapy far better than the leukemia cells. If a few leukemia cells escape the therapy - physicians call this minimal residual disease - the FDC ensure that the leukemia cells within the B-cell follicles have optimal growth conditions and proliferate. Dr. Heinig, Dr. Hpken and Dr. Rehm have now elucidated this process in detail in a mouse model, which is similar to human CLL.

Intensive interaction between leukemia cells and the FDC

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Why CLL there are often relapses after treatment

05.12.2014 - (idw) Max-Delbrck-Centrum fr Molekulare Medizin (MDC) Berlin-Buch

Chronic lymphocytic leukemia (CLL) is among the most frequent leukemias affecting adults in Western countries. It usually occurs in older patients, does not cause any symptoms for a long time and is often only discovered by accident. Despite treatment, relapses frequently occur. The immunologists Dr. Kristina Heinig and Dr. Uta Hpken (Max Delbrck Center for Molecular Medicine, MDC, Berlin-Buch) and the hematologist Dr. Armin Rehm (MDC and Charit Universittsmedizin Berlin) have now discovered why this is so (Cancer Discovery, doi: 10.1158/2159-8290.CD-14-0096).* In a mouse model they developed, the researchers demonstrated that crosstalk between the cancer cells and a group of stromal cells in the spleen is crucial for cancer growth. At the same time they were able to block the entry of cancer cells into the spleen as well as their proliferation and thus identified new targets for future therapies in humans.

A high number of malignantly mutated B lymphocytes is characteristic for CLL. B cells are normally an important component of the immune system. They produce antibodies with which the body combats pathogens (foreign antigens) and pathogenically modified structures. They acquire their final functionality in the germinal centers of lymphoid organs such as the spleen.

For this purpose, the healthy B cells migrate into the B-cell zone (B-cell follicle) of the spleen and lodge there in the stromal cell niche. There they interact with follicular dendritic cells (FDC). Unlike the similarly named classical dendritic cells, the FDC are not blood cells but rather stromal cells that form a network in the center of the B cell follicle. This stromal cell network lures B cells into it and exposes them to foreign antigens, which the B cells recognize and require for their activation and maturation. Only then are they fit for their task as antibody-producing immune cells.

The B cells enter the training center of the lymphoid organs via the messenger molecules of the immune system, the chemokines. They guide the B lymphocytes, which have a receptor on their surface for these chemokines. Leukemia cells, as malignant immune cells, also have these homing receptors on their cell surface to which these chemokines bind, thus enabling them to establish themselves in the stromal cell niche.

In their research project, Dr. Hpken and Dr. Rehm started from the hypothesis that the processes which normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle the survival and growth of malignant B cells may depend on the contact of the leukemia cells with the FDC.

In CLL, despite chemotherapy or radiotherapy, a relapse with renewed leukemic proliferation in lymphoid tissues can occur because the FDC usually survive chemotherapy or radiotherapy far better than the leukemia cells. If a few leukemia cells escape the therapy physicians call this minimal residual disease the FDC ensure that the leukemia cells within the B-cell follicles have optimal growth conditions and proliferate. Dr. Heinig, Dr. Hpken and Dr. Rehm have now elucidated this process in detail in a mouse model, which is similar to human CLL.

Intensive interaction between leukemia cells and the FDC As the researchers in Berlin showed, the chemokine CXCL13 and its receptor CXCR5 on the surface of the leukemia cells are absolutely essential to ensure that the leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDC secrete the chemokine CXCL13. But unlike healthy B cells, the leukemia cells migrate directly across the marginal zone without taking a detour via the T-cell zone into the stimulating stromal cell niche of the B-cell follicle. When the researchers blocked the chemokine receptor CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

The FDC also provide growth factors that promote the proliferation of leukemia cells in the stromal niche. When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDC with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDC and dramatically reduce tumor growth.

The researchers thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is the blockade of the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle. This homing receptor, Dr. Rehm explained, is increased on the leukemia cells of patients with CLL. Second, via the blockade of the lymphotoxin-beta receptor on the FDC, the reciprocal crosstalk between the leukemia cells and the FDC promoting tumor proliferation is interrupted and thus the tumor development is likewise significantly reduced.

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Why CLL is Often Characterized by Relapses after Treatment New Targets for Therapy Identified

How viruses predispose to bacterial superinfection
Bergthaler Lab, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Vienna, Austria. WWW: http://www.cemm.oeaw.ac.at. http://www.bergthaler1.at.

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How viruses predispose to bacterial superinfection - Video

PUBLIC RELEASE DATE:

25-Nov-2014

Contact: Eva Schweng press@genomaustria.at 43-140-160-70051 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

In many countries, genome sequencing technology is now starting to become available in the clinic, where it helps to diagnose rare Mendelian diseases and contributes to personalized cancer therapy. The analysis of personal genomes also creates unprecedented opportunities for predictive health counseling, ancestry research, and many more applications that are just starting to emerge.

Despite the strong impact that personal genome sequencing is likely to have in healthcare and beyond, public discussions on the societal and ethical aspects of this technology are only starting in most countries. Genom Austria thus aims to create a forum for such discussions at the interface of science and society.

To make personal genome sequencing concrete and tangible for people in Austria, the project will provide interested volunteers with the opportunity to have their genomes sequenced with state-of-the-art technology and to share the data with the public.

Participation is entirely voluntary and restricted to individuals who demonstrate adequate understanding of the implications of making their personal genomes publicly available. In its initial phase in 2015, Genom Austria will sequence the personal genomes of 20 selected volunteers who have consented to publish their genomes and related information openly and freely on the Internet.

Genom Austria will also contribute to science education by organizing a school project and open science workshops. Furthermore, it creates a forum for interdisciplinary dialog among experts and the general public in areas such as biology, medicine, ethics, sociology, psychology, history, and the arts.

Internationally, Genom Austria builds upon the pioneering work of the Personal Genome Project at Harvard, which was initiated by George Church in 2005 and currently has over 3,000 participants. Genom Austria is a member of the Global Network of Personal Genome Projects. It also collaborates with other member sites in the USA, Canada, and the UK, in order to exchange best practices in personal genomics, open science, participatory research, and engagement with society.

Genom Austria is physically based at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and jointly run with the Medical University of Vienna.

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Genom Austria launches as a new member of the Personal Genome Project

Reston, Va. (PRWEB) November 24, 2014

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) has released a new infographic showing how certain types of cancer can be treated using nuclear medicine therapy. Targeted Cancer Treatment with Nuclear Medicine Therapy is a visual guide to radioisotope therapy, a personalized treatment where a radioactive drug compound seeks and destroys cancer cells.

The infographic highlights the types of cancer that can be treated with targeted radioisotope therapy (TRT)including thyroid, liver, prostate, neuroblastoma, non-Hodgkins lymphoma, and metastatic neuroendocrine tumors. It breaks down the specific radioisotope treatment for each area and its effectiveness in patients.

Radioisotope therapy is a precision treatment that is highly selectivekilling cancer cells and minimizing damage to healthy cellsand can be tailored to the unique molecular properties of the tumor. Virtually all radioisotope therapies are performed as outpatient procedures, and side effect rates are typically less than those of less focused treatments

To view the infographic, visit: http://www.snmmi.org/therapyinfographic

For more information about radioisotope therapies, visit: http://www.snmmi.org/factsheets.

About the Society of Nuclear Medicine and Molecular Imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to raising public awareness about nuclear medicine and molecular imaging, a vital element of todays medical practice that adds an additional dimension to diagnosis, changing the way common and devastating diseases are understood and treated and helping provide patients with the best health care possible.

SNMMIs more than 18,000 members set the standard for molecular imaging and nuclear medicine practice by creating guidelines, sharing information through journals and meetings and leading advocacy on key issues that affect molecular imaging and therapy research and practice. For more information, visit http://www.snmmi.org.

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SNMMI Introduces Infographic Explaining Nuclear Medicine Therapy

Littleton, CO (PRWEB) November 20, 2014

CereScan has been awarded a three-year term of accreditation in nuclear medicine as the result of a recent review by the American College of Radiology (ACR). Nuclear medicine is a branch of medical imaging that uses safe amounts of radioactive material, to diagnose and treat a variety of diseases, including many types of cancers, heart disease, and certain other abnormalities within the body and brain.

The ACR gold seal of accreditation represents the highest level of image quality and patient safety. It is awarded only to facilities satisfying the ACR Practice Guidelines and Technical Standards after a peer-review evaluation by independent, board-certified physicians and medical physicists who are experts in the field. Image quality, personnel qualifications, adequacy of facility equipment, quality control procedures, and quality assurance programs are all assessed. The findings are reported to the ACR Committee on Accreditation, which subsequently provides the practice with a comprehensive report they can use for continuous practice improvement.

ACR accreditation confirms the quality and validity of our Nuclear Medicine SPECT imaging procedures and will give our research partners and patients added confidence regarding our evaluations, said Dr. Richard Fort, President & COO of CereScan.

The ACR is a national professional organization serving more than 36,000 diagnostic/interventional radiologists, radiation oncologists, nuclear medicine physicians, and medical physicists with programs focusing on the practice of medical imaging and radiation oncology and the delivery of comprehensive health care services.

CereScan is the nations leader in providing statistically measured brain diagnostics based on a new generation of imaging software and SPECT (Single Photon Emission Computed Tomography) neuroimaging technologies. Since 2009, patients from all over the country and throughout the world have consulted Denver-based CereScan and its leading physicians concerning chronic neurological and psychiatric issues.

Referring and treating medical experts can rely on CereScan to offer differentiated diagnoses on a wide array of brain-based disorders including:

About CereScan

CereScan combines state-of-the-art SPECT and PET/CT brain imaging technology with a patient centered model of care to provide the highest level of neurodiagnostics anywhere. Using quantitative functional brain imaging, advanced imaging software, and an extensive library of clinical data, the CereScan medical team provides physicians with unmatched objective diagnostic information. CereScan helps patients and their physicians better understand the biological basis of their conditions. In a variety of legal settings, CereScan provides objective evidence to attorneys and their clients regarding traumatic and toxic brain injuries. For researchers, CereScan provides independent pre- and post-treatment measures of organic changes in the brain along with measures of symptoms related to the brain disorder of interest. For more information, please call (866) 722-4806 or visit http://www.CereScan.com.

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CereScan Earns ACR Nuclear Medicine Accreditation

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Newswise Bethesda, MD, November 19, 2014:

The Association for Molecular Pathology (AMP), the premier global, non-profit organization serving molecular testing professionals and leading education initiatives, discussions, and policy actions central to improving the development and application of molecular diagnostics, announced its 2014 award winners. Recipients of the Award for Excellence in Molecular Diagnostics, Jeffrey A. Kant Leadership Award, and AMP Meritorious Service Award were presented at the AMP Annual Meeting this past week in National Harbor, Maryland.

Uta Francke, MD, Professor Emeritus of Genetics, Pediatrics/Medical Genetics at Stanford University received the AMP Award for Excellence in Molecular Diagnostics and Aaron D. Bossler, MD, PhD, Director of Molecular Pathology Laboratory and Molecular Genetic Pathology Fellowship Program at the University of Iowa Hospitals and Clinics received the AMP Meritorious Service Award. Both awards were presented by AMP President, Elaine Lyon, PhD.

AMP's highest award, the Award for Excellence in Molecular Diagnostics recognizes the lifetime of special achievements by Dr. Franke across several fields in molecular diagnostics and medicine. The Meritorious Service Award recognizes Dr. Bosslers exceptional contributions, over time and often behind-the-scenes, to provide invaluable service to AMP, its membership, and to the profession overall, said Dr. Elaine Lyon. Were thrilled to honor both Drs. Francke and Bossler and their ongoing devotion to advancing the clinical practice of molecular medicine.

The Jeffrey A. Kant Leadership Award, which recognizes the exceptional leadership in advancing the mission and goals of AMP was presented by AMP President Elect, Janina Longtine, MD, The Mount Sinai Medical Center, to AMP President, Dr. Lyon, Medical Director, Genetics Division, ARUP Laboratories.

Were excited to recognize Dr. Lyon for her remarkable guidance and direction this past year. Shes played a pivotal role in helping AMP address key issues important to our membership, said Dr. Longtine.

About the Association for Molecular Pathology The Association for Molecular Pathology (AMP) was founded in 1994 to provide structure and leadership to what was, at the time, the newlyemerging field of molecular diagnostics. Through the efforts of its Board of Directors, Committees, Working Groups, and members, AMP has established itself as the primary resource for expertise, education, and collaboration on what is now one of the fastest growing fields in healthcare. AMP members influence policy and regulation on the national and international levels; ultimately serving to advance innovation in the field and protect patient access to high quality, appropriate testing.

AMP's 2,300+ members include individuals from academic and community medical centers, government, and industry; including, basic and translational scientists, pathologist and doctoral scientist laboratory directors, medical technologists, and trainees. AMP members span the globe with members in more than 45 countries and a growing number of AMP International Affiliate Organizations. The number of AMP members is growing rapidly; they are united by the goal of advancing the science and implementation of molecular and genomic laboratory medicine. For more information, please visit http://www.amp.org.

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The Association for Molecular Pathology Announces 2014 Award Recipients

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Newswise Bethesda, MD, November 13, 2014:

The Association for Molecular Pathology (AMP), the premier global, non-profit organization serving molecular testing professionals around the world announced the creation of an Informatics Subdivision to address the important role of this scientific discipline in molecular pathology.

AMP members associate with one or more subdivisions. Informatics joins Infectious Diseases, Hematopathology, Solid Tumors, and Genetics. By adding an Informatics Subdivision, AMP is creating a professional home for informatics experts who practice within the molecular pathology space, said AMP President, Elaine Lyon, PhD, The Informatics Subdivision will represent AMP members who indicate that they have a professional interest in informatics which is inclusive of bioinformatics, clinical informatics and other informatics as it relates to molecular and genomic pathology.

Alexis Carter, MD has been appointed to Chair the new Informatics Subdivision. She helped form and has been the Chair of AMPs Informatics Interest Group. When asked how important this new subdivision is to AMP, Dr. Carter replied the launch of the Informatics Subdivision is a major milestone for AMP. It publicly recognizes the importance of informatics to the practice of molecular and genomic pathology and provides members with a forum to address cross-cutting informatics issues and project which are not limited to a particular area of interest. The Informatics Subdivision will help promote good informatics practices, research and discovery and, through collaboration, bolster the informatics efforts of the other subdivisions.

During the 2014 AMP Annual Meeting, Informatics experts will be highlighted in a symposia titled Bridging the Gaps between Clinical Informatics and Bioinformatics and hold a luncheon meeting with attendees interested in learning more about informatics. The AMP Informatics Subdivision allows members the increased organizational support to continue serving the clinical laboratory community by ensuring that the big data generated in AMP member labs, particularly in next generation sequencing, is translated into results that enable the delivery of precision medicine to their patients, said Dr. Lyon, look for enhanced educational offerings, volunteer opportunities and new projects regarding informatics to come from AMP throughout the year and next year during the Annual Meeting.

ABOUT AMP: The Association for Molecular Pathology (AMP) was founded in 1994 to provide structure and leadership to what was, at the time, the newly-emerging field of molecular diagnostics. Through the efforts of its Board of Directors, Committees, Working Groups, and members, AMP has established itself as the primary resource for expertise, education, and collaboration on what is now one of the fastest growing fields in healthcare. AMP members influence policy and regulation on the national and international levels; ultimately serving to advance innovation in the field and protect patient access to high quality, appropriate testing.

AMP's 2,300+ members include individuals from academic and community medical centers, government, and industry; including, basic and translational scientists, pathologist and doctoral scientist laboratory directors, medical technologists, and trainees. AMP members span the globe with members in more than 45 countries and a growing number of AMP International Affiliate Organizations. The number of AMP members is growing rapidly; they are united by the goal of advancing the science and implementation of molecular and genomic laboratory medicine. For more information, please visit http://www.amp.org.

CONTACT: Catherine Davidge cdavidge@amp.org 301-634-7400

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AMP Launches Informatics Subdivision

Sir David Weatherall on advances in malaria research
Leading expert on inherited haematological disorders, Sir David Weatherall, discusses how malaria research has changed during his 50 year career, and future directions. Weatherall founded...

By: BioMedCentral

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Sir David Weatherall on advances in malaria research - Video

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Newswise Scientists at the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) and their collaborators have developed a scoring scheme that predicts the ability of cancer cells to spread to other parts of the body, a process known as metastasis. This system, which is the first of its kind, opens up the possibility to explore new treatments that suppress metastasis in cancer patients. The findings were published in EMBO Molecular Medicine in September.

Led by Professor Jean Paul Thiery, Senior Principal Investigator, and Dr Ruby Huang, Principal Associate, both from CSI Singapore, the scientists developed a scoring scheme which monitors the epithelial-mesenchymal transition (EMT) mechanism. This process was shown to play a role in a large number of cancer-related events, including cancer invasion, metastasis, and chemo-resistance. To date, there are no existing tools to systematically quantify the EMT status of tumours. The newly-developed EMT scoring is thus a promising, versatile tool for investigating EMT roles and dynamics in the progression, treatment response and survival across different types of cancer. It can also be integrated with other molecular tests, such as the detection of mutations of cancer genes, to help identify patients at higher risks for treatment failure and decreased survival.

EMT mechanism and cancer metastasis

Cancer metastasis is responsible for 90 per cent of cancer deaths. One of the mechanisms of metastasis is through the EMT process, where tumour cells lose adhesion contacts with their neighbouring cells at the primary tumour site, and gain the ability to move to a secondary site. The ability to stay in tight contact is an important feature of epithelial cells whereas the ability to gain movement is a characteristic of mesenchymal cells. Tumour cells which undergo the EMT process lose their epithelial features and gain invasive, migratory properties typical of mesenchymal cells.

The EMT mechanism has a varying impact on different populations of cancer cells as they respond differently to the EMT cues. Not every cancer cell will undergo the same degree of loss of cell adhesion ability or gain the ability to move spontaneously, which is known as motility. As a result, tumours from different patients will exhibit a wide range of differences in the status of their EMT. To determine with precision the EMT status of the tumour, the research team developed a quantitative modelling system.

How the EMT scoring scheme was developed

In this study, the researchers utilised a total of 13,000 samples from publicly available databases containing gene expression information for more than 15 different types of cancers. A computational modelling scheme of EMT was established to define tumours having the most epithelial features and tumours having the most mesenchymal features. Subsequently, the tumours were rated on a continuous spectrum of different EMT scores. Tumours with mixed epithelial and mesenchymal features are at the in-between state. This transitional state signifies cancer cell populations that might become truly mesenchymal. Patients who have tumours at this intermediate state may be at higher risks compared to those with tumours at the epithelial state.

The clinical information from the databases, including patient survival and treatment responses, was compared against the EMT scoring scheme. The research team showed that the EMT scoring they developed has a good correlation with previously published, cancer-specific EMT signatures. They used this scoring scheme to establish an EMT spectrum across various cancers and noted good correlation between cancer cell lines and tumours. The scientists concluded that this scoring scheme may enable the objective and systematic investigation of EMT in cancer progression, survival and throughout the clinical response to therapy.

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Scientists Develop Scoring Scheme That Predicts Ability of Cancer Cells to Spread to Other Parts of the Body