#Uncovering Genetic Factors in Leukemia Northwestern Medicine scientists have discovered how a gene linked to leukemia functions,
a finding that may have important implications for children with Down syndrome who have a higher risk of developing the blood cancer.
Patients with Down syndrome have three copies of chromosome 21 in their cells. Theye also 20 times more likely to contract childhood B-cell acute lymphoblastic leukemia than the general population,
making that chromosome an important avenue for researching the genetic basis of the cancer. major goal of my laboratory is to identify the specific gene or genes on chromosome 21 responsible for the increased incidence of leukemia in this population,
said study senior author John Crispino, Ph d.,Robert i. Lurie, M d, . and Lora S. Lurie Professor in Medicine-Hematology/Oncology and Biochemistry and Molecular genetics,
and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. In previous work, Crispino and colleagues found that a gene on chromosome 21 called DYRK1A contributes to the development of leukemia.
Now, in a paper published in the Journal of Experimental Medicine, they expanded on that research by studying the gene in depth.
Specifically, they wanted to understand how DYRK1A plays a role in blood cell production. Over-production of immature lymphocytes is a hallmark of acute lymphoblastic leukemia.
With first author Benjamin Thompson M d.,Ph d.,a postdoctoral fellow, Crispino generated a mouse model that lacks DYRK1A in blood cells.
They saw that two types of white blood cells called B and T lymphocytes were blocked severely from developing without the gene.
Because they have extra copies of chromosome 21, children with Down syndrome have more DYRK1A than usual. his finding is exciting to us
because human B-cell acute lymphoblastic leukemia cases show increased levels of DYRK1A, said Crispino. he results suggest that DYRK1A may be a novel target for therapy in this form of leukemia.
This work was supported by a National institutes of health grant, the Samuel Waxman Cancer Research Foundation, the Leukemia and Lymphoma Society, the Rally Foundation and the Bear Necessities Foundation e
#Sleep Position May Impact Brain Ability to Clear Waste How you sleep on your side, on your back,
or face down is thought usually of as a personal preference, but body position might actually affect how efficiently the brain clears waste, according to new research out of Stony Brook University.
The findings could have implications for the prevention of neurodegenerative diseases that are characterized by plaque buildup.
Helene Benveniste, M d.,Ph d.,lead investigator and professor in the department of Anesthesiology and Radiology at Stony Brook University School of medicine in New york told Bioscience Technology that it is too early to comment on humans,
but n animals it is clear that the lateral position increases waste removal compared to other body positions. he research was published Tuesday in the Journal of Neuroscience.
Benveniste told Bioscience Technology. Read More: Researchers Discover Missing Link Between Brain and Immune Systemshe explained how the system lushesout waste:
which are critical for how efficiently the glymphatic system can get rid of waste because it allows water to move fast through the brain tissue so as to lushwaste products out efficiently.
Maiken Nedergaard, Ph d.,at the University of Rochester, a co-author on the study, previously demonstrated that the glymphatic pathway works better during sleep
or when one is under general anesthesia, compared to wakefulness. Since people change body positions during sleep,
Benveniste told Bioscience Technology. Benveniste and colleagues used dynamic contrast magnetic resonance imaging (MRI) to image the glymphatic pathway at work in rodentsbrains.
Three positions lateral (side), prone (down), and supine (up) were imaged using the method, along with kinetic modeling to quantify the CSF-ISF exchange rates in the rodents. he analysis showed us consistently that glymphatic transport was most efficient in the lateral position
when compared to the supine or prone positions, said Benveniste. ecause of this finding, we propose that the body posture
or cause brain diseases. o why is the glymphatic system more effective when sleeping in the lateral position?
and therefore overall waste clearance is diminished. his could have implications for prevention of certain neurodegenerative diseases. e speculate that
or postpone onset of neurodegenerative diseases such as Alzheimer, Benveniste told Bioscience Technology. Imaging testing in humans is needed still.
Up next Benveniste and colleagues are working to study how the glymphatic system can be controlled
and to prevent neurodegenerative diseases
#Capturing Cell Growth in 3d Replicating how cancer and other cells interact in the body is somewhat difficult in the lab. Biologists generally culture one cell type in plastic plates,
which doesn represent the dynamic cell interactions within living organisms. Now MIT spinout AIM Biotech has developed a microfluidics device based on years of research that lets researchers co-culture multiple cell types in a 3d hydrogel environment that mimics natural tissue.
Among other things, the device can help researchers better study biological processes, such as cancer metastasis, and more accurately capture how cancer cells react to chemotherapy agents,
said AIM Biotech cofounder Roger Kamm, the Cecil H. Green Distinguished Professor in MIT departments of mechanical engineering and biological engineering. f you want realistic models of these processes,
you have to go to a 3d matrix, with multiple cell types to see cell-to-cell contact
and let cells signal to each other, Kamm said. one of those processes can be reproduced realistically in the current cell-culture methods. esigned originally for Kamm lab,
the new commercial device is a plastic chip with three chambers: a middle chamber for hydrogel and any cell type, such as cancer cells or endothelial cells (which line blood vessels),
and two side channels for culturing additional cell types. The hydrogel chamber has openings along each side,
Cancer drugs or other therapeutics can then be added to better monitor how cells respond in a patient.
including studies of cancer and stem cell research, neuroscience, and the circulatory system. This month AIM Biotech will begin deploying the commercial devices to 47 research groups in 13 countries for user feedback.
Other systems for 3-D cell culturing involve filling deep dishes with hydrogels. Because of the distance these dishes must be kept from the microscope,
AIM Biotech devices, on the other hand, he said, can be put directly under the microscope like a traditional plate,
but surface tension keeps it from leaking into the side channels, while still allowing the cells to enter. hat the key,
surface tension drives where it goes, so we decided to use surface tension to our advantage. oon,
Kamm was using the device in his lab: In a 2011 study, researchers in his group discovered that breast cancer cells can break free from tumors
and travel against flows normally present inside the tissue; in a 2012 study, they found that macrophages a type of white blood cells were key in helping tumor cells break through blood vessels.
And in a 2013 study, Kamm was able to capture high-resolution videos of how the cells escape through minute holes in endothelial walls and travel through the body. eople try to do this in vivo,
but you can possibly get the kind of resolution you can within a microfluidic system, Kamm said.
After securing seed funding from Draper Laboratory, the National institutes of health, and SMART, Kamm brought the idea for the device to Innovation Teams (i-Teams),
where MIT students from across disciplines flesh out strategies for turning lab technologies into commercial products.
or something that is useful in the clinic, Kamm said. ne of the i-Teamsrecommendations was to develop systems for researchers.
IM Biotech launched in Singapore in 2012, under current CEO Kuan Chee Mun, who Kamm met through SMART.
is studying cancer metastasis as demonstrated with his own work to develop better treatments. In the body, cells break loose from a tumor
and migrate through tissue into the blood system, where they get stuck in the small blood vessels of a distant organ
or adhere to vessel walls. Then they can escape from inside the vessel to form another tumor.
AIM Biotech microfluidics device produces a similar microenvironment: When endothelial cells are seeded into the side channels or the central gel region,
they form a 3-D network of vessels in the hydrogel. Tumor cells can be introduced,
flowing naturally or getting stuck in the vessels. Kamm said this environment could be useful in testing cancer drugs,
as well as anti-angiogenesis compounds that prevent the development of blood vessels, effectively killing tumors by cutting off their blood supply.
While many such treatments have shown limited success, here a lot of interest in screening for new ones,
AIM Biotech may offer to more accurately screen cancer drugs for pharmaceutical companies. In fact, he said, AIM Biotech recently discovered that its devices revealed discrepancies in some clinically tested therapeutics.
In a study published in Integrative biology, MIT researchers used Kamm's microfluidics technology to screen several drugs that aim to prevent tumors from breaking up
and dispersing throughout the body. Results indicated that the level of drugs needed was often two orders of magnitude higher than predictions based on traditional assaid. o there no way to effectively predict, from the 2-D assaid,
what the efficacy of a particular drug was, Kamm said. If pharmaceutical companies were to winnow potential drugs from,
#Researchers Uncover New Pathways for Diabetes Research A new Florida State university study is changing how scientists look at diabetes research
and the drugs used to treat the disease. In the Proceedings of the National Academy of Sciences, Associate professor of Chemistry Brian Miller and postdoctoral researcher Carl Whittington report that a key enzyme involved in the body response to glucose can essentially be corrupted by a new mechanism that scientists
have not seen before. This discovery shifts the current understanding of how this enzyme participates in certain diseases,
including hyperinsulinemia and diabetes. n principle, our findings could open the door for a new approach to treat diseases of glucose homeostasis, such as diabetes,
Miller said. The enzyme is called glucokinase and serves as the body primary glucose sensor as it relays signals in the pancreas
and liver telling other areas of the body to take up and process glucose. When that enzyme function is impaired,
a person often suffers from diabetes, or other glucose-related illnesses. Because of its role in the cell, glucokinase has received considerable attention by pharmaceutical companies as a potential therapeutic target.
More than a decade ago researchers uncovered drugs that activate the enzyme, which offered hope for treating type 2 diabetes.
The focus, however, was on only one way that the enzyme was activated. Miller and Whittington research showed there is actually another avenue for activation. glucokinase The work showed that this new activation mechanism is operational in clinically characterized disease forms of the enzyme.
Activation of glucokinase is known a cause of hyperinsulinemia, a disease characterized by over secretion of insulin even in the absence of glucose,
often leading to insulin resistance. lucokinase-associated hyperinsulinemia varies in severity depending upon the level of activation of the enzyme,
Whittington said. ur study is important because it sheds new light onto how the functional properties of the enzyme can manifest in disease.
In addition to the direct medical implications, the new study also shifts a fundamental principle of biochemistry known as allostery.
Allostery is one way in which the function of proteins in the cell are controlled and regulated.
Previously, scientists believed that allosteric regulation of glucokinase depended on strict structural transitions of the biomolecule.
In collaboration with Professor Rafael Brüschweiler of The Ohio State university the FSU researchers used a method known as nuclear magnetic resonance,
and disease-variant forms of glucokinase. e can see which parts of the enzyme move at what rate and speed,
It may also generate renewed interest in glucokinase from the pharmaceutical arena. According to the American Diabetes Association, 29.1 million Americans have diabetes
and case numbers are expected to rise. There have been some complications with diabetes drugs that activate glucokinase.
As a result, some companies have started looking at other options to treat the disease, and the new findings might aid this process.
This research was funded by the National institutes of health, the National Science Foundation and the American Heart Association m
#Degenerating Neurons Respond to Gene therapy Treatment for Alzheimer Disease Degenerating neurons in patients with Alzheimer disease (AD) measurably responded to an experimental gene therapy in
report researchers at University of California, San diego School of medicine in the current issue of JAMA Neurology.
axonal sprouting and activation of functional markers, said lead author Mark H. Tuszynski, M d.,Ph d.,professor in the Department of Neurosciences, director of the UC San diego Translational Neuroscience
Institute and a neurologist at VA Medical center, San diego. The findings are derived from postmortem analyses of 10 patients who participated in phase
Administering NGF directly into the brain a first for treating of an adult neurodegenerative disorder was done for two reasons.
The gene therapy approach has progressed since to phase II trials at multiple test sites. Results have not yet been released.
The published findings come from AD patients who participated in safety trials from March 2001 to October 2012 at UC San diego Medical center.
The participants lived one to 10 years after treatment. ll of the Alzheimer disease brains showed anatomical evidence of a growth response to the growth factor,
said Tuszynski, who has been principal investigator for the trials from the beginning. his means that growth factors as a class consistently result in activation of dying cells in human neurodegenerative disorders. uszynski said the findings indicate NGF is extended safe over periods and that it merits continued
testing as a potential AD treatment. Currently, there is no effective treatment or cure for AD..
Funding support for this research came, in part, from the National institutes of health, the Veterans Health Administration, the Alzheimer Association, the Donald and Darlene Shiley Family Trusts and Ceregene, Inc. Disclosure:
#Researchers Use DNA'Clews'to Shuttle CRISPR-Cas9 Gene-editing Tool into Cells Researchers from North carolina State university and the University of North carolina at Chapel hill have created for the first time
and used a nanoscale vehicle made of DNA to deliver a CRISPR-Cas9 gene-editing tool into cells in both cell culture and an animal model.
But for Cas9 to do its work, it must first find its way into the cell.
This work focused on demonstrating the potential of a new vehicle for directly introducing the CRISPR-Cas9 complex-the entire gene-editing tool-into a cell."
"said Chase Beisel, co-senior author of the paper and an assistant professor in the department of chemical and biomolecular engineering at NC State."
instead of turning the cell into a Cas9 factory, we can ensure that the cell receives the active editing system
"said Zhen Gu, co-senior author of the paper and an assistant professor in the joint biomedical engineering program at NC State and UNC-CH."
it is highly biocompatible. It also self-assembles, which makes it easy to customize.""The nanoclews are made of a single, tightly-wound strand of DNA.
and Ph d. student in Gu's lab. When the nanoclew comes into contact with a cell,
But the nanoclews are coated with a positively charged polymer that breaks down the endosome, setting the nanoclew free inside the cell.
To test the nanoclew CRISPR-Cas delivery system, the researchers treated cancer cell cultures and tumors in mice.
"And they did work. More than a third of cancer cells stopped expressing the fluorescent protein, "Beisel said."
and additional work needs to be done -but it's very promising, "Gu said. The work was supported by the NC Tracs, NIH's Clinical and Translational Science Awards at UNC-CH,
and by National Science Foundation n
#Study in Mice Suggests How Anesthesia May Fight Lung Infections In use for more than a century,
inhaled anesthetics like nitrous oxide and halothane have made modern surgery possible. Now, in experiments in mice, researchers at Johns Hopkins and elsewhere have added to evidence that certain so-called"volatile"anesthetics--commonly used during surgeries--may also possess powerful effects on the immune system that can combat viral and bacterial infections in the lung,
including influenza and pneumonia. A report on the experiments is published in the September 1 issue of the journal Anesthesiology.
The Johns Hopkins and University of Buffalo research team built its experiments on previous research showing that children with upper viral respiratory tract infections who were exposed to the anesthetic halothane during minor surgical procedures had significantly less respiratory symptoms
and a shorter duration of symptoms compared with children who did not receive halothane during surgeries.
To examine just how some inhaled anesthetic drugs affect viral and bacterial infections, Krishnan Chakravarthy, M d.,Ph d.,a faculty member at the Johns Hopkins Institute of Nanobiotechnology and a resident physician in the department of anesthesiology and critical
care medicine at Johns hopkins university School of medicine and Paul Knight, M d.,Ph d.,a professor of anesthesiology at the University of Buffalo School of medicine and Biomedical sciences, along with others
exposed mice to both influenza virus and Streptococcus pneumoniae bacteria. The team discovered that giving the animals volatile anesthetics, such as halothane,
led to decreased bacterial burden and lung injury following infection. The researchers report that the anesthetics augmented the antibacterial immune response after influenza viral infection by blocking chemical signaling that involves type I interferon,
a group of proteins that help regulate the activity of the immune system. Using a combination of genetic, molecular,
and knockout animal techniques, the researchers found that animals that were exposed to halothane had 450-fold less viable bacteria compared with non-halothane exposed animals with respect to the initial inoculum dose,
and astoundingly, treatment made it as if the animals were infected never with a prior influenza virus. The investigators report that symptoms of piloerection (involuntary bristling of hairs of the skin), hunched posture, impaired gait, labored breathing, lethargy,
and weight loss (equal to or greater than 10 percent of body weight at the time of infection) were significantly less in mice exposed to halothane
and then infected with flu and S. pneumoniae. Similar results, they say, were seen in mice bred to lack the receptor for type
I interferon and not exposed to halothane before infection.""Our study is giving us more information about how volatile anesthetics work with respect to the immune system,
"said Chakravarthy.""Given that these drugs are the most common anesthetics used in the operating room,
suggest that volatile anesthetics may someday be helpful for combatting seasonal and pandemic influenza, particularly when there are flu vaccine shortages or limitations."
"A therapy based on these inhaled drugs may help deal with new viral and bacterial strains that are resistant to conventional vaccines
and treatments and could be a game changer in terms of our preparedness for future pandemics and seasonal flu outbreaks because it's focusing on host immunity,
"said Chakravarthy.""We hope our study opens the door to the development of new drugs
and therapies that could change the infectious disease landscape.""The investigators say they are currently testing an oral small molecule immune modulator in phase 2 clinical trials that acts like volatile anesthetics to help reduce secondary infections after someone becomes sick with the flu.
This study was supported by the following National institutes of health grants: National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious diseases Extramural Activities and the National Institute on Deafness and other Communication Disorders s
#Study Reveals the Genetic Start-up of a Human Embryo An international team of scientists led from Sweden's Karolinska Institutet has mapped for the first time all the genes that are activated in the first few days of a fertilized human egg.
The study, which is being published in the journal Nature Communications, provides an in depth understanding of early embryonic development in human
-and scientists now hope that the results will help finding for example new therapies against infertility.
At the start of an individual's life there is a single fertilized egg cell. One day after fertilization there are two cells
professor at the Department of Biosciences and Nutrition at Karolinska Institutet and also affiliated to the Scilifelab facility.
'but are in fact important in regulating gene expression. In the current study, the researchers show that the newly identified genes can interact with the'junk DNA,
We identified novel factors that might be used in reprogramming cells into so-called pluripotent stem cells for possible treatment of a range of diseases,
and potentially also in the treatment of infertility",said Outi Hovatta, professor at Karolinska Institutet's Department of Clinical Science, Intervention and Technology,
The work was supported by the Karolinska Institutet Distinguished Professor Award the Swedish Research Council, the Strategic Research Program for Diabetes funding at Karolinska Institutet, Stockholm County, the Jane & Aatos Erkko Foundation, the Instrumentarium Science Foundation,
and the Åke Wiberg and Magnus Bergvall foundations. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) X
#Bacterial Study Points to Possible New MRSA Vaccine New research led by NYU Langone has uncovered why a particular strain of Staphylococcus aureusnown as HA-MRSAECOMES more deadly than other variations.
These new findings open up possible new pathways to vaccine development against this bacterium, which the Centers for Disease Control and Prevention said accounts for over 10,000 deaths annually, mostly among hospital patients.
In a series of experiments in mice and in human immune cells in the lab, recently published in the journal Nature Communications online September 2,
the NYU Langone team found that the presence or absence of dueling toxins, or bacterial poisons, appears to explain the major difference between HA-MRSA,
and its less virulent and more common, community-based cousin, CA-MRSA, the two main types of MRSA infection.
and poison immune system white blood cells meant to fight the bacterial infection, but LUK-PV is secreted only by community-acquired MRSA,
According to study senior investigator and NYU Langone microbiologist Victor Torres, Phd, the newly discovered competing or ntagonisticrelationship between the two bacterial toxins helps explain how community-acquired MRSA is far more widespread and less deadly than hospital
Torres also said that these study results challenge the current mindset for finding a vaccine against staphylococcal infections,
an associate professor at NYU Langone. e have to take a broader view of the pathogen
in order to develop an effective vaccine. n a separate set of laboratory experiments previously described in the journal Cell Host & Microbe online August 27, researchers at Torreslaboratory and colleagues in The netherlands, France,
and Australia showed how LUK-ED attacked red blood cells to obtain nutrients, most notably iron, essential for its rapid growth and infection.
The international team found that the toxin split apart the red blood cells by attaching itself first to their so-called Duffy antigen protein receptor
His team next plans to analyze the biological mechanisms by which LUK-PV and LUK-ED target, attach
and red blood cells, making their host more vulnerable to infection. Other experiments are set to determine how widespread bacteremia from staphylococcal infections actually shuts down the mammalian body
causing death. Torres also has plans to study groups of Africans known to be genetically deficient in Duffy antigens and, hence, more resistant to malaria,
to see if they are resistant to staphylococcal infection, as well y
#Researchers Find New Clue to Halting Leukemia Relapse A protein domain once considered of little importance may be key to helping patients who are fighting acute myeloid leukemia (AML) avoid a relapse.
Researchers at Rice university, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, have made a small molecule that could deliver a one-two punch to proteins that resist chemotherapy
in patients with AML. The protein, called STAT3, interferes with chemotherapy by halting the death of cancerous cells
and allowing them to proliferate. The molecule discovered at Rice locates and then attacks a previously unknown binding site on STAT3,
disrupting its disease-promoting effects. The new work led by Rice chemist Zachary Ball, Baylor pediatrician Michele Redell and MD Anderson oncologist David Tweardy appears this week in the journal Angewandte Chemie.
The discovery and exploitation of this new drug target was made possible by an earlier discovery by Ball lab. That finding enabled researchers to identify, on a molecular level,
the target of action for drug molecules by using rhodium-based inorganic complexes that recognize specific folds in a protein chain
and catalyze minute changes in those sequences, creating a agfor later analysis. The STAT3 protein it stands for ignal transducer and activator of transcription 3is a suspected factor in the relapse of nearly 40 percent of children with AML.
and modifies an inhibitor-binding site on the protein coiled coil literally protein coils coiled around each other
to the modified site. his is the confluence of two ideas wee been working on around
and other cancers helps the cancer cells survive chemotherapy, so any new strategy we can develop to stop that process could mean real benefit for our patients,
who is also part of the leukemia and lymphoma teams at Texas Children Hospital. Ball said STAT3 has been a target for scientists trying to shut down cancer cells.
TAT fits in the broad category of what are called ndruggable protein-protein interactions. There a large surface area with weak interactions for which we have failed typically to find good drugs,
from a medicinal perspective, is that this compound also works in a mouse model, he said. ll the other compounds worked in cells,
Ball said. he discovery raises new questions about STAT3 biology and points the way to future anticancer approaches, including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents,
he said. The National institutes of health, the Robert A. Welch Foundation, the National Science Foundation and the Virginia and L. E. Simmons Family Foundation supported the research a
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