#New Hope for ALS Sufferers Researchers at the CHUM Research center and the University of Montreal report the discovery of a previously unknown link between the immune system and the death of motor neurons in Amyotrophic lateral sclerosis (ALS), also known as Lou gehrig's disease.
The scientists believe their research paves the way to an entirely new approach for finding a drug that can cure
or at least slow the progression of such neurodegenerative diseases as ALS, Alzheimer's, Parkinson's, and Huntington's diseases.
and trigger the disease, said Alex Parker, Ph d.,CHUM researcher and associate professor in the department of neuroscience at the University of Montreal.
Amyotrophic lateral sclerosis is a neuromuscular disease that attacks neurons and the spinal cord. Those affected gradually become paralyzed and typically die less than five years after the onset of symptoms.
If a mutation occurs in one of them, the person develops the disease. Scientists introduced a mutated human gene (TDP-43 or FUS) into C. elegans.
The worms became paralyzed within about 10 days. The challenge was to find a way of saving them from certain death. e had the idea of modifying another gene (tir-1) known for its role in the immune system,
lead investigator and doctoral student under the supervision of Dr. Parker. Results were remarkable noted Veriepe. orms with an immune deficit resulting from the tir-1 gene's mutation were in better health
and suffered far less paralysis, she added. This study highlights a never previously suspected mechanism:
even if the C. elegans worm has a rudimentary immune system, that system triggers a misguided attack against the worm's own neurons. he worm thinks it has a viral or bacterial infection and launches an immune response.
But the reaction is toxic and destroys the animal's motor neurons, Dr. Parker explained. Is the same scenario at work with people?
Most likely believes Dr. Parker. The human equivalent of the tir-1 genearm1as proved crucial to the nervous system's integrity.
This makes the TIR-1 protein (or SARM1 in humans) an excellent therapeutic target for development of a medication.
because we caused the disease. This allows us to administer treatment very early in the worm's life.
But ALS is a disease of aging, which usually appears in humans around the age of 55.
But we have demonstrated clearly that blocking this key protein curbs the disease's progress in this worm
#Pall Acquires Innovative Acoustic Wave Separation Technology Pall obtained an exclusive license for acoustic wave separation (AWS), a disruptive technology from Flodesign Sonics for cell culture clarification for both
thus streamlining a challenging step in the biologics manufacturing process within a small operating footprint. The technology will complement Pall's STAXTM depth filtration products to enable continuous clarification of cell culture, enabling integration of the bioreactor with downstream processing
according to Michael Egholm, president of Pall Biopharmaceuticals. The AWS technology works by applying acoustic forces across a flow channel to generate a three-dimensional standing wave.
When a cell culture passes through the flow channel, the cells are trapped at the nodes of the acoustic waves
and then aggregate, culminating in their precipitation from suspension as their buoyancy decreases. Important features are no temperature increase, no damage to cells or proteins,
and the process works in a robust manner at high yields, notes Egholm, who adds that the integration of the AWS technology expands the portfolio of continuous bioprocessing
and single-use products offered by Pall. The company recently acquired the Biosmb multicolumn continuous chromatography platform from Tarpon Biosystems."
"This approach helps to bridge the critical gap between bioreactor and the downstream processing train,"points out Egholm."
"The AWS products will eliminate the reliance on centrifugation for cell culture clarification, and will provide a continuous feed stream for direct integration with the Biosmb platform.
Pall plans to introduce a single-use product line using AWS technology for the clarification of cell culture at both bench scale
and GMP scale to match pilot and production bioreactor volumes, with predictable and reproducible performance over a wide range of cell densities. e
#New Molecular Inhibitor Stimulates Tissue Regeneration The ability to create agents that promote tissue regeneration would have overwhelmingly beneficial implications within the clinical setting.
Now, a collaboration of researchers from UT Southwestern Medical center, Case Western Reserve University, and the University of Kentucky has identified an enzyme they say regulates tissue regeneration.
The scientists believe that the inhibition of this enzyme could accelerate tissue recovery from injury, disease,
or even various surgical procedures in multiple organ systems. Investigators found that by blocking the enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH) in mice with a new compound called SW033291
"Patients undergoing bone marrow transplants and patients with colitis may benefit from this approach, "stated co-author James Willson, M d,
. associate dean of oncology programs at UT Southwestern Medical center and co-author on the current study.""We propose that SW033291 will be useful in accelerating recovery of bone marrow cells following a bone marrow transplant
and may also be a treatment for colitis."The findings from this study were published recently in Science through an article entitled"Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration."
"15-PDGH is a key enzyme responsible for the biological inactivation of a group of signaling molecules, called eicosanoids,
which are formed from the oxidation of long-chain fatty acid molecules. A subclass within the eicosanoids, prostaglandins are physiologically active lipid compounds that have diverse hormone-like effects in humans.
The new SW033291 molecule works by targeting a 15-PGDH-regulated pathway of bone marrow regeneration in
"explained co-author Dr. Joseph Ready, Ph d.,professor of biochemistry and member of the Simmons Cancer Center at UT Southwestern Medical center.
the collaborators wanted to investigate the therapeutic potential of 15-PGDH inhibitors in tissue regeneration.
the drug-treated mice showed a six-day-faster reconstitution of hematopoiesis after bone marrow transplantation. tudying mouse models,
our observations identify 15-PGDH as a therapeutic target and provide a chemical formulation, SW033291, that is an active 15-PGDH inhibitor in vivo and that potentiates repair in multiple tissues.
SW033291 or related compounds may merit clinical investigation as a strategy to accelerate recovery after bone marrow transplantation and other tissue injuries. e
#Novel Epigenetic Technique Opens Door to Combatting Virulent Strains of Bacteria Researchers from the Icahn School of medicine at Mount sinai say they have developed a novel method to more precisely analyze bacterial populations
and reveal epigenetic mechanisms that can drive virulence. The new technique holds the promise of a potent new tool to offset the growing challenge of antibiotic resistance by bacterial pathogens, according to the team.
The study (ingle molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes appears in Nature Communications,
and conducted in collaboration with New york University Langone Medical center and Brigham and Women Hospital of Harvard Medical school.
Individual DNA bases can be modified chemically with significant functional consequences. In the bacterial kingdom, the most prevalent base modifications are in the form of DNA methylations, specifically to adenine and cytosine residuals.
Beyond their participation in host defense, increasing evidence suggests that these modifications also play important roles in the regulation of gene expression, virulence,
which can collect data on base modifications simultaneously as it collects DNA sequence data. The instrument single molecule, real-time sequencing enables the detection of N6-methyladenine and 4-methylcytosine,
existing methods for studying bacterial methylomes rely on a population-level consensus that lack the single-cell resolution required to observe epigenetic heterogeneity. e created a technique for the detection
We found that a typical clonal bacterial population that would otherwise be considered homogeneous using conventional techniques has epigenetically distinct subpopulations with different gene expression patterns"said Gang Fang, Ph d,
. assistant professor of genetics and genomics at the Icahn School of medicine at Mount sinai and senior author of the study. iven that phenotypic heterogeneity within a bacterial population can increase its advantage of survival under stress conditions such as antibiotic treatment,
this new technique is quite promising for future treatment of bacterial pathogens, as it enables de novo detection and characterization of epigenetic heterogeneity in a bacterial population.
The researchers studied seven bacterial strains, demonstrating the new technique reveals distinct types of epigenetic heterogeneity.
For Helicobacter pylori, a pathogenic bacterium that colonizes over 40%of the world population and is associated with gastric cancer,
the team discovered that epigenetic heterogeneity can quickly emerge as a single cell divides, and different subpopulations with distinct methylation patterns have distinct gene expressions patterns.
This may have contributed to the increasing rate of antibiotic resistance of H. pylori. he application of this new technique will enable a more comprehensive characterization of the functions of DNA methylation and their impact on bacterial physiology.
Resolving nucleotide modifications at the single molecule, single nucleotide level, especially when integrated with other single molecule-or single cell-level data,
such as RNA and protein expression, will help resolve regulatory relationships that govern higher order phenotypes such as drug resistance,
. founding director of the Icahn Institute and professor of genomics at the Icahn School of medicine at Mount sinai. he approach we developed can also be used to analyze DNA VIRUSES and human MITOCHONDRIAL DNA,
both of which present significant epigenetic heterogeneity. c
#Novel Tissue Scaffold Technique Marks Milestone in Regenerative medicine Researchers say they have developed a new tissue scaffold technology that could one day enable the engineering of large organs.
The team from led by the Universities of Bristol and Liverpool has shown that it is possible to combine cells with a special scaffold to produce living tissue in the laboratory.
It is hoped this can then be implanted into patients as a way of replacing diseased parts of the body.
and paint the cells without affecting their biological function, said Adam Perriman, Ph d.,from the University of Bristol school of cellular and molecular medicine."
"However, we were surprised and delighted to discover that we could deliver the necessary quantity to the cells to supplement their oxygen requirements.
It's like supplying each cell with its own scuba tank, which it can use to breathe from
when there is not enough oxygen in the local environment.""The team's study (rtificial membrane-binding proteins stimulate oxygenation of stem cells during engineering of large cartilage tissue,
but also for other tissue such as cardiac muscle or bone, according to the University of Liverpool Anthony Hollander, Ph d.,head of integrative biology."
or knee osteoarthritis or the severe injuries caused by major trauma, for example in road traffic accidents or war injuries."
"Dr. Hollander's pioneering work includes the development of a method of creating cartilage cells from stem cells,
which helped to make possible the first successful transplant of a tissue-engineered trachea, utilizing the patient's own stem cells t
The team led by the Universities of Bristol and Liverpool has shown that it is possible to combine cells with a special scaffold to produce living tissue in the laboratory.
and paint the cells without affecting their biological function, said Adam Perriman, Ph d.,from the University of Bristol school of cellular and molecular medicine."
"However, we were surprised and delighted to discover that we could deliver the necessary quantity to the cells to supplement their oxygen requirements.
It's like supplying each cell with its own scuba tank, which it can use to breathe from
when there is not enough oxygen in the local environment.""The team's study (rtificial membrane-binding proteins stimulate oxygenation of stem cells during engineering of large cartilage tissue,
but also for other tissue such as cardiac muscle or bone, according to the University of Liverpool Anthony Hollander, Ph d.,head of integrative biology."
or knee osteoarthritis or the severe injuries caused by major trauma, for example in road traffic accidents or war injuries."
"Dr. Hollander's pioneering work includes the development of a method of creating cartilage cells from stem cells,
which helped to make possible the first successful transplant of a tissue-engineered trachea, utilizing the patient's own stem cells t
#Scientists Discover Specific Brain Receptor Role in Cocaine addiction Scientists at the University at Buffalo have discovered a previously unknown neural pathway that can regulate changes made in the brain due to cocaine use, providing new
"Dr. Gancarz, a former postdoctoral associate with the UB Research Institute on Addictions (RIA), worked on the study under the direction of senior author David Dietz, Ph d.,assistant professor in the department of pharmacology
and toxicology in UB's School of medicine and Biomedical sciences. The study found that by manipulating the activity of Activin receptors the researchers were able to increase
and gene therapies to prevent drug relapses, "explains Dr. Dietz.""If we can control this pathway,
#Scientists Smell Success for Treatment of Spinal cord Injuries Three years after they treated patients with spinal cord injury in a randomized clinical trial with transplanted cells from the patients'olfactory mucosa to build a bridge
and determined that the use of olfactory mucosa lamina propria (OLP) transplants was'promising and safe.'
and daily life activities, wrote the investigators in an article (utologous Olfactory Lamina Propria Transplantation for Chronic Spinal cord Injury:
and is currently freely available online as an unedited early e-pub. The researchers added that autologous olfactory ensheathing cells (OECS) are known to show high levels of nerve growth factor and neurotrophic receptor expression.
The team, based at Wenzhou Medical University in China, randomized 12 patients with complete spinal cord injury (SCI) to receive OLP transplants
and followed them for three years after transplantation, noting that similar studies had not been designed to include long-term patient follow-up. he postoperative images in our study demonstrated that the transplants in the OLP group bridged the proximal and distal stumps (of the severed spinal cord),
which may have provided assistance in establishing the integrity of the local neuronal signal circuit and conducting neural signals for early motor
or sensory recovery, said Hua-Zi Xu, M d.,department of spinal surgery, the second affiliated hospital of Wenzhou Medical University.'
'Most of the patients exhibited improvements within the first 12 to 24 months after surgery and their functional recovery slowly increased,
but plateaued at 24 months after surgery. Overall, wrote the researchers, there appeared to be a reater improvement in sensory function rather than motor function in the ASIA score assessment.
Eight of the 12 patients were without bladder sensation at the preoperative evaluation. ptimal outcomes may be related to age, severity and level of injury
the quality and quantity of transplants, surgical technique, and postoperative rehabilitation, continued the researchers.''We believe that to derive clinical benefits from OEC transplants a combination with other pharmacological agents is most likely to achieve significant axon regeneration
and reestablish functionally useful connections across the injured spinal cord. h
#Scientists Devise Promising Strategy to Tackle MERS A Purdue University-led team of scientists studying the Middle east Respiratory Syndrome (MERS) reports that it found molecules that shut down the activity of an essential enzyme
in the virus and could lead the way to better treatments for those infected. The virus is in the international spotlight again as South korea faces the largest MERS outbreak outside the Middle east.
Purdue's Walther Professor of Cancer Structural biology and professor of biological sciences and chemistry who leads the research team."
"It is a threat to public health we take very seriously, and there currently is no treatment or vaccine.
We continue to study the virus to improve our understanding of how it works and ways to prevent its spread."
"The team published a study, igand-induced dimerization of MERS coronavirus nsp5 protease (3clpro: Implications for nsp5 regulation and the development of antivirals, June 8 in the Journal of Biological Chemistry.
The study details the identification of molecules that inhibit an enzyme essential to MERS virus replication,
what our work with SARS and other related coronaviruses predicted. So, we investigated what was happening
which the virus cannot create more viruses to further an infection. Once inside the cell, the virus creates a long strand of a large viral protein that must be cut at specific points to release individual proteins that serve various functions in building new virus particles.
The 3c-like protease is responsible for making 11 of the necessary cuts for successful viral replication,
and bond very tightly to form the dimer. Dr. Mesecar and his colleagues found that the MERS protease is unusual in that it does not have a strong attraction to its identical proteases
and its dimer will break apart much more easily than the SARS protease or those of other coronaviruses.
The team found that formation of the MERS protease dimer can be stimulated by the binding of a third molecule at a particular site on its surface to trigger the formation of a strong dimer The particular site is where the protease would normally bond to the strand of protein it is meant to cut.
When this bond is formed, the protease has increased an affinity for other 3c-like proteases and creates a stronger bond as it forms its dimer,
explained Dr. Mesecar. This also was the site the team was targeting with an inhibitor molecule.
By sending another molecule to attach to and block this key site, the protease would be unable to bind to the strand of viral protein,
and viral replication would be shut down. However, there was a twist to what happened when the team began to add inhibitor molecules to interact with the protease.
If the second protease had a vacant binding site, it was capable of binding to
the scientists found that it would fill the target sites of all of the 3c-like proteases,
This makes it complicated as the work continues to turn this inhibitor into a viable treatment.
"We captured the protease's atomic structure through this work, which provides the map to design potent new drugs to fight MERS,
"said Dr. Mesecar, who also is deputy director of the Purdue University Center for Cancer Research e
#New Drug Prevents Cancer cells from Staging Last Stand Unlike many last stands in human history,
the last stands arranged by individual cancer cells often resist being overwhelmed, with dire consequences for cancer patients.
Cancer cells maintain themselves by coopting autophagy, an energy harvesting process that is normally used to recycle damaged organelles and proteins.
And autophagy is especially important to cancer cells that have been cut off from nutrient pathways, due to the attacks of cancer drugs such as rampamycin (mtor) inhibitors.
Now it appears a coordinated attack may be possible, one that would include a new drug,
a small molecule called SBI-0206965 that inhibits autophagy. Such a coordinated attack could effectively overrun cancer before it could muster one last defense,
and possibly survive to fight another day. The new drug targets ULK1, an enzyme that initiates autophagy.
The drug, which was developed by scientists at Salk Institute and Sanford Burnham Prebys Medical Discovery Institute (SBP), was described June 25 in Molecular Cell, in an article entitled, mall Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1
Substrates. We screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets,
wrote the authors. e utilized these ULK1 substrates to perform a cell-based screen to identify
and characterize a potent ULK1 small molecule inhibitor. According to this study, SBI-0206965 proved to be a highly selective ULK1 kinase inhibitor in vitro,
and it suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. In addition, SBI-0206965 combined with starvation or mtor inhibition leads to ULK1 degradation.
"The finding opens the door to a new way to attack cancer, "said Reuben Shaw, a senior author of the paper, professor in the Molecular and Cell biology Laboratory at the Salk Institute and a Howard hughes medical institute Early Career Scientist."
"The inhibitor will probably find the greatest utility in combination with targeted therapies.""""The key to success for this project came
when we combined Reuben's deep understanding of the fundamental biology of autophagy with our chemical expertise,"says Cosford."
"This allowed us to find a drug that targeted ULK1 not just in a test tube but also in tumor cells.
Another challenge was finding molecules that selectively targeted the ULK1 enzyme without affecting healthy cells.
Our work provides the basis for a novel drug that will treat resistant cancer by cutting off a main tumor cell survival process. i
#New Target Blocks Malaria Invasion and Transmission With close to 50%of the world population living in endemic areas and it being one of the leading causes of death in children under the age of 5,
malaria is a scourge that humans have endured since before they could walk fully upright. Moreover, the rate of resistance to current drug therapies is growing exponentially
and scientists are always on the hunt for novel targets that have the potential to not only treat symptoms of infected patients,
researchers from the Harvard T. H. Chan School of Public health have discovered what they believe will become an indispensable new target for the development of antimalarial drug therapies.
The scientists found that a malaria protein called calcineurin is essential for parasite invasion into red blood cells."
"Our study has great biological and medical significance, particularly in light of the huge disease burden of malaria,"explained senior author Manoj Duraisingh, Ph d.,professor of Immunology and Infectious diseases at the T. H. Chan School of Public health."
"As drug resistance is a major problem for malaria control and eradication, it is critical that that we continue to develop new antimalarials that act against previously unexploited targets in the parasite to keep priming the drug pipeline."
"The findings from this study were published recently in Cell Host Microbe through an article entitled"Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans."
"Using a mixture of reverse genetic and chemical genetic approaches the investigators were able to provide evidence for the function
implicating the protein as a potential target for blocking malaria transmission. Since there is much genetic conservation among parasites in the Apicomplexa phylum,
the Harvard group worked closely with a team from Boston College to determine if calcineurin had a similar effect on the parasite, Toxoplasma gondii.
as it prevented cellular attachment in this parasite species as wellpening up the potential that calcineurin could target other parasitic diseases in addition to malaria."
"In addition to a possible drug target, calcineurin underlies a very basic aspect of parasite biology. l
#Depersonalized Medicine Shows Promising Results Against Cancer Researchers at St louis University (SLU) say they have,
Unlike recent advances in personalized medicine that focus on specific genetic mutations associated with different types of cancer,
this research targets a broad principle that applies to almost every kind of cancer: its energy source.
The SLU study, which was conducted in animal models and in human tumor cells in the lab, showed that a specific drug can stop cancer cells without causing damage to healthy cells or leading to other severe side effects.
Thomas Burris, Ph d.,chair of pharmacology and physiology at SLU and colleagues at the Scripps Research Institute developed the novel therapeutic.
Cancer cells aggressively increase the process of metabolism, allowing mutated cells to grow unchecked at the expense of surrounding tissue."
"Targeting cancer metabolism has become a hot area over the past few years, though the idea is not new,"according to Dr. Burris.
Since the early 1900s, scientists have known that cancer cells prefer to use glucose as fuel even if they have plenty of other resources available.
In fact, this is how doctors use positron emission tomography to scan images to spot tumors. PET scans highlight the glucose that cancer cells have accumulated.
In a paper (road Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis published in Cancer cell
Dr. Burris reports that the Warburg effect is the metabolic foundation of oncogenic growth, tumor progression,
and metastasis as well as tumor resistance to treatment.""Cancer cells look for metabolic pathways to find the parts to grow and divide.
"The Warburg effect ramps up energy use in the form of glucose to make chemicals required for rapid growth
"If the Warburg effect and lipogenesis are key metabolic pathways that drive cancer progression, growth, survival, immune evasion, resistance to treatment,
and disease recurrence, then, Dr. Burris hypothesized, targeting glycolysis and lipogenesis could offer a way to stop a broad range of cancers.
He and his colleagues created a class of compounds that affect a receptor that regulates fat synthesis. The new compound, SR9243,
SR9243 suppresses abnormal glucose consumption and cuts off cancer cells'energy supply. When cancer cells don't get the parts they need to reproduce through glucose or fat,
it is effective without causing weight loss, liver toxicity, or inflammation, pointed out Dr. Burris.
and in human tumor cells grown in animal models. Because the Warburg pathway is a feature of almost every kind of cancer,
researchers are testing it on a number of different cancer models.""It works in a wide range of cancers both in culture and in human tumors developing in animal models,"explained Dr. Burris."
"Some are more sensitive to it than others. In several of these pathways, cells had been reprogramed by cancer to support cancer cell growth.
This returns the metabolism to that of more normal cells.""In human tumors grown in animal models,
it reportedly worked well on lung, prostate, and colorectal cancers and, to a lesser degree, in ovarian and pancreatic cancers."
"It also seems to work on glioblastoma, an extremely difficult to treat form of brain cancer,
though it isn't able to cross the brain-blood barrier very effectively. The challenge for researchers in this scenario will be to find a way to allow the drug to cross this barrier, the body's natural protection for the brain,
which can make it difficult for drug treatments to reach their target. When SR9243 is used in combination with existing chemotherapy drugs,
it increases their effectiveness, in a mechanism apart from SR9243's own cancer fighting ability, added Dr. Burris B
Overtext Web Module V3.0 Alpha
Copyright Semantic-Knowledge, 1994-2011