Athersys: A Potential Stroke Therapy Monopoly On Hand

(Editors' Note: This article covers a micro-cap stock. Please be aware of the risks associated with these stocks.)

In my last article on Athersys (ATHX) I took a look at the company's clinical pipeline, competition and near-term catalysts, to make a case as to why I felt the company's shares were significantly undervalued. This Tuesday after-hours, Cytomedix (CMXI.OB), who is Athersys' main competition in the stroke therapy market, announced that it plans to halt funding for its ischemic stroke therapy after this year in order to focus on its wound care division. Considering that Athersys and Cytomedix have both been assessed by analysts as being the two main companies' with potential blockbuster stroke treatments on hand, one can't help but wonder why Cytomedix is planning to halt funding for its therapy after this years end.

The Stroke Market

Ischemic stroke, which is considered by the CDC as being the #4 leading cause of death in the world following heart disease, cancer and respiratory failure, comprises a market opportunity of approximately $30B+ annually. While dozens of attempted stroke trials have ultimately failed over the past decade, the only current FDA approved drug for stroke treatment is Genetech's Activase. Activase, which is shown to be effective in some cases, is only used by approximately 3-5 percent of the stroke patient population due to its side effect of causing potential brain hemorrhaging. Aside from Activase, the only other current treatment option for ischemic stroke patients is a surgical attempt to remove the clot, yet needless to say this is not an ideal situation.

MultiStem

While currently the drug Activase dominates the stroke treatment market, this is certain to change if either Athersys or Cytomedix's stroke therapy receives FDA approval. Athersys which is currently conducting a Phase II stroke trial for its MultiStem® therapy is expecting results in Q2 of 2014. Per reviewing Athersys' numerous scientific journal publications documenting MultiStem's efficacy, as well as reviewing the company's past trial data from MultiStem applied to Ischemic stroke, I have an extremely optimistic outlook on the company's future Phase II trial results. Per Athersys' previous data presented at The American Heart Association's Stroke Conference, the company revealed that it's MultiStem therapy reduced damage and enhanced functional recovery in animals after an ischemic stroke. Specifically documented was that after receiving Athersys' MultiStem therapy these animals' experienced improved coordination, balance, motor skills, physical strength and neurological functioning. Since MultiStem is being developed as an off the shelf product which does not need to be prepared via extracting and processing a patients own cells, it provides an extremely convenient option for treatment. Following a stroke, MultiStem is administered intravenously into a patient's blood stream where the stem cells can then be transported to the patients area of injury and begin repairing damage.

ALDH-401

Unlike MultiStem which is targeted to be administered as soon as 1 day after experiencing a stroke, Cytomedix's ALDH-401 therapy is to be administered roughly 2 weeks after experiencing a stroke. While the time lag posed by Cytomedix's therapy is clearly not as convenient, the company's ALDH-401 therapy did show efficacy in pre-clinical results. Pre-clinical data revealed a 41% improvement in motor function after receiving Cytomedix's therapy in comparison to an 11% improvement in the control group. Yet in looking at how Cytomedix's stroke therapy is formulated and administered, one can gain a quick understanding as to why it is not the most ideal approach. While MultiStem is manufactured prior to a patient being hospitalized, ALDH-401 requires that a patient have their bone marrow extracted in order for their therapy to be manufactured post stroke. Adding further discomfort is the administration of this therapy. Unlike MultiStem which is simply injected into a patient's blood stream intravenously, ALDH-401 requires that a patient undergo an intracartoid infusion procedure. While there is no reason why both therapies could not be potentially administered to the same stroke patient theoretically, it is apparent that ALDH-401 is a much more arduous therapy in nature.

Conclusion

In looking at both Athersys and Cytomedix's stem cell therapies for Ischemic Stroke, it is evident that both products have shown clinical efficacy thus far. While Athersys' Phase II trial results are expected a few months earlier than Cytomedix's, this aspect is more of a superficial one in comparison to what the companies actual trial results show. However, in considering yesterday's press release by Cytomedix stating its plans to halt funding for its stroke program after this year, one has to seriously question whether the trial will even make it to the finish line. In spite of Cytomedix's positive pre-clinical stroke data thus far, it is not a bullish sign that the company plans to halt funding for this trial after 2013 in order to focus its efforts on developing its wound care division. All aforementioned being the case, it is my opinion that Athersys would be the clear best investment in the stroke sector currently.

Disclosure: I am long ATHX. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article. (More...)

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Rockwell Medical Inc: SFP's Market Potential

Introduction

On September 4th, Rockwell Medical (RMTI) reported CRUISE-2 results which were practically identical to CRUISE-1 results, opening the door for an NDA submission within 6 months.

Treating anemia in CKD patients requires the use of ESAs and supplemental iron. The first step is to increase the number of red blood cells in the body which is done by injecting ESAs. However, this process falters when the patient becomes iron-deficient, and so supplemental iron is provided to maintain hemoglobin levels. An additional benefit of supplemental iron is that it leads to a reduction in the needed dosing of ESAs.

IV Iron Therapy vs ESAs

There has been an ongoing debate in the dialysis industry about whether or not more IV iron therapy is preferred to a higher ESA dosing. A solution is only determinable with a long-term, large-scale, randomized trial where 1 arm is permitted IV iron, and the other isn't. Such a trial would be very costly due to the size and duration, unethical due to the restriction against IV iron use in the ESA-only arm, and produce confounding results. Regardless, what ESA or IV iron producer is going to finance this study if they aren't sure they would come out on top? What non-producer has the financial ability to execute such a grand trial?

The market cannot determine the right answer, which means that the choice between higher ESA dosing and more IV iron therapy will continue to be left to the judgment of dialysis providers. If a patient is susceptible to more risks, or in need of the additional benefits, of either ESAs or IV iron, then providers will act accordingly.

Consider this: When a provider is dealing with an issue in a patient, who hasn't taken IV iron before, what might be the more responsible solution? Introduce an entirely new drug along with its own associated risks, or simply increase the dosing of the already applied ESAs? Probably the latter, and the low use of IV iron therapy in the CKD demographic seems to support this reality.

For the most part, IV iron is used as a weapon of last resort, which is greatly hindering the market potential of current IV iron therapies. Recently, such drugs, along with ESAs, have been under-fire by the FDA due to increasing safety concerns.

The Solution for Dialysis Centers

Is there a drug that can perform the functions of supplemental iron without the safety concerns of current IV iron therapies, while still reducing ESA dosing? Yes, it's called SFP, and it has showcased superb clinical results this year.

The chemical properties of SFP make it safer than current IV iron therapies, while still retaining the functions of supplemental iron. Here is an excellent video that compares SFP with current IV iron therapies. The video goes into detail with regards to the advantages of SFP over current IV iron therapies. From recent clinical results, we know that continuous use of SFP does not lead to tissue iron overload or cause TSAT levels to exceed normal ranges. In addition, SFP has been shown to maintain or slow down the reduction in group ferritin levels, and maintain CHr levels. These endpoints have been crucial in distinguishing SFP's superiority over current IV iron therapies. The trials have confirmed SFP's ability to be continuously applied in the targeted demographic without concerning doctors with whether or not patients are being overloaded with iron. Using current IV iron therapies can lead to tissue iron overload, and to dangerous increases in TSAT and ferritin levels... They simply cannot be continuously applied.

With the results of the PRIME study, combined with the results for the primary endpoints of the CRUISE studies, SFP has proven that it will significantly reduce ESA dosages by 37.1%, while maintaining hemoglobin levels. Doing the PRIME study was quite a shrewd tactical move by management which will allow them to better negotiate with dialysis providers.

In conclusion, SFP is providing the benefits of supplemental iron without the risks that come with current IV iron therapies. SFP's convincing efficacy and safety data will encourage dialysis providers to use SFP across the board, since it's a low-risk method of consistently reducing their own operational costs.

Market potential for SFP

Rockwell Medical will be paid an approximate percentage of the savings associated with the reduction in ESA costs for dialysis centers. Since SFP can be applied continuously and consistently for any anemic CKD patient, the pricing scheme will be quite simple. Current IV iron therapies cannot operate in this stream-lined fashion due to their inconsistent application and risks associated with continuous use. As a result, using the market size of the current IV iron therapies does not provide an appropriate base for which we can estimate potential SFP sales. A better method would be to determine the percentage of expected savings dialysis providers will achieve if they use SFP.

Approximately 436k chronic kidney disease patients in the US are being treated for anemia with ESAs that cost around $8.5k/yr. This places the domestic market size of the ESA market for anemia at about $3.7B. Since SFP can reduce dosing by 37.1%, Rockwell Medical could save dialysis providers $1.37B each year in ESA costs. If we assume they share the savings 50/50 with the dialysis center, then that leaves SFP with potential domestic sales of $690M per year. Currently, Rockwell Medical has an established working relationship with DaVita (DVA) which owns a third of domestic dialysis centers. As a result of this partnership, Rockwell Medical already has access to potential sales of $227M/yr.

Miscellanious

Earlier this year, Rockwell Medical's stock price was negatively impacted from a depleting cash supply and dwindling profits from their base products. They have since raised money with dilutive and non-dilutive financing, and, in addition, the base revenues have bounced from their lows and look to be returning to previous highs.

After the successful CRUISE-1 results, short interest more than doubled, and, given post-CRUISE-2 price action, it's likely to only keep increasing. The shorts have done their best to keep price down despite the fair value being far higher. Clearly the shorts are expecting an imminent financing, but the company is not going to do a poorly-priced financing in the near-term.

The cash balance at the end of the 13Q2 was $42M, with a net loss of $11.9M/qt. At this rate they would deplete their cash reserves before the second half of 2014. However, during the second quarter both CRUISE trials were on-going. Management has guided that R&D expenses will drop as the clinical programs wrap up during the 13Q3-Q4 period. This will extend the life expectancy of the current cash supply to well into the second half of 2014, and perhaps to 14Q4. By then Calcitriol and increasing base product profits should start reducing the quarterly net loss to the point that the cash supply shouldn't dry up before Rockwell Medical starts operating at a net profit. This doesn't mean financing won't happen, only that if it does it will not be at a meaningful discount because Rockwell Medical will be raising from a position of strength, unlike earlier this year. If the company feels that they can get a fairly priced financing in the near-future, they may be motivated towards canceling their Hercule's debt which burdens the company with interest expenses. Financing or not, shorts are not going to be saved by a repeat March 2013 financing.

Finally, institutional ownership doubled during the second quarter of 2013, which suggests smart money believes Rockwell Medical will become a profitable enterprise in the near future with the launch of SFP and Calcitriol.

Company Valuation

Assumptions

Current base revenue will peak at $60M with 20% profit marginsCalcitriol is approved this quarter (very unlikely it isn't), leading to $25M in peak sales (<7% market capture) with 55% profit marginsSFP revenue operating at a 90% profit marginInitial revenue growth for SFP is dramatic given the pre-existing network with DaVitaAssuming initial Calcitriol sales underperform, no more than 5M additional shares will be added in second half of 2014.Overlap in marketing and commercialization costs between the 3 distinct revenue streamsDrastic reduction in R&D expenses due to ended CRUISE 1 & 2 trials.Rockwell Medical does not expand SFP outside of DaVita's domestic dialysis market (Quite unreasonable, especially considering Keryx (KERX) is trading as if it will tap into the entire market with their phosphate binder)

Price Targets

Near-term target: $11 (Calcitriol approval)6 month target: $15 (NDA submission and safety trial results)12 month target $20 (Initial Calcitriol sales and SFP approval)24 month target: $25

The day after CRUISE-2 results, Summer Street raised their price target from $20 to $25. It seems clear to us that they did not limit their projections by assuming Rockwell Medical does not expand outside of DaVita's market. Thus, our price targets should be considered conservative.

Note: Most of this article, including this price target section, was written while the stock was still trading at $6.

Disclosure: I have no positions in any stocks mentioned, but may initiate a long position in RMTI over the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article. (More...)

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Potential Upside From UnitedHealth's Optum Business

While traditional health insurance services like Private Health Insurance and Medicare And Retirement businesses have been UnitedHealth Group’s (UNH) main source of income accounting for nearly 77% of 2012 revenues, it is the Optum division which has shown the most promising signs of growth this year. The division, which consists of OptumHealth, OptumInsight and OptumRx, accounted for 23% of the company’s operating earnings through the first six months of 2013, with the figure surging 80% over the prior year.

OptumHealth reported a 110% increase in EBIT for the first half of 2013, accounting for more than 40% of the Optum division’s earnings while OptumInsight and Optum RX reported a 66% and 58% increase, respectively. The contribution to EBIT from these divisions was roughly 30% each. Growth in the division will be driven by expansion in the insurance market, but margin expansion from the business alignment could provide an upside.

Our $76 price estimate for UnitedHealth’s stock is in line with the current market price.

What Is Optum?

Optum provides health services to individuals, employers, government as well as life sciences companies. The division can be further subdivided into three subdivisions:

OptumHealth, which primarily provides health and wellness services such as behavioral solutions, care solutions, financial services, collaborative care and logistics health. The division covers over 61 million individuals across the U.S.

Behavioral solutions include disability solutions, mental health and substance abuse solutions, which include risk identification, targeted programs and therapy. Care solutions include providing personalized health management services such as benefit and claims support education for employees, cost estimates and analysis for health plans, specialized programs for conditions such as asthma and diabetes, women’s health services, and wellness programs such as fitness reimbursements and health discount programs. The behavioral solutions and care solutions divisions serve around 50 million and 40 million individuals each.

The company also allows employees and employers to deposit part of pre-tax income and get tax advantages and health savings in the future through the financial services subdivision. Collaborative care allows physicians to connect to each other and logistics health provides mobile care delivery. OptumHealth’s products are offered on a risk basis, wherein the company assumes responsibility for health care costs and in turn earns fixed monthly premiums from policyholders. For financial services, the company also earns investment income on managed funds.

OptumInsight, which provides software and information products and services as well as advisory and outsourcing services to clients. The division primarily caters to hospitals and physicians as Medicaid and Medicare administrators. State and Federal government bodies as well as biotechnology, pharmaceutical and medical device companies also avail OptumInsight services.

OptumRx, is responsible for processing and paying prescription drug claims of its clients. It offers pharmacy benefits management (PBM)) services serving more than 14 million people nationwide by processing over 300 million retail, mail and specialty drug prescriptions annually. The division reported 8 million new customers through the first six months of 2013, driving the aforementioned growth in earnings. The company primarily provides pharmacies a good number of customers and negotiates prescription costs and processes these prescriptions for its customers.

A large chunk of the Optum’s revenues come from intersegment transactions, through sales of pharmacy benefit products and services to customers enrolled in private health insurance or Medicare plans. Three-fourths of the Optum division’s revenues through the first six months of the current year were through intersegment transactions. Therefore, we expect a high correlation between the growth in Optum revenues and enrollments in the insurance divisions. As highlighted in our article "A Look At UnitedHealth’s Private Health Insurance Business," we expect employment and individual policyholders to grow from 27 million at the end of 2012 to around 30 million by the end of the decade. This increase will be driven by the Patient Protection and Affordable Care Act (PPACA) as well as the organic population growth in the U.S. and will also allow UnitedHealth to expand its Optum division.

However, the main upside to the Optum division comes from margin expansion. After eliminating intersegment transactions, the pre-tax (EBIT) margin for Optum went up from 16% in the first six months of 2012 to 25% in the same period in 2013. Margins for OptumHealth went from 16% in 2012 to 27% in 2013, while those for OptumInsight and OptumRx went up from 22% and 13%, to 31% and 18% respectively. The company attributed this margin expansion to productivity gain from disciplined focus on 10 product families. Our current forecast accounts for a marginal near term decline in margins due to increased competition arising from the implementation of the PPACA, as well as increasing medical costs. However, our estimate for UnitedHealth’s EBITDA could increase by 10%, should the company maintain the current year margins through the decade. There is a 10% upside to our price estimate in the scenario.

Disclosure: No positions.

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Anti-wrinkle ingredient: 'preventive potential' in Parkinson's disease

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Academic Journal
Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience;  Seniors / Aging;  Biology / Biochemistry
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Anti-wrinkle ingredient: 'preventive potential' in Parkinson's disease

Scientists say they have discovered that a chemical used in anti-wrinkle cream has potential to prevent early-onset Parkinson's disease.

The findings could be used to develop drugs to prevent the cell death seen in the brains of people with Parkinson's disease, say the researchers from the University of California in San Francisco (UCSF).

The study, published in the journal Cell, analyzes the use of kinetin triphosphate (KTP) - a plant hormone that promotes cell division - as a way of increasing mutant PINK1 enzyme activity in the nerve cells to levels that are nearly normal.

According to the researchers, mutated PINK1 enzymes are directly responsible for many early-onset cases of Parkinson's disease.

Once PINK1 enzymes are mutated, this causes harm to the mitochondria - parts of the cells that are responsible for the conversion of food energy into alternative forms of energy used by cells.

When the performance of mitochondria is harmed, this can cause the death of nerve cells that produce dopamine within a brain region called the substantia nigra. This area of the brain controls movement, and lack of dopamine in this region is a cause of tremors, a common symptom of Parkinson's disease.

Dr. Kevan Shokat, a chemist at UCSF, says:

"In light of the fact that mutations in PINK1 produce Parkinson's disease in humans, the finding that kinetin can speed mutated PINK1 activity to near normal levels raises the possibility that kinetin may be used to treat these patients."

The researchers also discovered that when nerve cells with non-mutated PINK1 interacted with kinetin, enzyme activity also sped up ahead of normal levels.

The study authors say these findings may be relevant for the most common forms of Parkinson's disease, where PINK1 is not mutated.

A previous study revealed that when PINK1 showed similar overactivity in a fruit-fly model, the abnormal movement of Parkinson's disease caused by another defect slowed down. In this case, the defect was increased production of alpha-synuclein - a cause of some inherited types of Parkinson's disease.

For this most recent study, Dr. Shokat decided to target the substrate of PINK1 called ATP - a molecule that binds to the enzyme and triggers a fast chemical transformation. This chemical reaction encourages the activation of the Parkin enzyme.

The authors describe how both the PINK1 and Parkin enzymes work together to monitor the health of mitochondria, helping to trigger the repair or disposal of damaged mitochondria within the cells, encouraging cell survival.

Dr. Shokat says that although there have been many drugs developed that inhibit the activity of kinases, none has yet been marketed that directly boosts the activity of kinase.

He explains:

"Therapeutic approaches for enhancing the activity of PINK1 had not been considered, because scientists had not conceived of the idea of developing a new substrate for the enzyme."

"We found that a small molecule, called KTP, speeds chemical reactions catalyzed by PINK1 better than ATP, the natural substrate. That kind of better-than-natural response is essentially unheard of."

The researchers add that these findings may prompt the development of similar pharmaceutical treatments that could be used to tackle other diseases, such as cancer and diabetes.

Written by Honor Whiteman

Copyright: Medical News Today
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QS inhibitor compounds offer potential for the treatment of P. aeruginosa infections

Main Category: MRSA / Drug Resistance
Article Date: 15 Aug 2013 - 1:00 PDT Current ratings for:
QS inhibitor compounds offer potential for the treatment of P. aeruginosa infections

The fight against antibiotic-resistant superbugs has taken a step forward thanks to a new discovery by scientists at The University of Nottingham.

A multi-disciplinary research team at the University's Centre for Biomolecular Sciences has uncovered a new way of inhibiting the toxicity and virulence of the notorious superbug, Pseudomonas aeruginosa.

This bacteria produces an armoury of virulence factors and is resistant to many conventional antibiotics. It is almost impossible to eradicate P. aeruginosa from the lungs of people with cystic fibrosis and is therefore a leading cause of death among sufferers. The bug also causes a wide range of infections particularly among hospital patients.

The new discovery concerns the bacterial cells' ability to 'talk' to each other by producing and sensing small chemical signal molecules. This is called 'quorum sensing' (QS) and enables a population of individual bacteria to act socially rather than as individuals. QS allows a population of bacteria to assess their numerical strength and make a decision only when the population is 'quorate'.

The mechanism through which QS signals work is by activating gene expression upon interaction of a QS signal molecule with a receptor protein. In many disease-causing bacteria, QS controls genes which are essential for infection. These genes code for virulence factors such as toxins which cause damage to host tissues and the immune system. Interfering with the QS signalling process blocks bacterial virulence and renders bacteria unable to cause infection. Consequently QS systems are molecular targets for the development of new anti-infective drugs which do not kill bacteria but instead block their ability to cause disease.

In a study published in the journal, PLOS Pathogens, the Nottingham team has described how they solved the 3D structure of a receptor protein called PqsR used by P. aeruginosa to sense alkyl quinolone QS signal molecules so that they could visualize the shape of the QS signal molecule-binding site within the PqsR protein.

Professor of Molecular Microbiology, Paul Williams, said: "We were able to synthesize and screen a library of chemical compounds which could fit within the PqsR binding site and block receptor activation by the QS signal molecules. The active compounds were screened for their ability to inhibit QS and through a process of chemical refinement some novel potent QS inhibitors were discovered which were tested biologically on P.aeruginosa and shown to block virulence gene expression."

Professor of Macromolecular Crystallography, Jonas Emsley, added: "This ground-breaking work establishes a platform for the future evaluation and further development of these new QS inhibitor compounds as potential drugs for the treatment of P. aeruginosa infections."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our mrsa / drug resistance section for the latest news on this subject.

Ilangovan A, Fletcher M, Rampioni G, Pustelny C, Rumbaugh K, et al. (2013) "Structural Basis for Native Agonist and Synthetic Inhibitor Recognition by the Pseudomonas aeruginosa Quorum Sensing Regulator PqsR (MvfR)" PLoS Pathog 9(7): e1003508. doi:10.1371/journal.ppat.1003508

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

University of Nottingham

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Potential for new antibiotics following finding that protein delays cell division in bacteria

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Genetics
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Potential for new antibiotics following finding that protein delays cell division in bacteria

In 1958 a group of scientists working in Denmark made the striking observation that bacterial cells are about twice as large when they are cultured on a rich nutrient source than when they are cultured on a meager one. When they are shifted from a nutrient-poor environment to a nutrient-rich one, they bulk up until they have achieved a size more appropriate to their new growth conditions.

It has taken 60 years to figure out how the bacteria are able to sample their surroundings and alter their cell cycles so that they grow to a size suited to the environment.

In 2007 Petra Levin, PhD, a biologist at Washington University in St. Louis, reported in Cell that a soil bacterium named Bacillis subtilis has a protein that senses how much food is available and, when food is plentiful, temporarily blocks the assembly of a constriction ring that pinches a cell in two to create two daughter cells.

Now Norbert Hill, a graduate student in her group, reports in a recent online edition of PLoS Genetics that Escherichia coli uses a similar protein to help ensure cell size is coordinated with nutrient conditions.

Delaying division even just a little bit leads to an increase in daughter cell size. Once stabilized at the new size, cells take advantage of abundant nutrient sources to increase and multiply, doubling their population at regular intervals until the food is exhausted.

Because both the B. subtilis and E. coli proteins interact with essential components of the division machinery, understanding how they function will help in the discovery of antibiotics that block cell division permanently. A group in Cambridge, England, is already working to crystallize the E. coli protein docked on one of the essential components of the constriction ring.

If they are successful they may be able to see exactly how the protein interferes with the ring's assembly. An antibiotic could then be designed that would use the same mechanism to prevent division entirely, killing the bacteria.

Why do bacteria get bigger on a good food source?

Bacteria increase and multiply by a process called binary fission. Each cell grows and then the divides in the middle to produce two daughter cells. What could be simpler?

But the closer you look, the less simple it becomes. For binary fission to work the cell must make a copy of its circular chromosome, unlink and separate the two chromosomes to create a gap between them, assemble a constriction ring in the middle of the cell and coordinate the growth of new cell membrane as the ring cinches tight and pinches the mother cell in two. To complicate matters, bacteria don't necessarily do these steps one by one but can instead work on several steps simultaneously.

Most of the time the goal is to produce daughters the same size as the mother cell. But when food is plentiful, bacteria start making more copies of their DNA (as many as 12) in anticipation of divisions to come, and they can't easily cram all the extra DNA into standard-sized cells. So they grow bigger to accommodate the extra genetic material and remain large as long as the food lasts.

The inventory of partly copied chromosomes fuels rapid population growth, because a cell doesn't start from scratch when it needs another copy of its chromosome. Under optimum conditions, E. coli, for example, divides once every 17 minutes. If they are allowed to grow unhindered this means that in 24 hours 1 bacterium becomes about 5 x 1021 bacteria (that is 5 with 21 zeros after it.)

How do bacteria know the pickings are rich?

In B. subtilis and E. coli the signal is a modified sugar called UDP-glucose. Presumably, the richer the growth medium, the higher the level of this sugar inside the cell.

In both bacteria UDP-glucose binds to a protein and the sugar-protein complex then interferes with the assembly of the constriction ring. In the case of B. subtilis the protein is called UgtP and in the case of E. coli it is OpgH.

"It's interesting," Hill said, "that both organisms, which are more different from one another than we are from bakers' yeast, are using the same system to coordinate changing size in response to nutrient availability."

UgtP and OpgH are bifunctional proteins that are "moonlighting" as elements of the cell-division control systems. In both cases their day jobs are to help build the cell envelope. "We think they are communicating not only how much glucose there is in the cell, but also how fast the cell is growing," Levin said. "The sensor says not only is food abundant, but we're also growing really fast, so we should be bigger."

Both proteins delay division by interfering with FtsZ, the first protein to move to the division site, where it assembles into a scaffold and recruits other proteins to form a constriction ring.

"Very little is known about the assembly of the ring," Hill said. "There are a dozen essential division proteins and we don't know what half of them do. Nor do we understand how the ring develops enough force to constrict."

"We do know FtsZ exists in two states," Hill added. "One is a small monomer and the other is many monomers linked together to form a multi-unit polymer. We think the polymers bind laterally to form a scaffold and then, with the help of other proteins, make a meshwork that goes around the cell.

UgtP and OpgH both interfere with the ability of FtsZ to form the longer polymers necessary for assembly of the constriction ring.

When nutrient levels are low, UgtP and OpgH are sequestered away from the division machinery. FtsZ is then free to assemble into the scaffold supporting the constriction ring so the cell can divide. Because division proceeds unimpeded, cells are smaller when they divide.

What about other bacteria?

This control system helps to explain the 60-year-old observation that bacterial cells get bigger when they are shifted to a nutrient-rich medium.

Comparing the mechanisms that govern cell division in E. coli and B. subtilis reveals conserved aspects of cell size control, including the use of UDP-glucose, a molecule common to all domains of life, as a proxy for nutrient availability, and the use of moonlighting proteins to couple growth-rate-dependent phenomena to the central metabolism.

But much more is known about these model organisms, which many labs study, than the average bacterium. Nobody is sure how many species of bacteria there are - somewhere between 10 million and a billion at a guess - and they don't all divide the way B. subtilis and E. coli do.

The whimsically named giant bacterium Epulopiscium fiselsoni ("Fishelson's guest at a fish's banquet") that lives in the guts of sturgeonfish, has the gene for FtsZ but doesn't divide by binary fission. And then there are bacteria like the pathogen Chlamydia traachomatis that don't have a gene for anything like FtsZ. "We don't know how these bacteria divide, much less maintain an appropriate cell size," Levin said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Potential new anti-cancer target: 'dark-horse' molecule

Main Category: Colorectal Cancer
Also Included In: Cancer / Oncology;  GastroIntestinal / Gastroenterology
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Potential new anti-cancer target: 'dark-horse' molecule

Australian researchers have identified a molecule called interleukin-11 as a potential new target for anti-cancer therapies.

Until now, the importance of interleukin-11 in cancer development has been underestimated, but researchers have recently identified this molecule as a 'dark horse' for the development of cancer. Their discovery suggests blocking interleukin-11 signalling could ultimately provide an exciting new approach to the treatment of bowel and stomach cancer, which are two of the most common cancers worldwide.

When a tumour develops, the normal (non-cancerous) tissues around it can become inflamed, and produce many different molecules, including the two related proteins interleukin-11 and interleukin-6. These hormone-like signalling molecules, referred to as cytokines, are thought to promote the growth and spread of cancer cells, but interleukin-11 was thought to have only a minor, if any, role during cancer development.

However Dr Tracy Putoczki and Associate Professor Matthias Ernst from the Walter and Eliza Hall Institute's Cell Signalling and Cell Death division have now shown that interleukin-11 is one of the most important cytokines that stimulate the growth and spread of cancers. Working with scientists at the Melbourne-based pharmaceutical company CSL Ltd, they discovered that blocking interleukin-11 in models of stomach and bowel cancer stopped tumour growth and could lead to tumour shrinkage, making this cytokine a promising potential new target for treating many types of solid cancers.

Dr Putoczki and Associate Professor Ernst made most of their discoveries while working at the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research, where Associate Professor Ernst is an institute member. Their findings are published online in the journal Cancer Cell.

Dr Putoczki said the team was stunned to discover that interleukin-11 was much more potent in promoting cancer development than interleukin-6. "When considering which cytokines drive cancer development, interleukin-6 has always been in the spotlight," she said. "Despite being very similar to interleukin-6, interleukin-11 has often been overlooked by cancer researchers. Our new research now shows that it might in fact be very important."

Associate Professor Ernst said the team had begun to explore how the discovery could be applied to potential new anti-cancer therapies. "Treating cancers with agents that block cytokine signalling is an exciting new approach that potentially has advantages over current treatment strategies," he said. "Drugs that block the action of cytokines have previously been developed for both inflammatory disease and cancer and, in the case of interleukin-11, our work does not suggest the likelihood of undesirable side-effects. Moreover, agents that inhibit interleukin-6 signalling are already in clinical trials for ovarian, kidney, prostate and breast cancer. Our discovery paves the way for trials of agents that stifle interleukin-11."

Dr Andrew Nash, senior vice president for research at CSL, agreed that the research had identified a potentially important role for interleukin-11 in stomach and bowel cancer. "We have developed a number of potential drug candidates that target the interleukin-11 receptor and this data provides preclinical evidence supporting progression into clinical studies," Dr Nash said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our colorectal cancer section for the latest news on this subject.

The research was supported by the Ludwig Insitute of Cancer Research, CSL Ltd, the Australian National Health and Medical Research Council, Cancer Australia, Cure Cancer Australia, German Cancer Aid, and the Victorian Government.

Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically Cancer Cell, Volume 24, Issue 2, 257-271, 12 August 2013. 10.1016/j.ccr.2013.06.017

Walter and Eliza Hall Institute

Ludwig Institute for Cancer Research

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Potential to repair any genetic defect offered by new gene repair technique

Main Category: Genetics
Article Date: 14 Aug 2013 - 1:00 PDT Current ratings for:
Potential to repair any genetic defect offered by new gene repair technique

Using human pluripotent stem cells and DNA-cutting protein from meningitis bacteria, researchers from the Morgridge Institute for Research and Northwestern University have created an efficient way to target and repair defective genes.

Writing in the Proceedings of the National Academy of Sciences, the team reports that the novel technique is much simpler than previous methods and establishes the groundwork for major advances in regenerative medicine, drug screening and biomedical research.

Zhonggang Hou of the Morgridge Institute's regenerative biology team and Yan Zhang of Northwestern University served as first authors on the study; James Thomson, director of regenerative biology at the Morgridge Institute, and Erik Sontheimer, professor of molecular biosciences at Northwestern University, served as principal investigators.

"With this system, there is the potential to repair any genetic defect, including those responsible for some forms of breast cancer, Parkinson's and other diseases," Hou said. "The fact that it can be applied to human pluripotent stem cells opens the door for meaningful therapeutic applications."

Zhang said the Northwestern University team focused on Neisseria meningitidis bacteria because it is a good source of the Cas9 protein needed for precisely cleaving damaged sections of DNA.

"We are able to guide this protein with different types of small RNA molecules, allowing us to carefully remove, replace or correct problem genes," Zhang said. "This represents a step forward from other recent technologies built upon proteins such as zinc finger nucleases and TALENs."

These previous gene correction methods required engineered proteins to help with the cutting. Hou said scientists can synthesize RNA for the new process in as little as one to three days - compared with the weeks or months needed to engineer suitable proteins.

Thomson, who also serves as the James Kress Professor of Embryonic Stem Cell Biology at the University of Wisconsin-Madison, a John D. MacArthur professor at UW-Madison's School of Medicine and Public Health and a professor in the department of molecular, cellular and developmental biology at the University of California, Santa Barbara, says the discovery holds many practical applications.

"Human pluripotent stem cells can proliferate indefinitely and they give rise to virtually all human cell types, making them invaluable for regenerative medicine, drug screening and biomedical research," Thomson says. "Our collaboration with the Northwestern team has taken us further toward realizing the full potential of these cells because we can now manipulate their genomes in a precise, efficient manner."

Sontheimer, who serves as the Soretta and Henry Shapiro Research Professor of Molecular Biology with Northwestern's department of molecular biosciences, Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, says the team's results also offer hopeful signs about the safety of the technique.

"A major concern with previous methods involved inadvertent or off-target cleaving, raising issues about the potential impact in regenerative medicine applications," he said. "Beyond overcoming the safety obstacles, the system's ease of use will make what was once considered a difficult project into a routine laboratory technique, catalyzing future research."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject.

Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis

Also contributing to the study, which was supported by funding from sources including the National Institutes of Health, the Wynn Foundation and the Morgridge Institute for Research, were Nicholas Propson, Sara Howden and Li-Fang Chu from the Morgridge Institute for Research.

Zhonggang Hou, Yan Zhang, Nicholas E. Propson, Sara E. Howden, Li-Fang Chu, Erik J. Sontheimer, and James A. Thomson. PNAS 2013 ; published ahead of print August 12, 2013, doi:10.1073/pnas.1313587110

University of Wisconsin-Madison

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Potential use of Excellagen to repair prenatally diagnosed birth defects using mesenchymal stem cells

Main Category: Stem Cell Research
Article Date: 14 Aug 2013 - 2:00 PDT Current ratings for:
Potential use of Excellagen to repair prenatally diagnosed birth defects using mesenchymal stem cells

Cardium Therapeutics has reported on a research collaboration with researchers at Boston Children's Hospital, to assess the medical utility of Excellagen® as a delivery scaffold to seed autologous mesenchymal fetal stem cells for ex-vivo engineering of tissue grafts for transplantation into infants to repair prenatally diagnosed birth defects.

Autologous mesenchymal fetal stem cells are derived prenatally from infants with a medical defect requiring life-saving tissue repairs. These stem cells are sourced from amniotic fluid, the placenta or umbilical cord blood. The stem cells are then seeded into a scaffold to promote the growth of an engineered tissue graft. These grafts will potentially be used to surgically repair, either in the fetus or immediately following birth, certain prenatally diagnosed birth defects that could include congenital diaphragmatic hernia, tracheal and chest wall defects, bladder extrophy and various cardiac anomalies. Preliminary pre-clinical research has confirmed that Excellagen collagen homogenate maintains mesenchymal fetal stem cell viability. Additional proof of concept studies are currently underway.

"Boston Children's team has made remarkable progress in the field of tissue regeneration and surgical repair of prenatally diagnosed congenital defects. We believe that Excellagen has an opportunity serve as a delivery platform in the field of stem cell therapy and we look forward to continuing to work with the Boston Children's team to help make their innovative therapeutic vision a new standard of care, and potentially advance stem cell therapies toward commercialization," stated Christopher J. Reinhard, Chairman and Chief Executive Officer of Cardium. "Excellagen was specifically designed to support advanced biologics and this new application further highlights its potential versatility as an important delivery agent for a variety of innovative therapeutic applications."

Cardium's FDA-cleared Excellagen is an aseptically-manufactured, quaternary fibrillar Type I bovine collagen homogenate that is configured into a staggered array of three-dimensional, triple helical, telopeptide-deleted, tropocollagen molecules. This linear array forms a flowable, biocompatible and bioactive structural matrix that can promote chemotaxis, cellular adhesion, migration and proliferation to stimulate tissue formation. The Excellagen homogenate represents a new product delivery platform that allows for the potential development of a portfolio of advanced tissue regeneration therapeutic opportunities that could include anti-infectives, antibiotics, peptides, proteins, small molecules, DNA, stem cells, differentiated cells and conditioned cell media.

Excellagen is a syringe-based, professional-use, pharmaceutically-formulated 2.6% fibrillar Type I bovine collagen homogenate that functions as an acellular biological modulator to activate the wound healing process and significantly accelerate the growth of granulation tissue. Excellagen's FDA clearance provides for very broad labeling including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/graft, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears) and draining wounds. Excellagen is intended for professional use following standard debridement procedures in the presence of blood cells and platelets, which are involved with the release of endogenous growth factors. Excellagen's unique fibrillar Type I bovine collagen homogenate formulation is topically applied through easy-to-control, pre-filled, sterile, single-use syringes and is designed for application at only one-week intervals.

There have been important, positive findings reported by physicians using Excellagen as part of Cardium's physician sampling, patient outreach and market "seeding" programs. In several case studies, physicians reported a rapid onset of the growth of granulation tissue in a wide array of wounds, including non-healing diabetic foot ulcers (consistent with the results of Cardium's Matrix clinical study), as well as pressure ulcers, venous ulcers and Mohs surgical wounds. In certain cases, rapid granulation tissue growth and wound closure have been achieved with Excellagen following unsuccessful treatment with other advanced wound care approaches. From a dermatology perspective, a previously unexplored vertical market, remarkable healing responses have been observed following Mohs surgery for patients diagnosed with squamous and basal cell carcinomas, including deep surgical wounds extending to the periosteum (a membrane that lines the outer surface of bones). Additionally, because of the easy-use and platelet activating capacity, physicians have been employing Excellagen in severe non-healing wounds at near-amputation status, in combination with autologous platelet-rich plasma therapy and collagen sheet products. These case studies and positive physician feedback provide additional support of Excellagen's potential utility as an important new tool to help promote the wound healing process. Excellagen case studies are available at http://www.excellagen.com/surgical-wounds.html.

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Physicists discover theoretical possibility of large, hollow magnetic cage molecules - potential for targeted non-invasive drug delivery

Main Category: Biology / Biochemistry
Article Date: 02 Aug 2013 - 1:00 PDT Current ratings for:
Physicists discover theoretical possibility of large, hollow magnetic cage molecules - potential for targeted non-invasive drug delivery

Virginia Commonwealth University researchers have discovered, in theory, the possibility of creating large, hollow magnetic cage molecules that could one day be used in medicine as a drug delivery system to non-invasively treat tumors, and in other emerging technologies.

Approximately 25 years ago, scientists first made the discovery of C60 fullerene - better known as the Buckminster Fullerene - a molecule composed of 60 carbon molecules that formed a hollow cage. Due to its unique hollow cage structure the molecule offers serious technological potential because it could hold other atoms or small molecules inside, and therefore, be used in applications such as drug delivery.

That potential has since spurred worldwide interest among scientists who have been searching for similar molecules. Although some hollow cage structures have been found, none of them is magnetic. Magnetic properties of the structure are of particular interest because a hollow magnetic structure carrying an embedded atom or molecule can be guided by an external magnetic field and may serve as an effective vehicle for targeted drug delivery.

In a new study, published online on July 22 in The Journal of Chemical Physics, two VCU scientists employing state-of-the-art theoretical methods show that magnetic hollow cages larger than the original C60 fullerene that carry giant magnetic moments are possible. A magnetic moment refers to the measure of the magnetic strength of a cluster.

An illustration of the VCU discovery also is featured on the cover of the July 28 print issue of the journal.

"The potential benefit of this finding is that it provides a route to the synthesis of molecular magnets with colossal magnetic moments," said co-lead investigator Puru Jena, Ph.D., distinguished professor of physics in the VCU College of Humanities and Sciences. Jena collaborated with Menghao Wu, Ph.D., co-author of the paper and a postdoctoral scholar in the VCU Department of Physics.

"These molecules can be used for targeted non-invasive drug delivery. When assembled, the molecules can also form new high strength magnets for device application," Jena said.

According to Jena, the pair of VCU researchers demonstrated the magnetic moment of the molecule by focusing on hetero-atomic clusters consisting of transition metal atoms such as cobalt (Co) and manganese (Mn) and carbon (C) atoms. In particular, Co12C6, Mn12C6, and Mn24C18 clusters consisting of 12 cobalt and six carbon atoms, 12 manganese and six carbon atoms, and 24 manganese and 18 carbon atoms, respectively, carry magnetic moments as large as 14, 38 and 70 Bohr magnetons. In comparison, the magnetic moment of an iron (Fe) atom in crystalline iron is 2.2 Bohr magnetons.

According to Jena, the team is still early in its discovery process.

"There is a long way to go. Experiments first have to be carried out to prove the predictions of our theory," said Jena.

"Ways must be found to synthesize large quantities of these molecules and study their magnetic properties once they are assembled. Finally, these molecules need to be functionalized by embedding desired atoms/molecules for practical applications."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This research was supported in part by the U.S. Department of Energy grant number DE-FG02-96ER45579.

Menghao Wu and Puru Jena, Magnetic hollow cages with colossal moments, Journal of Chemical Physics, doi: 10.1063/1.4813022

Virginia Commonwealth University

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Potential new drug for tuberculosis

Main Category: Tuberculosis
Also Included In: Clinical Trials / Drug Trials
Article Date: 04 Aug 2013 - 10:00 PDT Current ratings for:
Potential new drug for tuberculosis

A new drug capable of inhibiting growth of Mycobacterium tuberculosis is reported this week in Nature Medicine. The findings may improve therapeutic options for the treatment of drug resistant tuberculosis (TB).

One-third of the world's population is latently infected with M. tuberculosis and more than a million people die of TB each year. Multidrug-resistant strains of M. tuberculosis are spreading, and therefore the need to develop new and improved drugs is urgent.

Kevin Pethe and colleagues screened a chemical library for inhibitors of M. tuberculosis growth in macrophages and identified imidazopyrimidine amides as potential candidates. The team then optimized these chemicals in order to generate the compound Q203. This compound, which showed efficacy in vitro and in a mouse model of established TB, targets part of the M. tuberculosis electron chain and therefore inhibits ATP synthesis - which is needed for cellular energy production.

The findings support the concept of targeting ATP synthesis to potentially eradicate both active and latent M. tuberculosis and provide a new candidate for clinical validation.

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Stem cells in urine easy to isolate and have potential for numerous therapies

Main Category: Stem Cell Research
Article Date: 03 Aug 2013 - 0:00 PDT Current ratings for:
Stem cells in urine easy to isolate and have potential for numerous therapies

Could harvesting stem cells for therapy one day be as simple as asking patients for a urine sample? Researchers at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine and colleagues have identified stem cells in urine that can be directed to become multiple cell types.

"These cells can be obtained through a simple, non-invasive low-cost approach that avoids surgical procedures," said Yuanyuan Zhang, M.D., Ph.D., assistant professor of regenerative medicine and senior researcher on the project.

Reporting online in the journal Stem Cells, the team successfully directed stem cells from urine to become bladder-type cells, such as smooth muscle and urothelial, the cells that line the bladder. But the urine-derived cells could also form bone, cartilage, fat, skeletal muscle, nerve, and endothelial cells, which line blood vessels. The multipotency of the cells suggests their use in a variety of therapies.

"These stem cells represent virtually a limitless supply of autologous cells for treating not only urology-related conditions such as kidney disease, urinary incontinence and erectile dysfunction, but could be used in other fields as well," said Zhang. "They could also potentially be used to engineer replacement bladders, urine tubes and other urologic organs."

Being able to use a patient's own stem cells for therapy is considered advantageous because they do not induce immune responses or rejection. However, because tissue-specific cells are a very small subpopulation of cells, they can be difficult to isolate from organs and tissues.

Zhang's team first identified the cells, which are a small subset of the many cells found in urine, in 2006. The current research builds on earlier studies by confirming the multipotency of the cells. In addition, the research found that unlike iPS cells or embryonic stem cells, the urine derived-stem cells do not form tumors when implanted in the body, indicating they may be safe for use in patients.

The research involved obtaining urine samples from 17 healthy individuals ranging in age from five to 75 years. Isolating the cells from urine involves minimal processing, according to the authors. Next, they evaluated the cells' ability to become multiple cell types.

Importantly, the cells differentiated into the three tissue layers (endoderm, ectoderm and mesoderm) that are a hallmark of true stem cells and also differentiated into the specific cell types mentioned earlier.

Next, the researchers placed cells that had been differentiated into smooth muscle and urothelial cells onto scaffolds made of pig intestine. When implanted in mice for one month, the cells formed multi-layer, tissue-like structures.

The urine-derived stem cells have markers of mesenchymal cells, which are adult stem cells from connective tissue such as bone marrow. They also have markers for pericytes, a subset of mesenchymal cells found in small blood vessels.

Where do the cells come from? Researchers suspect that the cells originate from the upper urinary tract, including the kidney. Female study participants who had received kidney transplants from male donors were found to have the y chromosome in their urine-derived stem cells, suggesting the kidney as the source of the cells.

"Identifying the origins of the cells will lead to a better understanding of the biology of this multipotent population of mesenchymal cells within the urinary tract system," said Zhang.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our stem cell research section for the latest news on this subject.

Co-researchers were Shantaram Bharadwaj, Ph.D., Guihua Liu, M.D., Ph.D., Yingai Shi, M.D., Ph.D., Rongpei Wu, M.D., Ph.D., Bin Yang, M.D., Ph.D., Anthony Atala, M.D., and Jan Rohozinski, Ph.D ., Wake Forest Baptist; Tong-chan He, M.D., Ph.D., the University of Chicago Medical Center; Yuxin Fan, M.D., Ph.D., and Xinyan Lu, M.D., Baylor College of Medicine; Xiaobo Zhou, Ph.D., the Methodist Hospital Research Institute; and Hong Liu, Ph.D., University of Oklahoma.

Wake Forest Baptist Medical Center

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Study finds potential well water contaminants highest near natural gas drilling

Main Category: Water - Air Quality / Agriculture
Also Included In: Public Health
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Study finds potential well water contaminants highest near natural gas drilling

A new study of 100 private water wells in and near the Barnett Shale showed elevated levels of potential contaminants such as arsenic and selenium closest to natural gas extraction sites, according to a team of researchers that was led by UT Arlington associate professor of chemistry and biochemistry Kevin Schug.

The results of the North Texas well study were published online by the journal Environmental Science & Technology. The peer-reviewed paper focuses on the presence of metals such as arsenic, barium, selenium and strontium in water samples. Many of these heavy metals occur naturally at low levels in groundwater, but disturbances from natural gas extraction activities could cause them to occur at elevated levels.

"This study alone can't conclusively identify the exact causes of elevated levels of contaminants in areas near natural gas drilling, but it does provide a powerful argument for continued research," said Brian Fontenot, a UT Arlington graduate with a doctorate in quantitative biology and lead author on the new paper.

He added: "We expect this to be the first of multiple projects that will ultimately help the scientific community, the natural gas industry, and most importantly, the public, understand the effects of natural gas drilling on water quality."

Researchers believe the increased presence of metals could be due to a variety of factors including: industrial accidents such as faulty gas well casings; mechanical vibrations from natural gas drilling activity disturbing particles in neglected water well equipment; or the lowering of water tables through drought or the removal of water used for the hydraulic fracturing process. Any of these scenarios could release dangerous compounds into shallow groundwater.

Researchers gathered samples from private water wells of varying depth within a 13 county area in or near the Barnett Shale in North Texas over four months in the summer and fall of 2011. Ninety-one samples were drawn from what they termed "active extraction areas," or areas that had one or more gas wells within a five kilometer radius. Another nine samples were taken from sites either inside the Barnett Shale and more than 14 kilometers from a natural gas drilling site, or from sites outside the Barnett Shale altogether. The locations of those sites were referred to as "non-active/reference areas" in the study.

Researchers accepted no outside funding to ensure the integrity of the study. They compared the samples to historical data on water wells in these counties from the Texas Water Development Board groundwater database for 1989-1999, prior to the proliferation of natural gas drilling.

In addition to standard water quality tests, the researchers used gas chromatography - mass spectrometry (GC-MS), headspace gas chromatography (HS-GC) and inductively coupled plasma-mass spectrometry (ICP-MS). Many of the tests were conducted in the Shimadzu Center for Advanced Analytical Chemistry on the UT Arlington campus.

"Natural gas drilling is one of the most talked about issues in North Texas and throughout the country. This study was an opportunity for us to use our knowledge of chemistry and statistical analysis to put people's concerns to the test and find out whether they would be backed by scientific data," said Schug, who is also the Shimadzu Distinguished Professor of Analytical Chemistry in the UT Arlington College of Science.

On average, researchers detected the highest levels of these contaminants within 3 kilometers of natural gas wells, including several samples that had arsenic and selenium above levels considered safe by the Environmental Protection Agency. For example, 29 wells that were within the study's active natural gas drilling area exceeded the EPA's Maximum Contaminant Limit of 10 micrograms per liter for arsenic, a potentially dangerous situation.

The areas lying outside of active drilling areas or outside the Barnett Shale did not show the same elevated levels for most of the metals.

Other leaders of the Texas Gas Wells team were Laura Hunt, who conducted her post-doctoral research in biology at UT Arlington, and Zacariah Hildenbrand, who earned his doctorate in biochemistry from the University of Texas at El Paso and performed post-doctoral research at UT Southwestern Medical Center. Hildenbrand is also the founder of Inform Environmental, LLC. Fontenot and Hunt work for the EPA regional office in Dallas, but the study is unaffiliated with the EPA and both received permission to work on this project outside the agency.

Scientists note in the paper that they did not find uniformity among the contamination in the active natural gas drilling areas. In other words, not all gas well sites were associated with higher levels of the metals in well water.

Some of the most notable results were on the following heavy metals:

Arsenic occurs naturally in the region's water and was detected in 99 of the 100 samples. But, the concentrations of arsenic were significantly higher in the active extraction areas compared to non-extraction areas and historical data. The maximum concentration from an extraction area sample was 161 micrograms per liter, or 16 times the EPA safety standard set for drinking water. According to the EPA, people who drink water containing arsenic well in excess of the safety standard for many years "could experience skin damage or problems with their circulatory system, and may have an increased risk of getting cancer." Selenium was found in 10 samples near extraction sites, and all of those samples showed selenium levels were higher than the historical average. Two samples exceeded the standard for selenium set by the EPA. Circulation problems as well as hair or fingernail loss are some possible consequences of long-term exposure to high levels of selenium, according to the EPA. Strontium was also found in almost all the samples, with concentrations significantly higher than historical levels in the areas of active gas extraction. A toxicological profile by the federal government's Agency for Toxic Substances and Disease Registry recommends no more than 4,000 micrograms of strontium per liter in drinking water. Seventeen samples from the active extraction area and one from the non-active areas exceeded that recommended limit. Exposure to high levels of stable strontium can result in impaired bone growth in children, according to the toxic substances agency.

"After we put the word out about the study, we received numerous calls from landowner volunteers and their opinions about the natural gas drilling in their communities varied," Hildenbrand said. "By participating in the study, they were able to get valuable data about their water, whether it be for household or land use.

"Their participation has been incredibly important to this study and has helped us bring to light some of the important environmental questions surrounding this highly contentious issue."

The paper also recommends further research on levels of methanol and ethanol in water wells. Twenty-nine private water wells in the study contained methanol, with the highest concentrations in the active extraction areas. Twelve samples, four of which were from the non-active extraction sites, contained measurable ethanol. Both ethanol and methanol can occur naturally or as a result of industrial contamination. Historical data on methanol and ethanol was not available, researchers said in the paper.

The paper is called "An evaluation of water quality in private drinking water wells near natural gas extraction sites in the Barnett Shale formation." A Just Accepted version is available on the journal website.

Many from the research team are now conducting well water sampling in the Permian Basin region of Texas, establishing a baseline set of data prior to gas well drilling activities there. That baseline will be used for a direct comparison to samples that will be collected during and after upcoming natural gas extraction. The team hopes that these efforts will shed further light on the relationship between natural gas extraction and ground water quality.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our water - air quality / agriculture section for the latest news on this subject.

The paper is called “An evaluation of water quality in private drinking water wells near natural gas extraction sites in the Barnett Shale formation.” A Just Accepted version is available on the journal website.

Other co-authors include: Qinhong “Max” Hu, associate professor of earth and environmental sciences at UT Arlington; Doug D. Carlton Jr., a Ph.D. student in the chemistry and biochemistry department at UT Arlington; Hyppolite Oka, a recent graduate of the environmental and earth sciences master’s program at UT Arlington; Jayme L. Walton, a recent graduate of the biology master’s program at UT Arlington; and Dan Hopkins, of Carrollton-based Geotech Environmental Equipment, Inc.

Alexandria Osorio and Bryan Bjorndal of Assure Controls, Inc. in Vista, Calif., also are co-authors. The team used Assure’s Qwiklite™ system to test for toxicity in well samples and those results are being prepared for a separate publication.

The research published this week is representative of the important work going on at The University of Texas at Arlington, a comprehensive research institution with about 33,800 students and more than 2,200 faculty members in the heart of North Texas.

University of Texas at Arlington

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Parkinson's discovery yields potential to 'protect' nerve cells

Editor's Choice
Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Parkinson's discovery yields potential to 'protect' nerve cells

Biologists at The Scripps Research Institute in California have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons had been unclear.

The new report's senior author, Professor Steven Reed, said the Scripps team had now constructed a credible model in which parkin loss sharply reduces the level of another protein, Fbw7ß that normally helps protect neurons from oxidative stress.

Prof. Steven Reed said:

"This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases"

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of its characteristic tremor, muscle rigidity and slowness of movements.

These motor symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.

Most cases of Parkinson's disease are "sporadic", caused by a variable mix of factors such aging, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins.

However, 5-15% of cases are genetic, arising specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before they turn 40 years of age.

Parkin is one of the ubiquitin ligase family of enzymes, whose main function is to regulate the levels of other proteins by "tagging" their protein targets with ubiquitin molecules, marking them for disposal by roving protein-breakers in cells known as proteasomes. Thus researchers assumed that absence of parkin allowed other protein to accumulate abnormally and harm neurons.

But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's disease, consensus about the identity of this protein culprit has been elusive. "There have been a lot of theories, but no one has come up with a truly satisfactory answer," Prof. Steven Reed said.

In 2005, Prof. Reed and his wife, Susanna Ekholm-Reed, a postdoctoral research associate, decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7.

They found that parkin regulates Fbw7 levels by tagging it with ubiquitin, targeting it for degradation by the proteasome. Therefore loss of parkin leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß.

Steven and Suzanna observed elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice born without the parkin gene, and, most importantly, in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction. However, without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this oxidative stress - so that more of them undergo programmed self-destruction (apoptosis). Dopamine-producing substantia nigra neurons may be particularly vulnerable to oxidative stress, which has long been suspected as a contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," Susanna Ekholm-Reed said. A lack of funding, however, slowed the research.

A new breakthrough came after other researchers investigating Fbw7's role in cancer reported in 2011 that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis.

"We were very excited about that finding," Susanna Ekholm-Reed said.

The Scripps team followed up with a series of experiments that confirmed the key chain of events: parkin controls levels of Fbw7ß, which in turn keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress. The report suggests this is the principal explanation for how parkin mutations lead to Parkinson's disease.

The team also believe their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," Prof. Steven Reed said.

Written by: Nick Valentine

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our parkinson's disease section for the latest news on this subject. “Parkin-dependent degradation of the F-box protein Fbw7 ß promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1,” Ekholm-Reed S, Goldberg MS, Schlossmacher MG and Reed SI. Published ahead of print 15 July 2013. DOI: 10.1128/MCB.00535-13. Please use one of the following formats to cite this article in your essay, paper or report:

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29 Jul. 2013. APA

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'Parkinson's discovery yields potential to 'protect' nerve cells'

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Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Main Category: Parkinson's Disease
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin's loss sharply reduces the level of another protein that normally helps protect neurons from stress.

"We now have a good model for how parkin loss can lead to the deaths of neurons under stress," said TSRI Professor Steven I. Reed, who was senior author of the new study. "This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases."

Genetic Clues

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.

Most cases of Parkinson's are considered "sporadic" and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before age 40.

Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by "tagging" their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's, consensus about the identity of this protein culprit has been elusive.

"There have been a lot of theories, but no one has come up with a truly satisfactory answer," Reed said.

Oxidative Stress

In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. "We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome," said Ekholm-Reed.

Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß. The scientists observed these elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction, so that Fbw7ß levels fall. Without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this "oxidative stress" - so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," said Ekholm-Reed.

A New Neuroprotective Strategy

The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7's role in cancer reported that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis. "We were very excited about that finding," said Ekholm-Reed. The TSRI lab's experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7ß under control, and Fbw7ß keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.

Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson's disease. But perhaps more importantly, they believe that their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," said Reed.

Finding such an Mcl-1-boosting compound, he added, is now a major focus of his laboratory's work.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our parkinson's disease section for the latest news on this subject.

“Parkin-Dependent Degradation of the F-box protein Fbw7 ß Promotes Neuronal Survival in Response to Oxidative stress by Stabilizing Mcl-1,” Susanna Ekholm-Reed, Matthew S. Goldberg, Michael G. Schlossmacher and Steven I. Reed, Published ahead of print 15 July 2013, doi: 10.1128/MCB.00535-13

Funding for the study was provided in part by the National Institutes of Health (NS059904 and CA078343).

Scripps Research Institute

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