Snake Venom is Key to New Heart Drugs

Research led by the Univ. of Bath has identified two possible new routes for developing novel drugs for high blood pressure and heart disease.
The research, published in the prestigious Nature journal Scientific Reports, was led by Prof. Ravi Acharya in collaboration with the Universities of Leeds and Cape Town.
The scientists created images of the 3D molecular structures of two peptides, including one from snake venom, that inhibit angiotensin-I converting enzyme (ACE), a key protein that regulates blood pressure.

Molecular structure of ACE (red) with Ang-II peptide bound (yellow) Image: Univ. of Bath
ACE inhibitors, such as the drug Captopril, are taken by millions of people in the UK to treat high blood pressure (hypertension) and heart disease. However the drugs cause side effects such as a persistent cough and angioedema (swelling of the face and throat).
In this Medical Research Council funded study, the team produced images of a snake venom peptide BPPb binding to ACE. Although this peptide has been identified previously as a possible template for drug design, it is the first time scientists have been able to see at the molecular level how the peptide binds to ACE and blocks its action.
Acharya says, “We found that the BPPb peptide binds to a major portion of the active site of the ACE molecule pushing out a zinc atom which is essential for its correct functioning. This is the first time we’ve observed zinc-independent inhibition of ACE, and so these findings highlight a very exciting opportunity to design new antihypertensive drugs based on this peptide.”
In addition, the researchers looked at the structure of angiotensin-II (Ang-II) bound to ACE. Ang-II is a hormone produced by ACE that also inhibits it, creating a feedback loop that stops levels of Ang-II getting too high.
Acharya comments, “We already knew that Ang-II blocks ACE, but not how it does this at the molecular level. This study has shown for the first time how ACE self-regulates by producing a molecule that obstructs its active site when the concentration reaches a certain level.”
The next step is to use this structural knowledge as a basis for accelerating the on-going work carried out by Acharya and his collaborators on the development of next generation ACE inhibitors that have improved efficacy and fewer side effects.
The scientists will first use computers to predict the action of different drug designs, then take the best drug candidates and test them in vitro, followed by tests in animal models for hypertension.

Researchers Pinpoint Where Julius Caesar was Stabbed

A concrete structure three meters wide and over two meters high, placed by order of Augustus (adoptive son and successor of Julius Caesar) to condemn the assassination of his father, has given key to scientists. This finding confirms that the General was stabbed right at the bottom of the Curia of Pompey while he was presiding, sitting on a chair, over a meeting of the Senate. Currently, the remains of this building are located in the archaeological area of Torre Argentina, right in the historic center of the Roman capital.

This is the monumental complex in Torre Argentina (Rome), where Julius Caesar was stabbed.

 

Antonio Monterroso, Spanish National Research Council (CSIC) researcher from the Institute of History of the Center for Humanities and Social Sciences (CCHS-CSIC), states, "We always knew that Julius Caesar was killed in the Curia of Pompey on March 15th 44 BC because the classical texts pass on so, but so far no material evidence of this fact, so often depicted in historicist painting and cinema, had been recovered."
Classical sources refer to the closure (years after the murder) of the Curia, a place that would become a chapel-memory. The CSIC researcher explains, "We know for sure that the place where Julius Caesar presided over that session of the Senate, and where he fell stabbed, was closed with a rectangular structure organized under four walls delimiting a Roman concrete filling. However, we don't know if this closure also involved that the building ceased to be totally accessible."
Spaces of the assassination of Caesar
In Torre Argentina, in addition to the Curia of Pompey, researchers have started to study the remains of the Portico of the Hundred Columns (Hecatostylon). The aim is to identify what connecting links can be established between archaeology, art history and cinema in these spaces of the death of Julius Caesar. Monterroso adds, "We also aim to better understand that sense of closure and dismal place described in classical texts."
The two buildings are part of the monumental complex (about 54.000 square meters) that Pompey the Great, one of the greatest military leaders in the history of Rome, built in the capital to commemorate his military successes in the East around the year 55 BC.
Monterroso also states, "It is very attractive, in a civic and citizen sense, that thousands of people today take the bus and the tram right next to the place where Julius Caesar was stabbed 2056 years ago or even that they go to a theater, since the main theater of the capital is the Teatro Argentina, which is equally close."

Researchers Take Einstein’s Theory Beyond Light Speed

Univ. of Adelaide applied mathematicians have extended Einstein's theory of special relativity to work beyond the speed of light.

Einstein's theory holds that nothing could move faster than the speed of light, but Prof. Jim Hill and Barry Cox in the university's School of Mathematical Sciences have developed new formulas that allow for travel beyond this limit.
Einstein's theory of special relativity was published in 1905 and explains how motion and speed is always relative to the observer's frame of reference. The theory connects measurements of the same physical incident viewed from these different points in a way that depends on the relative velocity of the two observers.
"Since the introduction of special relativity there has been much speculation as to whether or not it might be possible to travel faster than the speed of light, noting that there is no substantial evidence to suggest that this is presently feasible with any existing transportation mechanisms," says Hill.
Hill goes on to say, "About this time last year, experiments at CERN, the European center for particle physics in Switzerland, suggested that perhaps neutrinos could be accelerated just a very small amount faster than the speed of light; at this point we started to think about how to deal with the issues from both a mathematical and physical perspective. Questions have since been raised over the experimental results but we were already well on our way to successfully formulating a theory of special relativity, applicable to relative velocities in excess of the speed of light. Our approach is a natural and logical extension of the Einstein Theory of Special Relativity, and produces anticipated formulae without the need for imaginary numbers or complicated physics."
The research has been published in the prestigious Proceedings of the Royal Society A. Their formulas extend special relativity to a situation where the relative velocity can be infinite, and can be used to describe motion at speeds faster than light.
"We are mathematicians, not physicists, so we've approached this problem from a theoretical mathematical perspective," says Cox. "Should it, however, be proven that motion faster than light is possible, then that would be game changing. Our paper doesn't try and explain how this could be achieved, just how equations of motion might operate in such regimes."

Eye Proteins Inspire New Antimicrobial Drugs

When it comes to germ-busting power, the eyes have it, according to a discovery by UC Berkeley researchers that could lead to new, inexpensive antimicrobial drugs.

A team of UC Berkeley vision scientists has found that small fragments of keratin protein in the eye play a key role in warding off pathogens. The researchers also put synthetic versions of these keratin fragments to the test against an array of nasty pathogens. These synthetic molecules effectively zapped bacteria that can lead to flesh-eating disease and strep throat (Streptococcus pyogenes), diarrhea (Escherichia coli), staph infections (Staphylococcus aureus) and cystic fibrosis lung infections (Pseudomonas aeruginosa).

Proteins in the eye can help keep pathogens at bay

The findings, to be published in the October issue of the Journal of Clinical Investigation, could lead to a powerful new weapon in the battle against disease-causing invaders. These keratin fragments are relatively easy to manufacture, making them good candidates for low-cost therapeutics, the study authors say.
“What’s really exciting is that the keratins in our study are already in the body, so we know that they are not toxic, and that they are biocompatible,” says the study’s principal investigator, Suzanne Fleiszig, a professor at UC Berkeley’s School of Optometry who specializes in infectious diseases and microbiology. “The problem with small, naturally occurring, antimicrobial molecules identified in previous research is that they were either toxic or easily inactivated by concentrations of salt that are normally found in our bodies.”
These new small proteins in the study were derived from cytokeratin 6A, one of the filament proteins that connect to form a mesh throughout the cytoplasm of epithelial cells.
“We used to think that cytokeratins were primarily structural proteins, but our study shows that these fragments of keratin also have microbe-fighting capabilities,” says study lead author Connie Tam, an assistant research scientist in Fleiszig’s lab. “Cytokeratin 6A can be found in the epithelial cells of the human cornea as well as in skin, hair and nails. These are all areas of the body that are constantly exposed to microbes, so it makes sense that they would be part of the body’s defense.”
In a commentary published alongside the study, Michael Zasloff, professor of surgery and pediatrics at Georgetown Univ.’s School of Medicine, says these “keratin-derived antimicrobial peptides appear to be exciting new biocompatible candidates for development as human anti-infective therapeutics.”
The researchers in Fleiszig’s lab came upon cytokeratin 6A in their efforts to solve the mystery behind the eye’s remarkable resilience to infection. They noticed that the surface of the eye, unlike other surfaces of the body, did not have bacteria living on it, and that corneal tissue could handily wipe out a barrage of pathogens in lab culture experiments.
“It is very difficult to infect the cornea of a healthy eye,” says Fleiszig. “We’ve even used tissue paper to damage the eye’s surface cells and then plastered them with bacteria, and still had trouble getting bacteria to enter the cornea. So we proposed that maybe there were antimicrobial factors that are unique to the eye.”
In the hunt for this mystery compound, the researchers cultured human corneal epithelial cells and exposed them to the P. aeruginosa bacteria. They used mass spectrometry to sort out which peptides were most active in fighting off the bacteria. Cytokeratin 6A-derived peptides emerged the winners, and surprisingly, peptide fragments as short as 10 amino acids were effective.
To confirm that they got the right protein, the researchers used gene-silencing techniques to reduce the expression of cytokeratin 6A in the cornea of mice. With a key defense disabled, the amount of bacteria that adhered to the corneas increased fivefold.
Tests showed that cytokeratin 6A-derived fragments could quickly kill bacteria in water and in a saline solution, showing that the salt contained in human tears would not dilute the protein’s effectiveness. Other experiments indicated that cytokeratin 6A fragments prevented the bacteria from attacking epithelial cells, and that the proteins cause bacterial membranes to leak, killing the pathogen within minutes.
The researchers note that further research could reveal numerous different keratin fragments in the body’s innate defense system.
“Keratins may represent a novel class of antimicrobials with the potential to be designed to selectively kill specific pathogens,” says Tam.
The Bill and Melinda Gates Foundation and the National Institutes of Health provided support for this research.

Some Deadly Breast Cancers Resemble Ovarian Tumors

The most comprehensive analysis yet of breast cancer shows that one of the most deadly subtypes is genetically more similar to ovarian tumors than to other breast cancers.
The findings, published online in Nature, suggest that most basal-like breast tumors and ovarian tumors have similar genetic origins and potentially could be treated with the same drugs, says the study’s co-leader Matthew Ellis, from Washington Univ. School of Medicine in St. Louis. The other co-leader is Charles Perou, at the Univ. of North Carolina.

A comprehensive analysis of breast cancer shows that one of the most deadly subtypes is genetically more similar to ovarian tumors than to other breast cancers. The findings suggest that basal-like breast cancer (above) and ovarian tumors have similar genetic origins and potentially could be treated with the same drugs. Image: Matthew Ellis, Washington Univ. in St. Louis

Basal-like tumors account for about 10 percent of all breast cancers and disproportionately affect younger women and those who are African-American.
The new research is part of The Cancer Genome Atlas project, which brings together leading genetic sequencing centers, including The Genome Institute at Washington Univ., to identify and catalog mutations involved in many common cancers. The effort is funded by the National Institutes of Health (NIH).
“With this study, we’re one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer,” says Ellis. “Now, we can investigate which drugs work best for patients based on the genetic profiles of their tumors. For basal-like breast tumors, it’s clear they are genetically more similar to ovarian tumors than to other breast cancers. Whether they can be treated the same way is an intriguing possibility that needs to be explored.”
Currently, for example, basal-like breast tumors often are treated like many other breast cancers, using anthracycline-based chemotherapy. But another of Ellis's studies recently showed that women with basal-like tumors don't benefit from these drugs, which also have severe side effects. At the very least, he says, the new data indicates that clinical trials should be designed to avoid the use of these drugs in basal-like tumors.
As part of the new research, a nationwide consortium of researchers analyzed tumors from 825 women with breast cancer. The scientists used six different technologies to examine subsets of the tumors for defects in DNA, RNA (a close chemical cousin of DNA) and proteins. Nearly 350 tumors were analyzed using all six technologies.
“By tying together those different data sets, we can build a story around the biology of each breast cancer subtype that is dictated by the genome, interpreted by the RNA and played out by the proteins at work inside each tumor,” says co-author Elaine Mardis, co-director of The Genome Institute. “These data can serve as a backdrop for other questions about how particular mutations affect survival or response to certain drugs.”
The study confirmed the existence of four main subtypes of breast cancer: luminal A, luminal B, HER2 and basal-like. The latter includes most triple-negative breast tumors, so-named because they lack receptors for the hormones estrogen, progesterone or human epidermal growth factor 2 (HER2). These tumors often are aggressive and do not respond to therapies that target hormone receptors or to standard chemotherapies.
Across the four subtypes, mutations in only three genes – TP53, PIK3CA and GATA3 – occurred in more than 10 percent of patients’ tumors. But, the scientists found unique genetic and molecular signatures within each of the subtypes. Their findings add to the growing body of evidence suggesting that tumors should be cataloged and treated based on the genes that are disrupted rather than the location in the body.
In general, compared to the other subtypes, basal-like and HER2 tumors had the highest mutation rates but the shortest list of significantly mutated genes. These genes are thought to be major drivers of cancer progression. For example, 80 percent of basal-like tumors had mutations in the TP53 gene, which have been linked to poor outcomes. About 20 percent of the tumors also had inherited mutations in BRCA1 or BRCA2 genes, which are known to increase the risk of breast and ovarian cancer.
“This suggests that it only takes a few hits to key genes that drive cancer growth,” Mardis explains.
A high frequency of TP53 mutations also occurs in ovarian cancer, the researchers note. Overall, the genetic profiles of basal-like and ovarian tumors were strikingly similar, with widespread genomic instability and mutations occurring at similar frequencies and in similar genes.
Finding new drug targets for basal-like breast tumors is critical, and the research suggests that patients with mutations in the BRCA genes may benefit from PARP inhibitors or platinum-based chemotherapy, which are already used to treat ovarian cancer.
By comparison, luminal cancers (which include estrogen receptor-positive and progesterone-receptor positive tumors) had the lowest mutation frequencies and longer lists of significantly mutated genes. This suggests defects in multiple genetic pathways can lead to the development of luminal breast cancers.
Most patients with luminal A cancer have good outcomes, and the most common mutation in that subtype occurred in PIK3CA, which was present in 45 percent of tumors. TP53 mutations only occurred in 12 percent.
Some patients with luminal B tumors do well but many experience recurrence years after treatment. Interestingly, the most common mutations in these tumors occurred in TP53 (linked to poor outcomes) and PIK3CA (linked to good outcomes), which may explain the disparate results seen in patients with this subtype.
“Now, we’re much closer to understanding the true origins of the different types of breast cancer,” Ellis says. “With this information, physicians and scientists can look at their own samples to correlate patients’ tumor profiles with treatment response and overall outcomes. That’s the challenge for the future – translating a patient’s genetic profile into new treatment strategies.”

Substance Makes Cancer Commit Suicide

The p53 gene plays a key role in the prevention of cancer, by blocking cell growth and triggering programmed cell death or apoptosis. If, however, p53 mutates and becomes defective, the cancer cells can acquire the ability to evade apoptosis and become more resistant to therapy. Researchers at Karolinska Institutet and Karolinska Univ. Hospital have now obtained results from the first tests using a new substance that can restore the function of defective p53 and activate apoptosis in cancer cells. This work was published in the Journal of Clinical Oncology.
The substance is known as APR-246 and has now been tested on humans in a phase I/II study, which was conducted on 22 patients with advanced blood or prostate cancer. Some of the patients came from the Haematology Centre at the Karolinska Univ. Hospital in, Stockholm, where the study’s lead investigator, consultant Sören Lehmann is based. The remainder of the patients were from other clinics in Gothenburg, Lund, Uppsala and Örebro.
The patients received daily infusions of APR-246 for four days. When the researchers analyzed the cancer cells taken before and after treatment, they saw indications that the p53 gene had been activated to varying degrees, and that this had triggered the suicide program in the cancer cells. Ten patients could be evaluated as regards the development of their cancer, and in two of them there were signs of tumor regression.
However, the study was actually not designed to test the clinical effects but to ascertain how well the substance was tolerated by the body. With the main adverse reactions confined to temporary tiredness, nausea, headache and confusion, their results would suggest that the substance is well tolerated.
"The side-effects were totally different to those produced by conventional chemotherapy, which bodes well for designing combination therapies," says Lehmann. "And it's in precisely this kind of combination that we think the substance has the greatest potential. In previous laboratory studies we've seen that APR-246 has generated synergy gains when used with chemotherapy due to the mutually enhancing effects of both substances."
Defective p53 is considered one of the most common factors behind the development of cancer. In some cancers, such as ovarian cancer, the vast majority of tumors have defective p53. In total, the p53 tumor suppressor gene is mutated in at least half of all tumors.
"In theory, a drug that restores p53 function should be effective against many different kinds of cancer, provided that the individual tumor contains defective p53," says study team member Prof. Klas Wiman. "We should keep in mind, however, that tumors are very complex."
APR-246 was discovered by Klas Wiman and colleagues at Karolinska Institutet. The present study was led from Karolinska Univ. Hospital in association with Aprea AB. Aprea AB's principal shareholder is Karolinska Development, a company listed on the NASDAQ OMX Stockholm exchange. Wiman is co-founder and shareholder of Aprea, and a member of its board

FDA Urged to Set Arsenic Standards for Rice After New Report

Consumer groups are pressuring the Food and Drug Administrationto set federal guidance on allowable levels of arsenic in rice, prompting the agency to study the issue and consider possible new standards.
So far, FDA officials say they have found no evidence that suggests rice is unsafe to eat. The agency is in the middle of conducting a study of 1,200 samples of grocery-store rice products — short and long-grain rice, cereals, drinks and even rice cakes  — to measure arsenic levels.

Arsenic is thought to be found in rice in higher levels than most other foods because it is grown in water on the ground, optimal conditions for the contaminant to be absorbed in the rice. There are no federal standards for how much arsenic is allowed in food.
Arsenic is naturally present in water, air, food and soil in two forms, organic and inorganic. According to the FDA, organic arsenic passes through the body quickly and is essentially harmless. Inorganic arsenic — the type found in some pesticides and insecticides — can be toxic and may pose a cancer risk if consumed at high levels or over a long period.
How much organic and inorganic arsenic rice eaters are consuming, and whether those levels are dangerous, still remain to be seen.
FDA Commissioner Margaret Hamburg says consumers shouldn't stop eating rice, though she does encourage a diverse diet just in case.
"Our advice right now is that consumers should continue to eat a balanced diet that includes a wide variety of grains — not only for good nutrition but also to minimize any potential consequences from consuming any one particular food," she says.
The agency today released 200 of the expected 1,200 samples after the magazine Consumer Reports released its own study and called for federal standards for arsenic in rice. The FDA will not complete its study until the end of the year, Hamburg says, and cannot draw any conclusions from the results until then.
Both studies show relatively similar levels of arsenic in rice. The FDA's analysis showed average levels of 3.5 to 6.7 micrograms of inorganic arsenic per serving, while Consumer Reports found levels up to 8.7 micrograms. The FDA released 200 samples, while Consumer Reports tested 223.
It is almost impossible to say how dangerous these levels are without a benchmark from the federal government. Consumer Reports uses New Jersey's drinking water standard — a maximum of 5 micrograms in a liter of water — as comparison because it is one of the strictest in the country. But it is unclear how accurate it is to compare arsenic levels in water and arsenic levels in rice — most people consume more water than rice, so drinking water standards may need to be tougher.
It is because of this uncertainty that consumer groups have urged the FDA to set a standard.
Urvashi Rangan of Consumer Reports says the group is not trying to alarm rice eaters and parents feeding their children rice, but to educate them so they can diversify their diets. Consumers should be more protected since arsenic is a known carcinogen, she says.
"It doesn't make sense not to have standards for rice," she says.
The Consumer Reports study found higher levels of arsenic in brown rice than white rice, a result of how the two different types are processed. It also found higher levels in rice produced in Southern U.S. states than in rice from California or Asia.
Hamburg cautioned that neither the FDA nor Consumer Reports had tested enough samples to be certain of any trend.
"These are very few samples and there is great variability in the levels," she says.
Scientists have known for decades that arsenic is present in rice, but the issue has renewed interest as consumers are more interested than ever in what they eat and technology has advanced to the point that inorganic and organic arsenic can be measured separately.
The consumer group's push on arsenic in rice comes a year after it pressured the FDA to define standards for arsenic in apple juice. Michael Taylor, the FDA's deputy commissioner for foods, says that the agency had completed that assessment and would be making recommendations soon. The levels found in apple juice are low, he says.