Points better than the new model of drug resistance in breast cancer treatment

In model of human breast cancer tumors metastatic carcinoma transplanted in mice, from the Washington University School of medicine Alvin j. Siteman Cancer Center (home) and provides insights into how to attack breast cancer unresponsive to medications used to treat them in the St. Louis and San Antonio Breast Cancer Symposium according to survey released 12/12.

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Messy children make better learners: Toddlers learn words for nonsolids better when getting messy in a highchair

Dec. 2, 2013 — Attention, parents: The messier your child gets while playing with food in the high chair, the more he or she is learning.

Researchers at the University of Iowa studied how 16-month-old children learn words for nonsolid objects, from oatmeal to glue. Previous research has shown that toddlers learn more readily about solid objects because they can easily identify them due to their unchanging size and shape. But oozy, gooey, runny stuff? Not so much.

New research shows that changes if you put toddlers in a setting they know well, such as shoving stuff in their mouths. In those instances, word learning increases, because children at that age are "used to seeing nonsolid things in this context, when they're eating," says Larissa Samuelson, associate professor in psychology at the UI who has worked for years on how children learn to associate words with objects. "And, if you expose them to these things when they're in a highchair, they do better. They're familiar with the setting and that helps them remember and use what they already know about nonsolids."

In a paper published in the journal Developmental Science, Samuelson and her team at the UI tested their idea by exposing 16-month-olds to 14 nonsolid objects, mostly food and drinks such as applesauce, pudding, juice, and soup. They presented the items and gave them made-up words, such as "dax" or "kiv." A minute later, they asked the children to identify the same food in different sizes or shapes. The task required the youngsters to go beyond relying simply on shape and size and to explore what the substances were made of to make the correct identification and word choice.

Not surprisingly, many children gleefully dove into this task by poking, prodding, touching, feeling, eating -- and yes, throwing -- the nonsolids in order to understand what they were and make the correct association with the hypothetical names. The toddlers who interacted the most with the foods -- parents, interpret as you want -- were more likely to correctly identify them by their texture and name them, the study determined. For example, imagine you were a 16-month-old gazing at a cup of milk and a cup of glue. How would you tell the difference by simply looking?

"It's the material that makes many nonsolids," Samuelson notes, "and how children name them."

The setting matters, too, it seems. Children in a high chair were more apt to identify and name the food than those in other venues, such as seated at a table, the researchers found.

"It turns out that being in a high chair makes it more likely you'll get messy, because kids know they can get messy there," says Samuelson, the senior author on the paper. The authors say the exercise shows how children's behavior, environment (or setting) and exploration help them acquire an early vocabulary -- learning that is linked to better later cognitive development and functioning.

"It may look like your child is playing in the high chair, throwing things on the ground, and they may be doing that, but they are getting information out of (those actions)," Samuelson contends. "And, it turns out, they can use that information later. That's what the high chair did. Playing with these foods there actually helped these children in the lab, and they learned the names better."

"It's not about words you know, but words you're going to learn," Samuelson adds. Lynn Perry, who helped design the study and analyze the data as part of her doctoral studies at the UI, is the first author on the paper. Johanna Burdinie, who was an UI undergraduate during the project, is a contributing author.

The National Institutes of Health (grant number: R01 HD045713) funded the research. Burdinie was funded by a fellowship from the Iowa Center for Research for Undergraduates.

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Eilat's corals stand better chance of resilience than other sites

Sep. 29, 2013 — Israel's southern Red Sea resort of Eilat, one of whose prime attractions is its colorful and multi-shaped underwater coral reefs, may have a clear advantage in the future over rival coral-viewing sites around the world, scientists at the Hebrew University of Jerusalem and Bar-Ilan University have found.

Coral reefs, earth's richest and most diverse ecosystem, are deteriorating rapidly. One of the most devastating causes for that deterioration is coral bleaching, which typically occurs when seawater temperatures exceed the local summer maximum by one-half to one and half degrees Celsius. At those higher temperatures, the coral's symbiotic algae are lost, leading to the coral's bleaching and eventually its death.

But, while the frequency of coral bleaching is globally increasing, no bleaching event has been observed in the Gulf of Eilat/Aqaba (Eilat sits at the northern end of the gulf), even when nominally bleaching conditions prevail.

The Israeli scientists explain the enigmatic lack of bleaching in the Gulf by the existence of a "warm-water barrier" at the southern Red Sea, allowing only heat-tolerant genotypes of corals to enter the Red Sea from the Gulf of Aden. This occurred following the disappearance of corals from the Red Sea during the last glacial period, some 15,000 years ago. The scientists predict that no bleaching is likely to occur in the Gulf of Eilat/Aqaba in the next 100 years, making it a unique refuge for coral reefs in the world's warming oceans.

The findings of the Israeli researchers, entitled "A Coral Reef Refuge in the Red Sea," was published on Sept. 23 in the journal Global Change Biology." The paper is the outcome of a joint study by Prof. Amatzia Genin of the Alexander Silberman Institute of Life Sciences at the Hebrew University; Dr. Hezi Gildor of the The Fredy & Nadine Herrmann Institute of Earth Sciences at the Hebrew University; and Dr. Maoz Fine of the Mina and Everard Goodman Faculty of Life Sciences at Bar-Ilan University. The work was carried out at the Interuniversity Institute for Marine Sciences in Eilat.

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The above story is based on materials provided by Hebrew University of Jerusalem, via AlphaGalileo.

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Journal Reference:

1. Maoz Fine, Hezi Gildor, Amatzia Genin. A coral reef refuge in the Red Sea. Global Change Biology, 2013; DOI: 10.1111/gcb.12356

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Wagon-wheel pasta shape for better LED lights

Sep. 29, 2013 — One problem in developing more efficient organic LED light bulbs and displays for TVs and phones is that much of the light is polarized in one direction and thus trapped within the light-emitting diode, or LED. University of Utah physicists believe they have solved the problem by creating a new organic molecule that is shaped like rotelle -- wagon-wheel pasta -- rather than spaghetti.

The rotelle-shaped molecule -- known as a "pi-conjugated spoked-wheel macrocycle" -- acts the opposite of polarizing sunglasses, which screen out glare reflected off water and other surfaces and allow only direct sunlight to enter the eyes.

The new study showed wagon-wheel molecules emit light randomly in all directions -- a necessary feature for a more efficient OLED, or organic LED. Existing OLEDs now in some smart phones and TVs use spaghetti-shaped polymers -- chains of repeating molecular units -- that emit only polarized light.

"This work shows it is possible to scramble the polarization of light from OLEDs and thereby build displays where light doesn't get trapped inside the OLED," says University of Utah physicist John Lupton, lead author of a study of the spoked-wheel-shaped molecules published online Sunday, Sept. 29 in the journal Nature Chemistry.

"We made a molecule that is perfectly symmetrical, and that makes the light it generates perfectly random," he adds. "It can generate light more efficiently because it is scrambling the polarization. That holds promise for future OLEDs that would use less electricity and thus increase battery life for phones, and for OLED light bulbs that are more efficient and cheaper to operate."

Lupton emphasizes the study is basic science, and new OLEDs based on the rotelle-shaped molecules are "quite a way down the road."

He says OLEDs now are used in smart phones, particularly the Samsung Galaxy series; in pricey new super-thin TVs being introduced by Sony, Samsung, LG and others; and in lighting.

"OLEDs in smart phones have caught on because they are somewhat more efficient than conventional liquid-crystal displays like those used in the iPhone," he says. "That means longer battery life. Samsung has already demonstrated flexible, full-color OLED displays for future roll-up smart phones." Lupton says smart phones could produce light more efficiently using molecules that don't trap as much light.

The large rotelle-shaped molecules also can "catch" other molecules and thus would make effective biological sensors; they also have potential use in solar cells and switches, he adds.

The study was funded by the Volkswagen Foundation, the German Chemical Industry Fund, the David and Lucille Packard Foundation and the European Research Council.

Lupton is a research professor of physics and astronomy at the University of Utah and also on the faculty of the University of Regensburg, Germany. He conducted the study with Utah physics graduate student Alexander Thiessen; Sigurd Hoger, Vikas Aggarwal, Alissa Idelson, Daniel Kalle and Stefan-S. Jester of the University of Bonn; and Dominik Wursch, Thomas Stangl, Florian Steiner and Jan Vogelsang of the University of Regensburg.

Freeing Trapped Light

While conventional LEDs use silicon semiconductors, OLEDs in some of the latest cell phones and TVs are made with "pi-conjugated polymers," which are plastic-like, organic semiconductors made of a chain of repeating molecular units.

"Conjugated polymers are a terrible mess," Lupton says. "They now make only mediocre OLEDs, although people like to claim the opposite."

For one thing, three-quarters of the light energy is in a state that normally is inaccessible -- a problem addressed by another recent University of Utah study of OLEDs. Lupton says his study deals with another problem, which exists even if the other problem is overcome: the polarization of light in pi-conjugated polymers that leads to the "trapping" or loss of up to 80 percent of the light generated.

"Light is an oscillating field like a wave, and a wave moves in a certain direction," Lupton says. "We call this direction of oscillation a polarization."

Because polymers are long molecules like spaghetti, when an electrical current is applied to a polymer, "the electrons can only flow in one direction and that generates the light waves," Lupton says. "Because those light waves only oscillate in one direction, the light can get trapped inside the OLED, which is a little bit like an optical fiber."

That, he adds, is why even with the latest OLED smart phones, "your battery is dead in two days because the display uses a lot of the electricity."

"The rotelle -- technically called oligomers -- are basically wrapped-up polymers," Lupton says. "They all have the same shape, but they do not emit polarized light because they are round. They generate waves that vibrate in all directions. The light doesn't have a fixed polarization; it doesn't vibrate in a fixed direction. It always can get out."

Lupton compares the ability of the wagon-wheel molecules to emit unpolarized light in all directions to what happens when a pencil is balanced perfectly on its tip and falls in a different, random direction each time.

Cooking up a Wagon Wheel-Shaped Molecule

The international team of physicists and chemists set out to make molecules that generate light waves in all directions rather than in a fixed direction. In the new study, they report how the created the spoked-wheel molecules, made images of them and did single-molecule experiments, including looking at photons, or light particles, emitted one at a time from a single molecule. In those experiments, they shined an ultraviolet light on the rotelle-shaped molecules to generate visible light photons.

"We showed that every photon that comes out has a scrambled polarization, the polarization changes randomly from photon to photon," Lupton says.

The emitted light is blue-green, Lupton says, but images accompanying the paper -- taken with a scanning tunneling electron microscope -- show the rotelle- and spaghetti-shaped molecules with a false yellow-brown color to provide good contrast.

Each wagon-wheel molecule measures only six nanometers wide, which is large for a molecule but tiny compared with the 100,000 nanometer width of a human hair.

Using rotelle-shaped oligomers instead of spaghetti-shaped polymers, "in principle, we should be able to double the efficiency of getting the light out" -- although that remains to be proved, Lupton says.

"Even if we scramble the polarization, we're always going to have a bit of light trapped in the OLED," he says. "Those losses are now 80 percent, and we probably could get down to 50 or 60 percent."

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Marriage associated with better cancer outcomes

Sep. 23, 2013 — People who are married when diagnosed with cancer live longer than those who are not, report researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital. Married patients also tended to have cancers diagnosed at an earlier stage -- when it is often more successfully treated -- and to receive more appropriate treatment.

The study's findings will be published online by the Journal of Clinical Oncology on Sept. 23.

"Our data suggests that marriage can have a significant health impact for patients with cancer, and this was consistent among every cancer that we reviewed," said Ayal Aizer, MD MHS, chief resident of the Harvard Radiation Oncology Program and the paper's first author. "We suspect that social support from spouses is what's driving the striking improvement in survival. Spouses often accompany patients on their visits and make sure they understand the recommendations and complete all their treatments."

Utilizing the National Cancer Institute's Surveillance, Epidemiology and End Results Program, the researchers conducted a retrospective analysis of 734,889 people who were diagnosed with cancer between 2004 and 2008. They focused on the ten leading causes of cancer deaths in the United States: lung, colorectal, breast, pancreatic, prostate, liver/bile duct, non-Hodgkin lymphoma, head and neck, ovarian, and esophageal cancer. They also adjusted the data to account for a number of demographic factors, including age, sex, race, residence type, education and median household income, that could have an effect on the health outcome.

Their analysis found that in comparison with married patients, unmarried cancer patients, including those who were widowed, were 17 percent more likely to have metastatic cancer (cancer that spread beyond its original site) and were 53 percent less likely to receive the appropriate therapy.

"We don't just see our study as an affirmation of marriage, but rather it should send a message to anyone who has a friend or a loved one with cancer: by being there for that person and helping them navigate their appointments and make it through all their treatments, you can make a real difference to that person's outcome," said the study's senior author Paul Nguyen, MD, a radiation oncologist at Dana-Farber and Brigham and Women's. "As oncologists, we need to be aware of our patients' available social supports and encourage them to seek and accept support from friends and family during this potentially difficult time."

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Washington U researchers have developed a new model of drug resistance in breast cancer treatment tips for better.

May be researchers in medicine, Washington University in St. Louis were transplanted into human breast cancer tumors are a valuable tool in search models of metastatic carcinoma of superior and better treatments are shown.

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New protein knowledge offers hope for better cancer treatment

Sep. 19, 2013 — When the pharmaceutical industry develops new medicines -- for example for cancer treatment -- it is important to have detailed knowledge of the body's molecular response to the medicine.

"With a better knowledge of the many complex processes which are activated in connection with illness and medication, the better the possibility of developing new drugs. We have now moved closer to targeting and treating certain cancers using the so-called PARP inhibitors -- medical inhibitors used in the latest types of cancer treatment. Certain types of tumours rely heavily on PARP proteins in order to self-repair, and PARP inhibitors can be used specifically to kill cancer cells," says Michael Lund Nielsen, Associate Professor at The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The researchers have developed an advanced method for identifying the proteins which are modified with ADP-ribosylation -- a biological modification affecting a cell's ability to repair DNA damage. The research findings have just been published in the scientific journal Molecular Cell.

The forms of cancer causing most deaths among women are lung cancer, breast cancer, colon cancer, pancreatic cancer and ovarian cancer. PARP inhibitors appear to be an effective treatment for hereditary breast and ovarian cancer, but little is known about the treatment details. Our new analysis method can help shed light on precisely how the PARP inhibitor treatment is working because it can offer us more knowledge about the biological function of PARP proteins. In the long term, it will enable us to design better and more precise PARP inhibitors, says Michael Lund Nielsen, Associate Professor at the Novo Nordisk Foundation Center for Protein Research.

DNA repair crucial for cell health

Every day, our DNA is exposed to damage which our healthy cells are capable of repairing and thus keep healthy. But the ability of certain cancer cells to repair their own DNA damage is impaired compared to standard cells and this is exploited using PARP inhibitors which block the repair systems of cancer cells. In principle, PARP inhibitors both damage healthy and cancer cells, but normal cells have different survival mechanisms in comparison to cancer cells. PARP inhibitors therefore appear to offer new and much improved cancer treatment options.

Treatment with PARP inhibitors

PARP treatment is a new and individualised type of cancer treatment. It is a so-called targeted treatment which exploits a weakness inherent in cancer cells. PARP inhibitors have yet to be marketed, but many companies are testing them in clinical (phase 1-3) trials. So far, the PARP inhibitors are only available for experimental purposes.

"Our analysis method makes it possible to map the movement of PARP inhibitors, opening up possibilities for the optimised treatment of breast and ovarian cancers with fewer side effects. It is also being examined whether PARP inhibitors can be used in combination with chemotherapy and/or radiation therapy in connection with other cancers. In particular, radiation therapy produces many unpleasant side effects, but there are indications that optimised treatment could be achieved by combining radiation therapy with PARP inhibitors, as PARP inhibitors make cancer cells more susceptible to radiation therapy," says Michael Lund Nielsen.

Using radiation and chemical compounds, the researchers started by damaging the DNA in cells. They then isolated proteins modified with the ADP-ribosylation and identified them using mass spectrometry, a technique making it possible to determine a protein's identity and the sites where the ADP-ribosylation chemical changes occur.

ADP-ribosylation

ADP-ribosylation is a biological protein modification controlling several key cellular processes, such as the repair of DNA damage. Every day, our DNA suffers damage between one thousand and one million times and it is therefore crucial that the cells can repair their DNA. Certain cancer cells are incapable of self-repair without ADP-ribosylation and this can be exploited for targeted cancer treatment via PARP inhibitors. By inhibiting the PARP proteins that perform ADP-ribosylation, it is thought that these cancer cells are prevented from self-repair and will therefore perish.

PARP and PARP inhibitors

PARP is a group of DNA repair proteins that play an important role in some cancers as certain types of tumours are highly dependent on PARP in order to repair themselves. These tumours are therefore vulnerable to targeted treatment using PARP-inhibiting compounds. PARP inhibitors block the DNA repair system of cancer cells, but few details are known about the molecular aspects surrounding the PARP inhibitors, including which proteins are affected by them. The researchers' new analysis method makes it possible to map the movement of PARP inhibitors, which enables optimised treatment with fewer side effects.

Protein modifications

Proteins are chain-shaped biological macromolecules built up of amino acids. The cells are predominantly controlled by proteins, and many of the characteristics of the protein functions are controlled by, among others, molecular modifications that can be attached to amino acids. Functions that are controlled by protein modifications include: the localisation of proteins at specific locations in the cell, the marking of proteins for degradation and the turning on/off of the biological activity of the protein. Studies of the modifications that proteins contain are therefore important for understanding a wide range of cellular processes.

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New test aims to better detect viral infections

WASHINGTON (AP) — It happens too often: A doctor isn't sure what's causing someone's feverish illness but prescribes antibiotics just in case, drugs that don't work if a virus is the real culprit.

Now Duke University researchers are developing a blood test to more easily tell when a respiratory illness is due to a virus and not a bacterial infection, hoping to cut the dangerous overuse of antibiotics and speed the right diagnosis.

It works by taking a fingerprint of your immune system — how its genes are revving up to fight the bug. That's very different from how infections are diagnosed today. And if the experimental test pans out, it also promises to help doctors track brand-new threats, like the next flu pandemic or that mysterious MERS virus that has erupted in the Middle East.

That viral "signature could be quite powerful, and may be a game-changer," said Dr. Geoffrey Ginsburg, Duke's genomic medicine chief. He leads the team that on Wednesday reported that a study involving 102 people provided early evidence that the test can work.

Today, when symptoms alone aren't enough for diagnosis, a doctor's suspicion guides what tests are performed — tests that work by hunting for evidence of a specific pathogen. Fever and cough? If it's flu season, you might be tested for the flu virus. An awful sore throat? Chances are you'll get checked for strep bacteria. A negative test can leave the doctor wondering what germ to check for next, or whether to make a best guess.

Moreover, rapid in-the-office tests aren't always accurate and can miss infections. So patients may have blood or other samples sent to labs to try to grow any lurking bacteria and tell if it's to blame, additional testing that can take days.

"This is something we struggle with every day," said Dr. Octavio Ramilo, infectious disease chief at Nationwide Children's Hospital in Columbus, Ohio, who wasn't involved in the new study. Particularly with children, a respiratory virus and a bacterial infection "in the beginning look completely alike," he added.

Hence researchers at a number of universities are trying to harness a fairly recent discovery: As your immune system detects an invading bug, different genes are activated to fend off a viral infection than to fight a bacterial or fungal one. Those subtle molecular changes appear to be occurring even before you feel any symptoms. And they form distinct patterns of RNA and proteins, what's called a genomic fingerprint.

The Duke team discovered 30 genes that are switched on in different ways during a viral attack. The test essentially is a freeze-frame to show "what those genes are doing at the moment in time that it's captured," explained Duke lead researcher Dr. Aimee Zaas, an infectious disease specialist.

Small studies spotted that viral signature in people who volunteered to be infected with different influenza strains for science.

For a more real-world simulation, the researchers then analyzed blood samples stored from feverish people who had come to the emergency room — and who were eventually diagnosed, the old-fashioned way, with either some type of virus or a bacterial infection.

The genomic test proved 89 percent accurate in sorting out who had a virus, and did even better at ruling out those who didn't, Zaas reported Wednesday in the journal Science Translational Medicine.

It took 12 hours to get results. The researchers hope to speed that up so that it might work as quickly as some in-office tests.

Still, "it's a promising tool," said Ramilo, an Ohio State University professor who is doing similar research. He called the Duke study an important step toward creating a commercial test, and predicts one might reach the market within five years.

Why would a doctor want to know merely that a virus is present and not which virus? That's enough information to rule out antibiotics, Zaas said. Unnecessary antibiotic use is one factor in the growing problem of drug-resistant germs, which the government blames for more than 23,000 deaths a year.

Plus, if a dangerous new virus begins spreading, like MERS, this approach could help avoid quarantining people unnecessarily by telling right away which ones are virus-free, Ginsburg added.

In Ohio, Ramilo is exploring a more immediate need: When young infants have high fevers, they're often hospitalized while doctors run a battery of tests to find the fraction who have a serious bacterial infection. He is leading a study involving 22 pediatric emergency rooms to see if a genomic fingerprint approach could separate which babies really need all that testing.

But the virus-or-not question is just the beginning, Ramilo said. His research suggests genomic fingerprints also can distinguish a flu strain from other common viruses. And the Duke team is analyzing a huge study of students living in dormitories, to see if the genomic test detected who was incubating the flu before their first sniffle — and thus might be useful in stemming outbreaks.

Copyright c 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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New mutation identified, associated with better survival in lung cancer patients

Sep. 12, 2013 — Japanese researchers have identified a mutation associated with a higher incidence of lung cancer in Japanese women who do not smoke, but better survival in lung cancer patients. In a study published today in the journal PLOS ONE, the team from the RIKEN Center for Life Science Technologies shows that the mutation, a single nucleotide polymorphism (SNP) in a gene that protects cells from oxidative stress, is found four times more frequently in women than in men.

Lung cancer is the leading cause of cancer-related deaths in many industrialized countries. Most deaths are due to long-term exposure to cigarette smoke, but non-smokers account for 10 -- 15% of cases.

Dr. Toshihisa Ishikawa and his team analyzed the DNA of patients with primary lung cancer and found that non-smoking Japanese women with two copies of the SNP (-617A) in the NFR2 gene had a markedly higher incidence of adenocarcinoma of the lung, as compared with non-smoking, homozygous males.

Furthermore, they find that both male and female lung cancer patients homozygous for the same SNP in the NRF2 gene survive lung cancer much better.

Nuclear factor erythroid-derived 2 (NF-E2)-related factor (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidation and detoxification genes, and protects normal cells from external toxic challenges and oxidative stress.

Their study also suggests that lung cancer patients harboring a SNP (-617A) allele in the NRF2 gene in combination with the wild-type allele of the MDM2 gene have better prognosis.

"This is the first report providing clinical evidence that homozygous alleles for the SNP (-617A), one of the intrinsic genetic polymorphisms in the NRF2 gene, are associated with the overall survival of lung cancer patients," explains Dr. Ishikawa.

"The study strongly suggests that the presence of homozygous alleles for this SNP is a good prognostic biomarker for the assessment of the overall survival chances of patients with adenocarcinoma, as well as a practical tool for personalized cancer therapy," he concludes.

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The above story is based on materials provided by RIKEN.

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Journal Reference:

1. Yasuko Okano, Uru Nezu, Yasuaki Enokida, Ming Ta Michael Lee, Hiroko Kinoshita, Alexander Lezhava, Yoshihide Hayashizaki, Satoshi Morita, Masataka Taguri, Yasushi Ichikawa, Takeshi Kaneko, Yutaka Natsumeda, Tomoyuki Yokose, Haruhiko Nakayama, Yohei Miyagi, Toshihisa Ishikawa. SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women. PLoS ONE, 2013; 8 (9): e73794 DOI: 10.1371/journal.pone.0073794

Note: If no author is given, the source is cited instead.

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A better malaria-fighting machine

Sep. 10, 2013 — Although the asymptomatic liver stage of malaria is a crucial part of the parasite's development inside humans, it remains an unexplored black box. Until recently, scientists were convinced that malaria parasites were so adept at taking over liver cells that any attempt by the liver cell to attack the parasite would be futile. Now, researchers at Seattle BioMed are using systems biology to begin to unravel part of this mystery, with the finding that liver cells infected with malaria parasites are more vulnerable than previously thought, and that existing drugs can be leveraged to force those infected cells to self destruct while leaving the healthy cells intact. These results are published this month in Cell Death & Disease.

Malaria targets the liver

When a malaria-infected mosquito bites a human, parasites migrate from the mosquito's salivary glands to the human liver, where they find and occupy a cell. Over the next seven to ten days, the parasite multiplies hundreds of thousands of times over, dramatically expanding the size of the liver cell but causing no other symptoms. Finally, the parasites burst into the blood stream, causing symptoms that include fever, chills, and nausea, and in some cases death. Malaria kills nearly a million children every year, with a child dying of the disease every 43 seconds.

Conventional scientific wisdom regarding the "liver stage" of disease was that the malaria parasites make their host cells exceptionally resistant to death. This meant that bombarding the liver with drugs that cause cells to commit cell suicide, or apoptosis, would destroy healthy liver cells while allowing infected cells to escape unscathed. Now, new data collected by Alexis Kaushansky, Ph.D., and Stefan Kappe, Ph.D., of Seattle BioMed shift this paradigm.

Finding the vulnerabilities in malaria's defenses

The work published this month in Cell Death & Disease is the second major breakthrough in this area in recent months. In March, Kaushansky and Kappe demonstrated that malaria-infected cells were not the indestructible survivors as previously believed. By using drugs to stimulate p53, a classic tumor suppressor molecule, Kaushansky and Kappe were able to help liver cells fight off the malaria parasite. This piece of knowledge led them to wonder: How many other targets could make malaria-infected cells vulnerable? Is the pool of drugs that can effectively target malaria parasites before they cause symptoms larger than we imagined?

The goal was simple: find a pathway that, when activated, kills infected cells while leaving healthy cells unaffected, and eliminates malaria parasites before they cause disease. Kaushansky had noticed in the previous study that infected cells showed higher levels of survival molecules -- ones that suppressed apoptosis -- in the mitochondria. She wondered if stimulating cells to kill themselves using that particular pathway would result in more damage to infected cells, with little or none in healthy cells.

By administering chemotherapy sensitization agents that target a molecule called Bcl-2, Kaushansky was able to stimulate that cell death pathway, causing the parasite-infected cells to kill themselves while leaving healthy liver cells mostly intact. This finding represents a fundamentally new way to kill malaria parasites while in the liver.

Uncovering the range of weapons already at our disposal against malaria

"Malaria still threatens a quarter of the world's population despite decades of eradication efforts, and thus to effectively combat this disease a fresh approach must be taken," says Kaushansky. "Using systems biology, we were able to show the existence of additional pathways that can be used to fight infected cells, demonstrating that our previous research involving p53 was not an isolated case and that we have only begun to scratch the surface of how broad these kinds of host-based therapeutics can be."

The broader range of targets means that the drug possibilities for fighting off the liver stage of malaria are much larger than previously thought. "In this study, we looked at an entirely separate pathway, working by an entirely different mechanism, and it still worked to help kill infected cells," says Kappe. "This gives us hope that there are many other pathways that may also work as drug targets, and we look forward to conducting additional research into other potential pathways that may also hold potential for treating malaria."

Using existing drugs to target the liver stage of malaria also carries other potential benefits. Because the drugs tested have already been developed for other purposes, explains Kaushansky, there are substantial economic benefits in repurposing the drugs for malaria. Additionally, because the drugs target the host liver cell rather than the parasite, the potential for drug resistance to grow against these therapies is far lower. "This could fundamentally change the way we think about fighting the malaria parasite," she says.

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Antibiotics prevent UTIs better than probiotics

AppId is over the quota
AppId is over the quota

NEW YORK (Reuters Health) - Antibiotics are still better than probiotics at preventing urinary tract infections, but at least "good bacteria" don't add to a person's antibiotic resistance, a new study concludes.

Recurring UTIs are common among some women and low-dose antibiotics are sometimes used to prevent them. The worry is that overuse of the drugs also reduces their effectiveness by making disease-causing bacteria like E. coli resistant.

"This is an increasing worldwide problem, resulting into less and less treatment options for (severe) bacterial infections in all countries of the world," Dr. Suzanne Geerlings, from the Academic Medical Center at the University of Amsterdam in The Netherlands and one of the new study's authors, wrote in an email to Reuters Health.

Geerlings and her colleagues recruited 252 women between January 2005 and September 2007 for a trial to compare the use of antibiotics and probiotics to prevent UTIs.

The participants, who lived in communities surrounding the medical center, were all postmenopausal -- a time when vulnerability to UTIs increases because of hormonal changes, according to the researchers.

All the participants reported having had at least three UTIs in the year before the trial began, and the average number was seven.

The women were separated into two groups of about the same size. One group took a single dose of the antibiotic co-trimoxazole (Bactrim, Septra and others) every day for twelve months, while the other group took two capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, both types of beneficial bacteria, daily.

All the participants also took placebo pills so the patients and the people dispensing the pills wouldn't know who received which treatment -- to minimize any influence on the study's results.

The researchers then tracked how many UTIs occurred in each group of women over a year. They also collected vaginal swabs and samples of the women's urine and feces every month to test for the presence of good bacteria and infection-causing bacteria like E. coli.

In addition, women took a monthly survey asking about symptoms of UTIs, side effects, other infections and antibiotic use.

Overall, the antibiotics were slightly better at keeping UTIs at bay.

About 69 percent of the women in the group taking the antibiotic had one or more UTIs within the year. On average, the antibiotic group had 2.9 UTIs per woman.

As for the probiotic group, about 79 percent had a UTI within the year, with an average of 3.3 UTIs per woman.

The women taking the antibiotic also seemed to go twice as long without a UTI -- six months, compared with three months among women taking the probiotics.

Based on the women's urine and feces samples, however, resistance to a range of antibiotics seemed to increase within the first month in the antibiotic group.

Before the study, about 20 percent to 40 percent of E. coli in samples from all the women's bodies were resistant to co-trimoxazole.

At the 12-month mark, between 80 percent and 95 percent of the bacteria were resistant in the women taking the antibiotic.

Rates of resistant E. coli were slightly lower at 12 months in women taking the probiotics than when the study began.

Similar changes in antibiotic resistance were seen for a range of other antibiotics, including ciprofloxacin and gentamicin, among both groups of women -- which the researchers speculate might be because the same mechanism in certain bacteria allows them to resist several different drugs.

The absence of increased resistance among women taking the probiotics means that "lactobacilli may be an acceptable alternative for prevention of UTIs, especially in women who dislike taking antibiotics," the researchers wrote in the Archives of Internal Medicine.

The study, however, had several limitations.

More than 80 women dropped out of the study by the end of the year because of side effects and other reasons. A greater number of those taking the probiotics had diarrhea compared to those taking the antibiotics, for instance. Other reasons for dropping out included the participant not thinking the treatment was working, or she couldn't adhere to study's directions.

As a result, the researchers did not have the number of participants in each group they would have liked to give the findings statistical weight.

Despite the study's weaknesses, a commentary published in the same journal called the findings "exciting and compelling."

"I think we need to appreciate that the normal flora in our body is another system we need for good health and antibiotics disrupt it and leave lasting effects… We need to think of antibiotics as a situation that has some risk," Dr. Barbara Trautner, one of the commentary's authors, told Reuters Health.

Trautner, of the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine in Houston, said that probiotics may be an acceptable alternative but they need further exploration.

Topical estrogen creams are sometimes used to prevent UTIs in menopausal women, but many women prefer to avoid using hormones.

In her commentary, Trautner wrote that 60 percent of women in the United States experience UTIs or bladder infections during their lifetimes, and they recur in about a third of those women.

"We don't have terrific preventive strategies so a probiotic approach would be beneficial and promising," Trautner said.

For right now, she said most women with recurring UTIs have exhausted any type of behavioral changes that might help prevent the infections, and are left with low-dose antibiotics as their only recourse.

SOURCE: http://bit.ly/JUywUA and http://bit.ly/JUyDzE Archives of Internal Medicine, May 2012.

Exercise Controls Weight in White Girls Better Than in Black Girls: Study

AppId is over the quota
AppId is over the quota

WEDNESDAY, June 6 (HealthDay News) -- Exercise appears less likely to prevent obesity among black teenage girls than their white peers, a new study shows.

British researchers who gauged the effect of exercise on more than 1,100 girls, aged 12 to 14, surmised that black teen girls may be less sensitive than white teen girls to the effects of physical activity to prevent obesity.

"Higher levels of physical activity were associated with lower risk of obesity among white girls but not among black girls," wrote study authors James White and Russell Jago.

This is of concern because obesity rates are increasing at a greater rate among black teen girls than other U.S. youths, putting them at greater risk for heart disease, according to background information in the study. Black American girls were 80 percent more likely than white girls to be overweight in 2007-2010, the U.S. Department of Health and Human Services' Office of Minority Health reported. And about four out of five black American women are overweight or obese.

"At present, we don't know whether these differences can be attributed to genetics," said White, a researcher at Cardiff University in Wales. While other studies have found black girls consume more calories than white girls, he said this study took those differences into account, suggesting there may be other reasons. "These may be genetic, but we don't really know," he said.

However, at least one expert believes the study results may reflect lifestyle differences, which can be addressed, not just genetics.

White and Jago, of the University of Bristol in England, evaluated data on girls who participated in the long-running National Heart, Lung, and Blood Institute Growth and Health Study.

The researchers were looking at factors associated with obesity and the development of heart disease risk factors.

For this study, published in the June issue of the Archives of Pediatric and Adolescent Medicine, the research team focused on 538 black girls and 610 white girls for whom they had data on physical activity, obesity and other measures.

The girls' overall level of physical activity was measured for three days with a device that could detect frequency of movement and speed. Their TV viewing hours, height, weight, body-mass index (BMI), percent of body fat and daily calorie intake were also recorded. BMI, a calculation based on height and weight, is a reference used to determine obesity.

At age 12, the activity levels were higher in white girls than in black girls. The black girls had a higher BMI and body fat percentage, and ate more calories daily. They also watched more TV: The median -- meaning half watched more, half watched less -- was 44.3 hours a week for black girls vs. 24.5 for white girls.

Median daily caloric intake was slightly higher for black girls -- 1,912 vs. 1,906 for white girls.

At 12 years of age, 14 percent of the black girls were obese, compared to 4.3 percent of the white girls. At 14 years, 15.6 percent of the black girls and 5.1 percent of the white girls were obese.

That no link was found between physical activity levels and obesity among black girls is consistent with other research showing that fat-burning rates in response to physical activity are lower in black girls during puberty and adulthood than in whites.

Lifestyle issues, rather than genetics, may partly explain the results, said Pete McCall, an exercise physiologist with the American Council on Exercise.

Noting that black girls watch much more TV than white girls, he said, "That would be one area to change." They could shut off the TV and get exercise, "but the neighborhood may not be conducive," he said.

Parent education and income might affect the results, too, McCall speculated. More than half the parents of white girls had a college degree, but fewer than one-quarter of the black girls' parents did. The incomes of white girls' parents were higher, too.

"College education and income levels [of the parents] can play a role in the amount of physical activity a person gets," he added.

The authors noted that the black girls began menstruating earlier than the whites, which could also influence weight gain.

Encouraging black teen girls to exercise is still important, but different approaches may be needed to prevent obesity in black girls, the authors said.

"Our findings require replication before any real recommendations can be made," White said. "They do, however, suggest that black girls should be particularly attentive in controlling their caloric intake."

More information

To learn more about obesity and black Americans, visit the U.S. Office of Minority Health.

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