Genetic Fingerprints Track Drug-Resistant Malaria Parasites

Genetic Fingerprints Track Drug-Resistant Malaria Parasites29 Apr 2013-nbsp;-nbsp;-nbsp;




New artemisinin-resistant strains of the malaria-causing parasite Plasmodium falciparum are spreading rapidly in Cambodia, an

international group of scientists says in a research paper that also reveals how the drug-resistant strains can be identified from their genetic

fingerprints.

Senior author Dominic Kwiatkowski, from the University of Oxford and the Wellcome Trust Sanger Institute near Cambridge, and colleagues,

discovered the new artemisinin-resistant strains in western Cambodia, a known hotspot for drug-resistance. They write about this, and how they

were able to identify distinct genetic patterns for each of the strains, in the 28 April online issue of Nature Genetics.

Artemisinin is the key drug against malaria, which is caused when the parasite P. falciparum gets into the bloodstream through a mosquito

bite. However, according to the World Health Organization (WHO), the emergence of drug-resistant strains of the parasite is weakening the

impact of artemisinin, putting hundreds of thousands of lives at risk.

Co-author Nicholas White, a professor from the Centre for Tropical Medicine at the University of Oxford, says in a statement:

"Artemisinin resistance is an emergency which could derail all the good work of global malaria control in recent years. We desperately need

methods to track it in order to contain it, and molecular fingerprinting provides this."

Using new genome sequencing technologies, the international group sequenced the entire DNA of 825 P. falciparum samples from South

East Asia and Africa and found an "unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western

Cambodia".

The technologies enabled them to pick out genetic patterns or "fingerprints" for each of the artemisinin-resistant strains.

Kwiatkowski tells the press:

"Our survey of genetic variation showed that western Cambodian malaria parasites had a population structure that was strikingly different to those

of the other countries we analysed."

"Different not just from countries in Africa, but also different from malaria parasite populations in neighbouring Thailand, Vietnam, and even

Eastern Cambodia," he adds.

The findings also give some important clues about how resistance emerges and persists in certain parasite populations.

The researchers suggest their approach offers a useful new way to detect and track the global emergence of drug resistance. One important benefit, for

instance, is that you don't have to know the genetic causes of drug resistance to identify resistant strains.

This counts as an important step toward surveillance and efforts to eliminate malaria worldwide. Health authorities need fast and efficient tools

for genetically detecting drug-resistant parasites in order to track their emergence and spread.

In their paper, the authors show that applying their techniques would allow the authorities to monitor the spread and evolution of drug-resistant parasites in real time.

At first the group thought they were just finding anomalies. But further investigations revealed three distinct artemisinin-resistant parasite

populations that differed not just from the other populations that were still susceptible to the drug, but also from each other.

"It is as if there are different ethnic groups of artemisinin-resistant parasites inhabiting the same region," Kwiatkowski explains.

The findings also offer some new clues as to why western Cambodia is such a hotspot for the emergence of drug-resistant malaria parasites,

something that has been puzzling researchers for some time. Resistance to other malaria drugs, chloroquine and sulfadoxine/pyrimethamine, first

began in Southeast Asia and spread to Africa.

As well providing what the researchers describe as "a population-level genetic framework for investigating the biological origins of artemisinin

resistance", they believe their findings also provide a way of "defining molecular markers to assist in its elimination".

White, who is also based at the Mahidol-Oxford Tropical Medicine Research Unit at Mahidol University, in Bangkok, Thailand, says:

"Whilst we have not yet identified the precise mechanism of action or resistance to artemisinin, this research represents substantial progress in

that direction."

In its World Malaria Report 2012, the WHO suggests that the massive

progress in the fight against malaria achieved over the last decade could stall because of lack of money.




Written by Catharine Paddock PhD













Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today

Cancer Cells Are Nimbler Than Non-Malignant Cells

Cancer Cells Are Nimbler Than Non-Malignant Cells29 Apr 2013-nbsp;-nbsp;-nbsp;





Clues about how cells become cancerous are revealed in a new catalogue of their physical and chemical features. The catalogue shows,

among other things, how malignant cells that break out of tumors and invade other organs are nimbler and more aggressive than non-malignant

ones: they are able to pass more easily through small spaces, and they exert a greater force on their environment.

To compile the catalogue, 100 researchers from 20 different centers across the US teamed up to explore the physics and chemistry that shapes the

development of cancer cells, a process that is somewhat unclear from a physical science perspective.

The researchers, who belong to the Physical Sciences-Oncology Centers (PS-OC) sponsored by the National Cancer Institute, hope their catalogue

will aid the earlier detection of cancerous cells, and even someday help prevent or treat metastatic cancer, that is cancer that has spread and

started new tumor sites in other parts of the body, and which is responsible for the vast majority of all cancer deaths.

In a paper published online on 26 April in the journal Scientific Reports, they describe how they carried out a systematic molecular and

biophysical comparison between two cell lines, one of metastatic breast cancer cells and the other of non-malignant breast cells, and listed major

differences that offer new insights into how cells change from being non-malignant to metastatic.

Robert Austin, professor of physics and leader of the Princeton University PS-OC in New Jersey, says in a statement:

"By bringing together different types of experimental expertise to systematically compare metastatic and nonmetastatic cells, we have advanced

our knowledge of how metastasis occurs."

Metastatic Cells Are Essentially "Jailbreakers"

For instance, they found the two kinds of cell showed differences in in mechanical properties, how they stick to surfaces, how they migrate,

respond to oxygen, and produce protein.

Austin and the team in the Princeton PS-OC discovered that even though they travel more slowly than non-malignant cells, metastatic

cells travel further and go in a straighter line.

They created an environment made of silicon that simulates the structure of tissue inside the body and observed what happened as the cells made

their way through tiny cell-sized chambers and channels etched in the silicon.

Austin says metastatic cells "are essentially jailbreakers", because they can break through the extracellular matrix, the tough

membrane wall that the body creates in an attempt to seal the tumor off from healthy tissue.

Princeton's physicists and engineers have expertise in microfabrication technology, which is used to make integrated circuits and solar cells. They

called on this expertise to make the tiny silicon chambers used in the study.

The Princeton PS-OC also includes teams from the Johns Hopkins University School of Medicine, the Salk Institute for Biological Studies and the

University of California-Santa Cruz.

Metastatic Cells More Resilient to Low Oxygen and Make Proteins that Make them More Mobile

In their paper the researchers also describe how they found metastatic cells recover more quickly from the stress of a low-oxygen

environment than do non-malignant cells, confirming results of previous studies.

Many metastatic cells do perish when oxygen supply is low, but those that survive rebound with great vigour, confirming the view that individual

cells play an important role in the spread of cancer.

The Princeton PS-OC also discovered malignant cells make proteins that make them more mobile and able to invade the extracellular

matrix and escape the tumor. They discovered this by comparing total protein production with that produced in metastatic cells.

Measuring How Cells Push on Surrounding Cells to Expression of Genes and Proteins

Across all the PS-OC network, the researchers use the same two breast epithelial cell lines: non-tumorigenic MCF-10A and metastatic MDA-MB-

231, commonly used models of cancer metastasis. They also use the same reagents and protocols so that results can be compared.

Their lab methods ranged from taking physical measures of how the cells push on surrounding cells to measuring their gene and protein

expression.

Nastaran Zahir Kuhn, program manager for the PS-OC at the National Cancer Institute, says in a statement:

"Roughly 20 techniques were used to study the cell lines, enabling identification of a number of unique relationships between observations."

Metastatic Cells Are Softer and Exert More Force On their Surroundings

For instance, using a technique called atomic force microscopy, the researchers found that metastatic cells seem to be softer than nonmalignant cells, while

another approach, called traction force microscopy, indicated they exert more force on their surroundings.

These two properties give important clues about how metastatic cells escape their walled-in tumor prison. These could help them for instance,

stick to, migrate on, and remodel the tough extracellular matrix that the body has surrounded the tumor with. But at the same time, being softer,

metastatic cells can also squeeze through the small spaces in the membrane.

Kuhn says the aim of the nationwide PS-OC program is to pool the expertise of physicists, engineers, computer scientists, chemists and biologists

in helping us better understand cancer, and:

"The results of this study demonstrate the utility of such an approach, particularly when studies are conducted in a standardized manner from the

beginning."

In another intriguing study published in January 2013, researchers exploring the interaction between cells and the extracellular matrix suggest knowing how cells know they aren't upside down may also help fight

cancer.





Written by Catharine Paddock PhD













Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today

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