Labslink Research News

Breakthrough in how pancreatic cancer cells ingest nutrients points to new drug target

Mon, 13 May 2013 16:25:12 PDT

In a landmark cancer study published online in Nature, researchers at NYU School of Medicine have unraveled a longstanding mystery about how pancreatic tumor cells feed themselves, opening up new therapeutic possibilities for a notoriously lethal disease with few treatment options. Pancreatic cancer kills nearly 38,000 Americans annually, making it a leading cause of cancer death. The life expectancy for most people diagnosed with it is less than a year........> Full story

An IRB study contributes to the understanding and prevention of the side effects caused by drugs

Fri, 19 Apr 2013 19:33:18 PDT

Yellow vision, pseudo-pulmonary obstruction, involuntary body movements, respiratory paralysis. These are some of the 1,600 known side effects (SEs) produced by drugs. Adverse effects are one of the main causes of hospital admission in the west. These effects are difficult to predict, and in practice specific assays are required to test the safety of agents in pre-clinical phases, thus these effects are often not discovered........> Full story

Discovery could increase efficacy of promising cystic fibrosis drug

Thu, 21 Mar 2013 18:35:30 PDT

A little more than a year after the FDA approved Kalydeco (Vx-770), the first drug of its kind to treat the underlying cause of cystic fibrosis, University of Missouri researchers believe they have found exactly how this drug works and how to improve its effectiveness in the future.........> Full story

Prescription problems for vets on reflux drug

Wed, 20 Feb 2013 16:43:36 PDT

U.S. veterans diagnosed with gastroesophageal reflux disease (GERD) are frequently prescribed doses of proton pump inhibitors (PPIs), such as omeprazole (commonly known by brand names such as Prilosec), that are much higher than recommended --- and they are kept on the drug far too long, according to a new Northwestern Medicine® study......> Full story

Researchers create flexible, nanoscale 'bed of nails' for possible drug delivery

Tue, 15 Jan 2013 16:46:29 PDT

Researchers at North Carolina State University have come up with a technique to embed needle-like carbon nanofibers in an elastic membrane, creating a flexible “bed of nails” on the nanoscale that opens the door to development of new drug-delivery systems........> Full story

Univ. of MD School of Medicine to study drug-resistant malaria in Myanmar

Mon, 17 Dec 2012 14:28:45 PDT

University of Maryland School of Medicine researchers have launched groundbreaking research into the spread of potentially deadly drug-resistant malaria in the developing Southeast Asian nation of Myanmar, also known as Burma. The scientists, working as part of a large international team coordinated by the World Health Organization (WHO), have identified several promising genetic markers that could be used to develop tests to identify and track the spread.......> Full story

Combination of two pharmaceuticals proves effective in the treatment of multiple sclerosis

Mon, 26 Nov 2012 14:59:24 PDT

Multiple sclerosis is an inflammatory disease that affects the central nervous system. It destroys the insulation of the nerve cell signaling system, the myelin sheaths of the neural axons. The consequence of this process is the malfunction of signaling and finally cell death resulting in permanent........> Full story

Seizures linked to surgery drugs can be prevented by anesthetics, U of T team finds

Mon, 26 Nov 2012 14:56:37 PDT

Two drugs commonly given during cardiac surgery can lead to convulsive seizures, but anesthetics can help cut the risk, according to new research from the Faculty of Medicine at the University of Toronto........> Full story

Free 2nd World Drug Discovery Online Conference, October 16-18, 2012

Tue, 02 Oct 2012 17:29:19 PDT

Target Meeting's 2nd World Drug Discovery Online Conference will be held on October 16 - 18, 2012. The 12 sessions, which will be spread over three days, will discuss Herbal drug development, General pharmaceutical research, Biotechnology and biopharmaceuticals, Drug delivery & targeting, Vaccine development, Preclinical development, Clinical trial, and many more.

Researchers and medical professionals can enjoy many benefits by participating in the conference:

Learn about and follow up on major developments taking place in the areas of interest
Meet the best international speakers and world-renowned researchers in real time
An opportunity for networking and exchanging views with the target audience directly
Participants can ask questions, discuss problems, and exchange their ideas using an online platform
The conference presents the ultimate opportunity to discuss proposals and initiatives with global experts, something that perhaps would not have been possible using other methods of communication or correspondence

More than 60 leading professors and researchers will give oral presentations at the online conference. The international speakers will include:

Ayman M. Noreddin, Chair, Hampton University School of Pharmacy, USA.
Michael Rieder, CIHR-GSK Chair in Paediatric Clinical Pharmacology, Western University, Canada.
Ilaria Ferlenghi, Director Novartis Vaccines Academy, Novartis Vaccines & Diagnostics, Italy.
Yvonne Will, Pfizer R&D, Compound Safety Prediction- WWMC, USA.
Asier Unciti-Broceta, Chief Scientific Officer, University of Edinburgh, UK.
Abdel Halim, Director, Daiichi-Sankyo Pharma Development, Edison, USA.
Ting-Chao Chou, Professor, Memorial Sloan-Kettering Cancer Center, USA.
Anwar Rayan, CEO, GeneArrest LTD Company, Al Qasemi Academic College, Israel.
Armando González- Stuart, Professor, University of Texas at El Paso, USA.
Ana Krtolica, CEO and Chief Scientific Officer, StemLifeLine Inc., USA.
Andrew G Weinstein, Associate Clinical Professor Pediatrics, Thomas Jefferson Medical University, President, Asthma Management Systems, USA.
Pr. Patrick Leoni, Professor, Euromed Management, an elite business school in France.
Galina I. Botchkina, Associate Professor, Stony Brook University, USA.
Giovanni Rizzo, Director, Specialist Consultant, Intercept Pharmaceuticals Italy.
Iuliana M. Lazar, Associate Professor, Virginia Polytechnic Institute, USA.
Jitendra Trivedi, Professor, C.S.M.Medical University U.P, India.
Iuliana Lazar, Associate Professor, Department of Biological Sciences, Virginia Tech, USA.
Giampietro Corradin, Associate Professor, Biochemistry Department, University of Lausanne, Switzerland.
Byung I. Kim, Associate professor, Department of physics, Boise State University.
Raluca-Ioana Stefan-van Staden, Professor and Head, National Institute of Research of Electrochemistry and Condensed Matter, Romania.
Su Chen, Chief Executive Officer, the Chainon Neurotrophin Biotechnolohy Inc, Texas, USA.
Bashir Jarrar, Professor, AL- Jouf University, Saudi Arabia.

Attendees just connect to the online conference's servers to participate in real time with distinguished counterparts from across the globe. No special equipment or software is needed to participate, only a computer with internet connection are required. Target Meeting will provide a certificate of attendance for participants in the conference.

Upcoming Free Online Conferences at Target Meeting

October 16-18, 2012, TM's 2nd world drug discovery online conference.
January 8-11, 2013, TM's 2nd world cancer online conference.
February 5-8, 2013, TM's 2nd world molecular & cell biology online conference.
March 19-21, 2013, TM's 2nd world Immunology online conference.
April 16-18, 2013, TM's 2nd world virology & microbiology online conference.
May 21-23, 2013, TM's 2nd world genetics & genomics online conference.
June 18-20, 2013, TM's 2nd world neuroscience online conference.
And many more...

Body heat, fermentation drive new drug-delivery 'micropump'

Tue, 11 Sep 2012 13:50:07 PDT

Researchers have created a new type of miniature pump activated by body heat that could be used in drug-delivery patches powered by fermentation........> Full story

Study pinpoints malignant mesothelioma patients likely to benefit from drug pemetrexed

Wed, 29 Aug 2012 14:51:53 PDT

Previous studies have hypothesized that low levels of the enzyme thymidylate synthase (TS) likely mark patients who will benefit from the drug pemetrexed – but results have been inconclusive at best and at times contradictory........> Full story

Not all lung cancer patients who could benefit from crizotinib are identified by FDA-approved test

Tue, 28 Aug 2012 17:25:43 PDT

Break apart a couple worm-like chromosomes and they may reconnect with mismatched tips and tails – such is the case of the EML4-ALK fusion gene that creates 2-7 percent of lung cancers. Almost exactly a year ago, the FDA approved the drug crizotinib to treat these ALK+ lung cancer patients, who were likely never smokers. Informed doctors use the test called a FISH assay to check for the EML4-ALK fusion gene, and then if the test is positive, ALK+ patients benefit greatly from crizotinib........> Full story

Sanctuary chimps show high rates of drug-resistant staph

Tue, 21 Aug 2012 16:43:16 PDT

Chimpanzees from African sanctuaries carry drug-resistant, human-associated strains of the bacteria Staphlyococcus aureus, a pathogen that the infected chimpanzees could spread to endangered wild ape populations if they were reintroduced to their natural habitat, a new study shows.......> Full story

Moffitt Cancer Center researcher & colleagues test new drug for patients with neuroendocrine tumors

Mon, 06 Aug 2012 17:24:54 PDT

A researcher at Moffitt Cancer Center and his international team of colleagues have reported study results on a novel multireceptor-targeted somatostatin analogue called pasireotide (SOM230) manufactured by Novartis Pharma AG. The Phase II,......> full story

Penn engineers convert a natural plant protein into drug-delivery vehicles

Tue, 03 Jul 2012 17:16:17 PDT

Finding biocompatible carriers that can get drugs to their targets in the body involves significant challenges. Beyond practical concerns of manufacturing and loading these vehicles, the carriers must work effectively with the drug and be safe to consume. Vesicles, hollow capsules shaped like double-walled bubbles........> Full story

Computer model successfully predicts drug side effects

Mon, 11 Jun 2012 16:55:56 PDT

A new set of computer models has successfully predicted negative side effects in hundreds of current drugs, based on the similarity between their chemical structures and those molecules known to cause side effects, according to a paper appearing online this week......> Full story

Investigational diabetes drug may have fewer side effects

Mon, 04 Jun 2012 17:17:28 PDT

Drugs for type 2 diabetes can contribute to weight gain, bone fractures and cardiovascular problems, but in mice, an investigational drug appears to improve insulin sensitivity without those troublesome side effects, researchers.......> Full story

MIT-designed cooler preserves tuberculosis drugs, records doses

Wed, 30 May 2012 16:44:33 PDT

Tuberculosis, now largely controlled in the industrialized world, remains a stubbornly persistent killer in most of Africa, as well as parts of Asia and South America. The spread of multidrug-resistant strains of TB has slowed progress against the devastating disease, which is estimated to strike more than 10 million people annually. Now a modified soft-drink cooler, developed by researchers at MIT’s D-Lab, could make a dent in the disease’s impact........> Full story

A better delivery system for chemotherapy drugs

Wed, 30 May 2012 16:42:11 PDT

Because cancer cells grow very quickly, chemotherapy is designed to target cells whose numbers grow rapidly. But this treatment comes with a heavy price — many healthy cells essential for body functions are also targeted and killed by the toxin. This dangerous side-effect has prompted researchers to seek better and more selective ways to kill cancer cells inside the body........> Full story

Tongue analysis software uses ancient Chinese medicine to warn of disease

Fri, 25 May 2012 16:47:17 PDT

For 5,000 years, the Chinese have used a system of medicine based on the flow and balance of positive and negative energies in the body. In this system, the appearance of the tongue is one of the measures used to classify the overall physical status of the body, or zheng. Now, University of Missouri researchers have developed computer software that combines the ancient practices and modern medicine by providing an automated system for analyzing images of the tongue.......> Full story

Drug allergy discovery

Thu, 24 May 2012 17:24:31 PDT

The finding could lead to the development of a diagnostic test to determine drug hypersensitivity.......> Full story

UMD team gives drug dropouts a second chance

Tue, 08 May 2012 16:59:31 PDT

A cross-disciplinary team of researchers at the University of Maryland has designed a molecular container that can hold drug molecules and increase their solubility, in one case up to nearly 3000 times. Their discovery opens the possibility of rehabilitating drug candidates that were insufficiently soluble. It also offers an opportunity to improve successful drugs that could be made even better with better solubility........> Full story

Combination drug treatment can cut malaria by 30 percent

Mon, 02 Apr 2012 17:07:56 PDT

Malaria infections among infants can be cut by up to 30 per cent when antimalarial drugs are given intermittently over a 12 month period, a three-year clinical trial in Papua New Guinea has shown. The trial showed the drug regime was effective against both Plasmodium falciparum and Plasmodium vivax malaria, the first time antimalarial drugs have been shown to prevent infections........> Full story

Solving mystery of how sulfa drugs kill bacteria yields 21st century drug development target

Thu, 01 Mar 2012 16:32:57 PDT

More than 70 years after the first sulfa drugs helped to revolutionize medical care and save millions of lives, St. Jude Children’s Research Hospital scientists have determined at an atomic level the mechanism these medications use to kill bacteria. The discovery provides the basis for a new generation of antibiotics that would likely be harder for bacteria to resist and cause fewer side effects.......> Full story

The end of the 'Lily of the Valley phenomenon' in sperm research?

Tue, 28 Feb 2012 17:23:55 PDT

Sperm have a long journey ahead in their quest for the egg cell or ovum, and just a few of the million sperm reach their destination. The ovum supports the sperm in their quest by transmitting “chemical signposts”, known as attractants. Researchers first discovered this ingenious system in sea urchins and found out that attractants.......> Full story

Researchers describe link between prescription and illicit drug misuse in high-risk groups

Mon, 27 Feb 2012 17:06:05 PDT

A new report from researchers at the Drexel University School of Public Health identifies patterns in the misuse of illicit drugs among young adults who also misuse prescription drugs. The report, “Misuse of Prescription and Illicit Drugs among High-Risk Adults” in Los Angeles and New York, was recently published in the first issue of the Journal of Public Health Research.......> Full story

American Society of Hematology statement on critical methotrexate drug shortage

Wed, 15 Feb 2012 16:46:47 PDT

As the world’s largest professional society concerned with the causes and treatment of blood disorders, many of ASH's more than 16,000 members are on the front lines of dealing with the country’s severe shortage of methotrexate, a drug critical in the treatment of children with acute lymphocytic leukemia (ALL). This morning the Food and Drug Administration (FDA) reported that two manufacturers plan additional releases.......> Full story

A step closer to understanding, averting drug resistance

Wed, 01 Feb 2012 17:21:48 PDT

The multidrug transporter EmrE functions as an asymmetric antiparallel dimer (molecule with two subunits). Drug (blue) transport from the inside to the outside of the cell membrane is accomplished by exchange between inward (left) and outward (right) facing........> Full story

Chemists unlock potential target for drug development

Fri, 20 Jan 2012 17:08:19 PDT

A receptor found on blood platelets whose importance as a potential pharmaceutical target has long been questioned may in fact be fruitful in drug testing, according to new research from Michigan State University chemists........> Full story

UC Davis researchers refine nanoparticles for more accurate delivery of cancer drugs

Thu, 19 Jan 2012 17:08:59 PDT

A new class of nanoparticles, synthesized by a UC Davis research team to prevent premature drug release, holds promise for greater accuracy and effectiveness in delivering cancer drugs to tumors. The work is published in the current issue of Angewandte Chemie, a leading international chemistry journal.......> Full story

New 'smart' nanotherapeutics can deliver drugs directly to the pancreas

Thu, 12 Jan 2012 17:09:36 PDT

A research collaboration between the Wyss Institute for Biologically Inspired Engineering at Harvard University and Children's Hospital Boston has developed "smart" injectable nanotherapeutics that can be programmed to selectively deliver drugs to the cells of the pancreas........> Full story

Scientists fixate on Ric-8 to understand trafficking of popular drug receptor targets

Wed, 28 Dec 2011 17:05:14 PDT

Half the drugs used today target a single class of proteins – and now scientists have identified an important molecular player critical to the proper workings of those proteins critical to our health........> Full story

Supercomputer reveals new details behind drug-processing protein model

Tue, 06 Dec 2011 16:59:18 PDT

Supercomputer simulations at the Department of Energy's Oak Ridge National Laboratory are giving scientists unprecedented access to a key class of proteins involved in drug detoxification.......> Full story

Andromeda Biotech: A drug for type 1 diabetes

Tue, 22 Nov 2011 17:05:45 PDT

The clinical trial was random, regulated, double-blinded and broad-based. The drug was tested on 457 patients, aged 16-45, who had been diagnosed with Type 1 diabetes a short time before joining the trial.......> Full story

Contrasting patterns of malaria drug resistance found between humans and mosquitoes

Tue, 15 Nov 2011 16:40:04 PDT

A study conducted by researchers at the Johns Hopkins Malaria Research Institute and their Zambian colleagues detected contrasting patterns of drug resistance in malaria-causing parasites taken from both humans and mosquitoes in rural Zambia. Parasites found in human blood samples showed a high prevalence for pyrimethamine-resistance.......> Full story

Parkinsonian worms may hold the key to identifying drugs for Parkinson's disease

Thu, 10 Nov 2011 17:14:45 PDT

Researchers at The University of Texas at Austin have devised a simple test, using dopamine-deficient worms, for identifying drugs that may help people with Parkinson’s disease........> Full story

Blood-pressure-lowering drug after stroke aids recovery, study finds

Fri, 21 Oct 2011 18:25:27 PDT

A commonly prescribed blood pressure-lowering medication appears to kick start recovery in the unaffected brain hemisphere after a stroke by boosting blood vessel growth, a new University of Georgia study has found........> Full story

Children with certain dopamine system gene variants respond better to ADHD drug

Fri, 21 Oct 2011 18:22:01 PDT

Children with certain dopamine system gene variants have an improved response to methylphenidate - the most commonly prescribed medication for Attention Deficit Hyperactivity Disorder - in a finding that could help eliminate the guesswork from prescribing effective medications for children with ADHD. Researchers reporting their results in the Oct. 21 Journal of the American Academy of Child and Adolescent Psychiatry tested 89 children with ADHD between ages 7 and 11. They found that children with specific variants of the dopamine transporter (DAT) and dopamine receptor D4 (DRD4) genes showed greater improvement in hyperactivity and impulsivity after taking methylphenidate compared to children with alternative DAT and DRD4 versions. "Physicians don't have a good way of predicting who will experience great improvement in ADHD symptoms with a particular medication, so currently we use a trial-and-error approach. Unfortunately, as a result, finding an effective treatment can take a long time," explained Tanya Froehlich M.D., lead investigator on the study and a physician in the division of Developmental and Behavioral Pediatrics at Cincinnati Children's Hospital Medical Center. "With more information about genes that may be involved in ADHD medication response, we may be able to predict treatment course, tailor our approach to each child, and improve symptom response while decreasing health care costs," she added. The study is the first-ever placebo-controlled pharmacogenetic drug trial for ADHD in school age children to evaluate the effects of dopamine system genes variants using teacher as well as parent ratings of children's symptoms. Given the importance of academic functioning for children with ADHD, Dr. Froehlich said it is crucial to consider medication impact at school as well as at home. Children in the study were not already taking stimulant medications for their ADHD. Participants were prescribed one week each of placebo and three different doses of methylphenidate for their ADHD. Parents and teachers assessed and scored the children's behavioral symptoms based on the Vanderbilt ADHD Parent and Teacher Rating Scales. The researchers analyzed DNA from saliva samples to see which ADHD-related gene types the children carried. They looked initially at four genes frequently implicated in ADHD – DRD4, DAT, COMT and ADRA2A. DRD4 and DAT, the most well studied genes for ADHD, showed the strongest effects on methylphenidate dose-response in study participants, according to the researchers. The DRD4 gene encodes the dopamine receptor protein, which helps control the synthesis and release of dopamine and the firing rate of neurons. The DAT gene encodes the dopamine transporter protein, which removes dopamine from the brain synapses. Children who lack what is known as the DAT 10-repeat variant showed greater improvement after taking methylphenidate compared to those carrying the 10-repeat. Children without the DRD4 gene 4-repeat variant showed less symptomatic improvement with methylphenidate compared to 4-repeat carriers. A "repeat" is a short nucleotide coding sequences in a gene that is repeated. Dr. Froehlich and her colleagues indicate in their study that although findings are promising, additional research is needed in larger patient samples to confirm current study findings and their clinical relevance.

Marijuana component could ease pain from chemotherapy drugs

Thu, 06 Oct 2011 16:43:26 PDT

A chemical component of the marijuana plant could prevent the onset of pain associated with drugs used in chemo therapy, particularly in breast cancer patients, according to researchers at Temple University's School of Pharmacy. The researchers published their findings, "Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice," in the journal Anesthesia and Analgesia. The researchers developed animal models and tested the ability of the compound cannabidiol, which is the second most abundant chemical found in the marijuana plant, to relieve chemo-induced neuropathic pain, said Sara Jane Ward, research assistant professor of pharmaceutical sciences in Temple's School of Pharmacy and the study's lead author. "We found that cannabidiol completely prevented the onset of the neuropathic, or nerve pain caused by the chemo drug Paclitaxel, which is used to treat breast cancer," said Ward, who is also a research associate professor in Temple's Center for Substance Abuse Research. Ward said that one of cannabidiol's major benefits is that, unlike other chemicals found in marijuana such as THC, it does not produce psycho-active effects such as euphoria, increased appetite or cognitive deficits. "Cannabidiol has the therapeutic qualities of marijuana but not the side effects," she said. Ward's research has long focused on systems in the brain that are impacted by marijuana and whether those systems could be targeted in the treatment of various disorders. "Marijuana binds to the cannabinoid receptors in the body and researchers have long been interested in whether there is therapeutic potential for targeting this receptor system," she said. Ward became interested in this current study after attending a conference in which she learned about a pain state that is induced by chemo-therapeutic agents, especially those used to treat breast cancer, which can produce really debilitating neuropathic pain. Cannabidiol has also demonstrated the ability to decrease tumor activity in animal models, said Ward, which could make it an effective therapeutic for breast cancer, especially if you "combined it with a chemo agent like Paclitaxel, which we already know works well." According to Ward, there are currently about 10 clinical trials underway in the United States for cannabidiol on a range of different disorders, including cannabis dependence, eating disorders and schizophrenia. Because of this, she believes it will be easier to establish a clinical trial for cannabidiol as a therapeutic against neuropathic pain associated with chemo drugs.

Enzymes possible targets for new anti-malaria drugs

Tue, 27 Sep 2011 17:36:14 PDT

Researchers at the Perelman School of Medicine at the University of Pennsylvania, Monash University, and Virginia Tech have used a set of novel inhibitors to analyze how the malaria parasite, Plasmodium falciparum, uses enzymes to chew up human hemoglobin from host red blood cells as a food source. They have validated that two of these parasite enzymes called peptidases are potential anti-malarial drug targets. The research appeared in the Aug. 15 early online issue of the Proceedings of the National Academy Sciences. "The basis for this research was to use small molecule inhibitors to help understand the biology of the malaria parasite and to find new drug targets as drug-resistant parasites necessitate the discovery of new antimalarials," said Doron C. Greenbaum, assistant professor of pharmacology at Penn, who lead the collaborative study. The P. falciparum parasite, delivered in a mosquito bite, causes malaria once it takes up residence in the human host's red blood cells and begins to digest hemoglobin, the protein that carries oxygen. The parasite multiplies and is picked up from the bloodstream when the mosquito feeds. Scientists are interested in determining which enzymes are responsible for generating amino acids from the hemoglobin in the feeding process. Two enzymes, called aminopeptidases, have been proposed as being responsible for releasing single amino acids from proteins, or peptides. However, "there has been controversy regarding where this takes place and which enzymes are responsible," said Michael Klemba, associate professor of biochemistry with the Vector-Borne Infectious Disease Research Group at Virginia Tech, who collaborated on the evaluation of new aminopeptidase inhibitors with Greenbaum's lab. "It has been difficult to study their specific roles in breaking down hemoglobin." The Penn team developed chemical genetic tools called activity-based probes that enabled the researchers to specifically inhibit one or the other of the enzymes. "When we inhibited the parasite enzyme PfA-M1, it blocked hemoglobin degradation, starving the parasite to death," said Greenbaum. Inhibition of a second enzyme, leucyl aminopeptidase, showed it to have an important role, but earlier in the parasite's life cycle within the red blood cell. "Our collective data suggest that these two MAPs are both potential antiparasitic drug targets," said Greenbaum. Other co-authors on the paper are Geetha Velmourougane, postdoctoral fellow at Penn; Seema Dalal, research scientist in biochemistry at Virginia Tech; Gilana Reiss, graduate student in Pharmacology, Penn; James C. Whisstock, Monash University, Logan Fellow and scientific director of the Victorian Bioinformatics Consortium; Ozlem Onder, postdoctoral associate in biology, and Dustin Brisson, assistant professor of biology, both at Penn; Sheena McGowan, senior research fellow at Monash University. "Dr. Greenbaum's team developed the probes and Virginia Tech's researchers tested the probes on purified enzymes and determined the potency of the probes against each of the two aminopeptidases," said Klemba. "Dr. Whisstock's team at Monash University did the structural biology, providing the high-resolution atomic structure of the enzymes."

Soy peptide + chemo drug block colon cancer's spread to liver

Mon, 19 Sep 2011 17:39:58 PDT

A University of Illinois study reports a promising new weapon in treating metastatic colon cancer, particularly in patients who have developed resistance to chemotherapy. U of I researcher Elvira de Mejia has found that the soy peptide lunasin binds to a specific receptor in highly metastatic colon cancer cells, preventing them from attaching to the liver. "When lunasin was used in combination with the chemotherapy drug oxaliplatin, we saw a sixfold reduction in the number of new tumor sites," said de Mejia, a U of I associate professor of food chemistry and food toxicology. The study appears in the most recent issue of Cancer Letters and can be accessed online at http://www.sciencedirect.com/science/article/pii/S0304383511005325 . In a separate study, the scientists showed that lunasin induces cell death in highly metastatic human colon cancer cells. According to de Mejia, almost all colon cancer deaths are caused when cancer metastasizes—or spreads—to the liver. Until now chemotherapy has targeted the primary tumor because the process of metastasis is not well understood, she said. "In this study, we have learned that lunasin can penetrate the cancer cell, cause cell death, and interact with at least one type of receptor in a cell that is ready to metastasize," said Vermont P. Dia, a U of I postdoctoral fellow in the de Mejia laboratory and lead author of the study. When that receptor is blocked, new blood vessels can't form and differentiate, and that prevents cancer from spreading. Binding such receptors has emerged as a promising target for developing cancer therapies, he said. In the study, which mimicked the spread of colon cancer in humans, mice were separated into four groups: a control group; a group that was injected daily with lunasin; a group injected with the chemo drug oxaliplatin; and a group that received both lunasin and oxaliplatin. After 28 days, the mice were examined to learn the extent of cancer's involvement in the liver. "The group that received lunasin alone had 50 percent fewer metastatic sites. But an even more exciting result was seen in the group that received both lunasin and the chemotherapy drug—only 5 new cancer sites when compared with 28 in the control group," de Mejia noted. "This huge reduction in metastasis was achieved with the amount of lunasin in only 25 daily grams of soy protein, the amount recommended in the FDA health claim," Dia said. The researchers said they recently analyzed commercial soy milks available in their area, and all contained lunasin. However, the amount of lunasin depended on the type of soy product that was used to prepare the soy milk. "Two glasses of soy milk a day generally provide half the amount of lunasin used in our study," said de Mejia. "It certainly seems feasible to create a lunasin-enriched product that people could consume in a preventive way." The scientists said their next step will be a colon cancer study in which they make lunasin part of the animals' diet—rather than injecting the peptide—to see if digestion and absorption alter its effectiveness. Soon they hope to be able to move on to human trials. Dia received the American Oil Chemists Society's 2011 Hans Kaunitz Award for his work with lunasin.

New strategy likely to speed drug development for rare cancers

Thu, 15 Sep 2011 17:00:05 PDT

Researchers have identified promising new therapies for ependymoma, a rare tumor with few treatment options. St. Jude Children's Research Hospital investigators led the effort, which used a new, faster drug development system that combines the latest drug screening technology with the first accurate animal model of the tumor. Investigators identified several dozen new and existing drugs as possible ependymoma treatment candidates. The drugs were found by screening 5,303 existing medicines, natural products and other compounds for activity against the tumor, which develops in the brain and spine of children and adults. The work is published in the current edition of the scientific journal Cancer Cell. The list of candidate drugs included 5-fluorouracil (5-FU). 5-FU has been widely used to treat a variety of adult cancers but has not been formally tested against ependymoma. Based on study results, St. Jude is planning a clinical trial of 5-FU in young ependymoma patients, said senior author Richard Gilbertson, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center. Gilbertson credited the method used in this study with highlighting 5-FU's potential. Researchers hope to use the same system to expand chemotherapy options for patients with other cancers. "This approach should significantly advance the efficiency and speed with which we discover and develop new treatments for rare cancers and cancer subtypes," the investigators noted. Jennifer Atkinson, Ph.D., a former St. Jude postdoctoral fellow, is the first author. R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics, and Gilbertson are corresponding authors. Rather than waiting years for clinical trial results, this system promises to take just months to provide key information about a drug's effectiveness and optimal administration, Gilbertson said. The results are good news for patients with ependymoma and other cancers where treatment options are limited and the outlook remains bleak. While overall childhood cancer survival rates are now almost 80 percent, ependymoma remains incurable in up to 40 percent of patients. The tumor is found in 150 to 200 U.S. children annually, making it the third most common pediatric brain tumor. Treatment has changed little in the past 40 years and is limited to surgery and radiation. Along with identifying and prioritizing drug development candidates against ependymoma, the research provided insight into the tumor's biology. The screening identified several messenger proteins, known as kinases, as possible new regulators of the tumor cell proliferation that makes cancer deadly. The abnormal tumor kinase activity occurred in certain pathways in tumor cells, including the insulin-signaling pathway and the centrosome cycle. This study builds on earlier research led by Gilbertson that showed ependymoma includes nine different tumor subtypes. Each begins when particular mutations occur in stem cells from different regions of the brain or spine. Stem cells are the specialized cells that can divide and take on more specific functions. For this project, investigators focused on a subtype D ependymoma. In earlier research, Gilbertson and his colleagues showed that extra copies of the EPHB2 gene caused this tumor subtype. The investigators used this information to develop an accurate model of subtype D ependymomas in mice. The mouse model includes the same mutation in the same neural stem cell responsible for the human disease and was crucial for speeding drug development. Researchers used an automated system to check 5,303 existing drugs, natural products and other compounds for activity against four different types of mouse brain cells, including normal neural stem cells, subtype D ependymoma tumor cells and cells from a different brain tumor. Of the 634 compounds that showed activity against subtype D ependymoma cells, four demonstrated a two-fold greater ability to block the growth of the tumor cells, but not normal cells. The drugs included 5-FU and two closely related compounds. The fourth was beta-escin, which belongs to a family of drugs that are generating interest as potential chemotherapy agents. 5-FU also proved more effective than four other chemotherapy drugs in slowing tumor growth and extending the lives of mice with subtype D ependymoma. 5-FU also appeared less toxic to normal mouse brain cells than another drug, bortezomib, included in the study. The findings provided preliminary evidence that the screening system might provide an early indication of drug toxicity. The information could help guide treatment and prioritize drugs for development, researchers said. The screening also highlighted a possible role for kinase inhibitors. Those are drugs that block activity of proteins that help drive cell division and sustain tumors. More than 18 inhibitors are in clinical trials that target the kinases this study tied to proliferation of both normal and ependymoma tumor cells.

Novel drug combination offers therapeutic promise for hard-to-treat cancers

Mon, 12 Sep 2011 17:21:10 PDT

Researchers at Brigham and Women’s Hospital (BWH) have identified a new combination of targeted therapies that, together, may treat two aggressive tumor types that until now have not had effective treatments. These findings are published in Cancer Cell on September 13, 2011.......> Full story

Whole-parasite malaria vaccine shows promise in University of Maryland School of Medicine clinical trial

Fri, 09 Sep 2011 19:03:13 PDT

For the first time, a malaria vaccine that uses the entire malaria parasite has proven safe and shown promise to produce a strong immune response in a clinical trial, according to a new study co-authored by researchers at the University of Maryland School of Medicine Center for Vaccine Development. The vaccine is unique in that it employs the entire malaria parasite, while most experimental malaria vaccines consist of just one or at most a few proteins found in the parasite. Researchers found that the vaccine— the first whole parasite vaccine to be approved by the U.S. Food & Drug Administration for clinical trials — could provide unprecedented immune responses against malaria when administered intravenously. The study was published online in the journal Science this week (www.sciencexpress.org). "This is the first whole organism malaria vaccine ever produced," says Kirsten Lyke, M.D., associate professor of medicine and a research scientist at the Center for Vaccine Development at the University of Maryland School of Medicine. Dr. Lyke was one of three lead authors and two senior authors on the study, along with colleagues from the U.S. Military Malaria Vaccine Program at the Naval Medical Research Center, the Vaccine Research Center at the National Institutes of Health (NIH), and the Rockville-based biotechnology firm Sanaria, Inc., which developed and manufactured the vaccine. "No vaccine has completely protected against malaria in a challenge trial, in which vaccinated volunteers are subjected to the bite of an infected mosquito to measure their immunity," says Dr. Lyke. "This vaccine showed strong promise. We hope that with further study it could help revolutionize the field and prevent death and illness from malaria worldwide, and be used to eliminate malaria from certain areas." Though malaria has been largely eliminated in much of the developed world, it is still a widespread threat in warm, tropical areas where infected mosquitoes thrive, such as Africa. Malaria, caused by a parasite transmitted through the bite of an infected mosquito, kills nearly one million people and infects 300 million annually worldwide. The condition can be treated with anti-parasite drugs, but can have fatal consequences for vulnerable patients who have no immunity to the disease. Children under the age of five succumb at high rates to the neurological and cardiac effects of malaria, particularly in Africa. Researchers found that the vaccine produced a partial protective response in the 80 volunteers who were immunized subcutaneously, or under the skin, by traditional needle and syringe in the trial at the Center for Vaccine Development in Baltimore. However, this response was significantly less than the 80 percent to 90 percent protective immunity the research team is intent on achieving. Researchers suspected that administering the vaccine more directly into the bloodstream, accelerating its path to the liver, might produce an even stronger response. Further study conducted by collaborating authors from the Vaccine Research Center at the NIH found that administering the vaccine intravenously produced a very high level of immune response in animal subjects. "Our hope is that we can optimize the delivery of this vaccine to prevent and eliminate malaria on a global level," says Dr. Lyke. She and her colleagues are already at work designing new studies to find the best way to administer the vaccine. Scientists consider a whole parasite vaccine to be the "holy grail" of malaria vaccine research. Such a vaccine is believed to be more capable of broadly protecting people against the scores of varying strains of malaria. Historically, vaccines are comprised of various proteins found in the virus or, in the case of malaria, the parasite. Recombinant vaccines — those comprised of various components of the parasite — often are narrowly protective against just certain strains. Whole parasite vaccines have seemed unattainable because of the many challenges of large-scale production and preservation of whole parasites, which can only be produced by infecting mosquitoes with malaria-infected blood. Using mosquitoes raised in aseptic conditions, Sanaria Inc. developed a unique large-scale production and cryopreservation process, allowing the parasite to be frozen, shipped to remote locations and safely thawed. Dr. Lyke collaborated with fellow University of Maryland School of Medicine scientists including Matthew B. Laurens, M.D., M.P.H., assistant professor of pediatrics and medicine, and Christopher Plowe, M.D., professor of medicine, epidemiology and public health and microbiology and immunology and leader of the Malaria Group at the School of Medicine. Dr. Plowe is also a Doris Duke Distinguished Clinical Scientist and an investigator at the Howard Hughes Medical Institute. Robert Edelman, M.D., clinical professor of medicine and pediatrics at the School of Medicine, also contributed to the paper. The group co-authored the study with colleagues from the Howard Hughes Medical Institute, the Walter Reed Army Institute of Research, the PATH Malaria Vaccine Initiative and the biotechnology firm Protein Potential LLC. The parasite used in the vaccine is a sporozoite, an early life-cycle stage of the parasite Plasmodium falciparum, the most dangerous type of malaria parasite. The sporozoite is carried in the salivary glands of a mosquito, where it infects a human through the mosquito's bite. The sporozoites used in the vaccine were rendered harmless when Sanaria's manufacturing team administered radiation to the mosquitoes carrying the parasites. The radiation leaves the sporozoites incapable of reproducing and incapable of causing malaria once the human is bitten. Instead, the sporozoite is intended to stimulate the body's immune response, creating immunity to malaria. Previous studies have shown that the bites of infected, irradiated mosquitoes have the ability to immunize humans against malaria. In fact, previous trials pioneered at the University of Maryland School of Medicine and the U.S. Navy almost 40 years ago showed that 90 percent of humans bitten by at least 1,000 irradiated malaria-carrying mosquitoes did not contract malaria from the bites of ordinary malaria-infected mosquitoes. However, the bite of a mosquito — essentially using a mosquito as a syringe and needle — is not a practical method of administering a vaccine to large groups of people. Sanaria's large-scale production and cryopreservation process creates the potential for the vaccine to be administered globally. "The University of Maryland School of Medicine and its Center for Vaccine Development have a world-leading malaria research program with a prominent global presence, including in remote areas of Africa where malaria rates are at their worst," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs for the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and dean, University of Maryland School of Medicine. "This research is the culmination of decades of study in this field, and brings hope to the millions of people worldwide who face daily threat of malaria." The study included 98 adult volunteers, 18 of whom served as control volunteers. As a Phase I trial, the study's focus was to establish that the vaccine was safe and well tolerated. The results have guided the design of the next study, a Phase II clinical trial in which scientists will administer the vaccine intravenously to human volunteers and measure immunity to determine the effectiveness of Sanaria's vaccine. Scientists have traditionally regarded intravenous delivery as an impractical strategy for large-scale global immunization, but Dr. Lyke said the researchers will evaluate its potential in future studies. Other possibilities for administering the vaccine might include novel microneedle injection devices. If these studies continue to show promise, the next step would be to test the whole parasite vaccine's ability to prevent malaria in people naturally exposed to malaria. "We would love to test this vaccine in Mali," says Dr. Plowe, who leads the Malaria Section at the University of Maryland School of Medicine and has led several malaria vaccine trials in Mali, West Africa. There, his team found that highly variant malaria parasites are difficult to prevent with single-strain, single-protein vaccines. "That will be the real test — does this vaccine have enough immunological firepower to protect against all the different strains circulating in the field, not just the strain the vaccine is based upon? If the whole parasite doesn't work, I don't know what will — this is the best chance we've got."

Moffitt Cancer Center researchers use new tool to counter multiple myeloma drug resistance

Fri, 09 Sep 2011 19:02:05 PDT

"Acquired drug resistance" (ADR) is a major problem encountered in treating some forms of cancer. The ability to monitor the proteins involved in drug resistance has been a hurdle facing cancer researchers. However, a team of researchers at Moffitt Cancer Center, and colleagues, are pioneering promising research utilizing a monitoring technology that could provide a better understanding of ADR and assist in clinical decision-making for developing individualized patient treatments for multiple myeloma. The technique has potentially broader applications to other types of cancer as well........> Full story

Study points to strategy for overcoming resistance to targeted cancer drug

Wed, 07 Sep 2011 17:15:28 PDT

Scientists at Dana-Farber Cancer Institute and colleagues overseas have discovered a pair of backup circuits in cancer cells that enable the cells to dodge the effect of a widely used cancer drug. Jamming those circuits with targeted therapies may heighten or restore the drug's potency, according to a study published in the Sept. 7 issue of Science Translational Medicine. The research focused on the drug cetuximab, an antibody that interferes with cancer cell growth by blocking a structure known as the epidermal growth factor receptor (EGFR). Cetuximab is effective in many patients with colorectal cancer or squamous cell cancer of the head and neck, but the benefits rarely last longer than a year, and some patients receive no benefit from the drug. Until now, scientists haven't known why cancers that initially respond to cetuximab become resistant to it, or how to overcome such resistance. In the new study, researchers led by Pasi Janne, MD, PhD, of Dana-Farber and Kimio Yonesaka, MD, PhD, formerly of Dana-Farber and now at Kinki University School of Medicine, in Osaka, Japan, found that in some cetuximab-resistant cancer cells, a protein known as ERBB2 was actively sending "grow" signals, circumventing the "stop growing" signals triggered by cetuximab. The researchers discovered that ERBB2's activity sprang from an oversupply of the protein's parent gene, Her2/neu, or by a related protein, ERBB3, when prompted by high levels of the protein heregulin. In both cases, the new growth messages are unaffected by cetuximab. "ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab's function," says Janne, the study's co-senior author with Kazuhiko Nakagawa, MD, PhD, of Kinki University. "Because ERBB2 isn't affected by cetuximab, this is an easy way for cancers to become resistant to the drug." The findings suggest that combining cetuximab with ERBB2-inhibiting drugs could be an effective therapy for cancers that are cetuximab-resistant from the start or for those that become resistant over time, the study authors say. Several such inhibitors have already been approved, while others are undergoing clinical study. "We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance," Yonesaka remarks. "We've identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors." Janne estimates that up to 40 percent of colorectal cancers are cetuximab-resistant when first diagnosed. He notes that although the ERBB2 pathway may be responsible for many cases of cetuximab resistance, there are undoubtedly other pathways, yet to be discovered, that play a similar role. Further research is needed to confirm ERBB2's role in cetuximab resistance and to develop strategies for testing ERBB2 inhibitors and cetuximab in clinical trials.

Nanosensors made from DNA may light path to new cancer tests and drugs

Wed, 07 Sep 2011 17:13:12 PDT

Sensors made from custom DNA molecules could be used to personalize cancer treatments and monitor the quality of stem cells, according to an international team of researchers led by scientists at UC Santa Barbara and the University of Rome Tor Vergata. The new nanosensors can quickly detect a broad class of proteins called transcription factors, which serve as the master control switches of life. The research is described in an article published in Journal of the American Chemical society. "The fate of our cells is controlled by thousands of different proteins, called transcription factors," said Alexis Vallée-Bélisle, a postdoctoral researcher in UCSB's Department of Chemistry and Biochemistry, who led the study. "The role of these proteins is to read the genome and translate it into instructions for the synthesis of the various molecules that compose and control the cell. Transcription factors act a little bit like the 'settings' of our cells, just like the settings on our phones or computers. What our sensors do is read those settings." When scientists take stem cells and turn them into specialized cells, they do so by changing the levels of a few transcription factors, he explained. This process is called cell reprogramming. "Our sensors monitor transcription factor activities, and could be used to make sure that stem cells have been properly reprogrammed," said Vallée-Bélisle. "They could also be used to determine which transcription factors are activated or repressed in a patient's cancer cells, thus enabling physicians to use the right combination of drugs for each patient." Andrew Bonham, a postdoctoral scholar at UCSB and co-first author of the study, explained that many labs have invented ways to read transcription factors; however, this team's approach is very quick and convenient. "In most labs, researchers spend hours extracting the proteins from cells before analyzing them," said Bonham. "With the new sensors, we just mash the cells up, put the sensors in, and measure the level of fluorescence of the sample." This international research effort –– organized by senior authors Kevin Plaxco, professor in UCSB's Department of Chemistry and Biochemistry, and Francesco Ricci, professor at the University of Rome, Tor Vergata –– started when Ricci realized that all of the information necessary to detect transcription factor activities is already encrypted in the human genome, and could be used to build sensors. "Upon activation, these thousands of different transcription factors bind to their own specific target DNA sequence," said Ricci. "We use these sequences as a starting point to build our new nanosensors." The key breakthrough underlying this new technology came from studies of the natural biosensors inside cells. "All creatures, from bacteria to humans, monitor their environments using 'biomolecular switches' –– shape-changing molecules made from RNA or proteins," said Plaxco. "For example, in our sinuses, there are millions of receptor proteins that detect different odor molecules by switching from an 'off state' to an 'on state.' The beauty of these switches is that they are small enough to operate inside a cell, and specific enough to work in the very complex environments found there." Inspired by the efficiency of these natural nanosensors, the research group teamed with Norbert Reich, also a professor in UCSB's Department of Chemistry and Biochemistry, to build synthetic switching nanosensors using DNA, rather than proteins or RNA. Specifically, the team re-engineered three naturally occurring DNA sequences, each recognizing a different transcription factor, into molecular switches that become fluorescent when they bind to their intended targets. Using these nanometer-scale sensors, the researchers could determine transcription factor activity directly in cellular extracts by simply measuring their fluorescence level. The researchers believe that this strategy will ultimately allow biologists to monitor the activation of thousands of transcription factors, leading to a better understanding of the mechanisms underlying cell division and development. "Alternatively, since these nanosensors work directly in biological samples, we also believe that they could be used to screen and test new drugs that could, for example, inhibit transcription-factor binding activity responsible for the growth of tumor cells," said Plaxco.

Novel method for increasing antibiotic yields

Mon, 05 Sep 2011 18:25:35 PDT

A novel way of increasing the amounts of antibiotics produced by bacteria has been discovered that could markedly improve the yields of these important compounds in commercial production. It could also be valuable in helping to discover new compounds. With the ever-growing threat from antibiotic resistance, these tools will be very useful in ensuring that we have enough of these useful compounds in the future. The majority of antibiotics we know of today are produced naturally by a group of soil bacteria called Streptomyces. For commercial production of these antibiotics for clinical use, it is necessary to increase the yield. This has typically been achieved by randomly inducing mutations and screening for strains that show increased production, a process that takes many years. When technology had progressed sufficiently to analyse how this had been achieved scientists found that, in some cases, the increase in yield was due to repeated copies of the genes needed for antibiotic production. In almost all cases, the genes needed to produce these antibiotics are clustered together in the bacterial genome. In work carried out initially at the John Innes Centre, which is strategically funded by the Biotechnology and Biological Sciences Research Council, Professor Mervyn Bibb and collaborator Dr Koji Yanai from a Japanse laboratory discovered 36 repeating copies of one gene cluster in a strain of Streptomyces that had been repeatedly selected to over-produce the antibiotic kanamycin. "This suggested to us that controlled and stable amplification of antibiotic gene clusters might be possible, and that if it was, it would be a valuable tool for engineering high yielding commercial strains of bacteria," said Prof Bibb. The researchers then went on to identify the components within Streptomyces responsible for creating the 36 repeating clusters that led to kanamycin overproduction. These consist of two DNA sequences that flank the gene cluster, and a protein, known as ZouA, that recognises the two sequences and replicates them. In research to be published in the journal Proceeding of the National Academy of Sciences, Prof Bibb and colleagues Dr Takeshi Murakami and Prof Charles Thompson, working at the University of British Columbia, together with the same Japanese pharmaceutical laboratory, describe a system for the targeted amplification of gene clusters. The researchers were able to engineer these components into genetic 'cassettes' and then insert these into another strain of Streptomyces. They successfully used the system to make Streptomyces coelicolor overproduce actinorhodin, a blue-pigmented antibiotic. They believe the system will work equally as well for many other Streptomyces strains and antibiotics, and have also shown that it functions in an unrelated bacterium, Escherichia coli. The system may also uncover new, undiscovered antibiotics. A number of Streptomyces species have had their entire genomes sequenced, and many more are expected. Researchers have been able to identify other gene clusters within these sequences with unknown products. It is likely that many of these 'cryptic' gene clusters produce potentially new antibiotics, but at an undetectable level, or only under specific environmental conditions. Using the gene cluster amplification system identified here, it will be possible to amplify these cryptic gene clusters, identify their products, and potentially discover new antibiotics for the battle against resistant superbugs.

Malaria discovery gives hope for new drugs and vaccines

Wed, 31 Aug 2011 17:34:16 PDT

An investigation into the mysterious inner workings of the malaria parasite has revealed that it survives and proliferates in the human bloodstream thanks in part to a single, crucial chemical that the parasite produces internally. According to scientists at the University of California, San Francisco (UCSF) and Stanford Medical School, reporting today in the journal PLoS Biology, this insight immediately provides a powerful new tool for discovering and designing drugs to treat malaria, which infects hundreds of millions of people around the world each year and claims about a million lives – mostly children. The work also gives researchers a hypothetical new vaccine to test: a weakened version of the parasite, which the scientists grew in the test tube by supplying it with the chemical it needed to live while at the same time treating it with drugs to eliminate its ability to produce that chemical on its own. "It's as if we designed a ticking time bomb inside the parasite that's ready to go off – and when it does, the parasite dies," said Joseph DeRisi, PhD, a Howard Hughes Investigator at UCSF and vice-chair of the Department of Biochemistry and Biophysics, who led the work. In theory, health officials could inoculate people living in areas where malaria is common with a similar "attenuated" form of the parasite. If it works, the modified parasite would not make those people sick but would give them resistance to the pathogen if they were later exposed to it – although that approach would need to be tested in clinical trials to determine whether it would work. "It is an intriguing possibility that must be explored," said Ellen Yeh, MD, PhD, the co-author of the study. Yeh is a postdoctoral researcher at UCSF and also on the faculty of the Pathology Department at Stanford University. Slow, Brutish and Incomplete: A Short History of Malaria Control Few diseases in history have been as widely spread, poorly understood and fruitlessly fought as malaria. The name itself evokes centuries of misunderstanding – a misnomer that comes from an old Italian construction that means "bad air." People once thought it was caused by swamp gasses, since it seemed to be prevalent in wet, marshy places. Since the dawn of modern microbiology research, beginning in the 19th century, scientists have known that the disease is actually caused by a microscopic parasite called Plasmodium, which is spread by mosquitoes common to wet, marshy places. Two of the earliest Nobel prizes went to the scientists who made these basic discoveries, and at the dawn of the 20th century, the situation had never seemed brighter. The possibility that malaria would be eliminated or eradicated was exciting and real then. History proved otherwise. Full malaria eradication was a major public health effort in the first half of the 20th century and was intensively pursued after World War II. Since that effort was launched, 108 countries have eliminated malaria from within their borders, with another 39 countries en route to that goal. Despite those efforts, malaria remains a major cause of illness in many parts of the world. Today almost half the world's population lives in places where the disease is common. According to the CDC, about 1,500 cases of malaria still occur in the United States each year, but most are imported when people travel abroad. The real problem exists in several Asian and sub-Saharan African countries, where malaria is both a major leading cause of death and a significant drain on the economy. The World Health Organization estimates that the disease eats up nearly half of all public health expenditures and measurably lowers the gross domestic product of countries where it is common. Several new approaches to controlling malaria have become available in the last few decades, like insecticide-treated bed nets, but there remains a dire need for new drugs and for effective vaccines to control it. Hope for Vaccine Lies in the Parasite Itself The Plasmodium parasite leads a strange and complicated life, crisscrossing between two "host" species – humans and mosquitoes. Within the short span of just a few weeks, the organism cycles through a half dozen radically different sizes and shapes and alternatively makes its home in the human liver, a person's bloodstream, the insect stomach, and a mosquito's spit. For years scientists knew that the most fruitful way to fight the parasite would be to target the form in which it exists in the bloodstream, since that is where the majority of clinical symptoms occur. Existing drugs, like quinine and artemisinin, both target the parasite in the blood. About 15 years ago, scientists discovered a potential new source of drug targets in a tiny, factory-like enveloped organelle called an apicoplast that exists within the parasite. It was unlike anything found normally in the human body, which suggested that drugs designed to interfere with it might kill the parasite while essentially leaving people unharmed. "It was a very exciting discovery," DeRisi said, "but in the years since, the prospect of finding drugs to target it has been frustrating and disappointing in many respects." In the last decade, the evolutionary history of this strange organelle has unfolded. The apicoplast is the strange remnant of collisions between competing cells far back in evolutionary history. Scientists reason that through the course of evolution, the apicoplast arose from its origin as a standalone bacterium into its current form through a series of at least two endosymbiotic events, in which one cell engulfs and permanently acquires genetic material and cellular machinery of another for its own benefit. The discovery of this strange organelle in modern Plasmodium immediately suggested that there might be ways to target it with new drugs. However, even after extensive research revealed the genes of this apicoplast, efforts to raise new drugs against it were mostly fruitless – largely because nobody knew what the organelle actually did while the parasite was inside the human bloodstream. Now DeRisi and Yeh have shown that the sole essential function of the apicoplast while the parasite is in the blood is to produce a single chemical known as isopentenyl pyrophosphate (IPP), a necessary building block the parasite uses to construct a variety of other molecules. They discovered this by growing samples of Plasmodium falciparum within red blood cells in the test tube. If they treated the parasite with antibiotic drugs that kill the apicoplast, the parasites would all die. If they fed the parasites IPP at the same time, they lived – even though the parasites lost the organelle completely over time. The work provides a new tool for probing the basic biology of the Plasmodium parasite, and it also suggests a new way of discovering promising new drugs to fight malaria. While many previous drug-screening efforts have identified multitudes of compounds that appear to inhibit growth of the parasites, most are without a known target within the parasites. Knowing the target of a drug greatly enables the necessary process of medicinal chemistry, in which the compound is optimized with respect to the target. Now, DeRisi and Yeh's discovery has provided a simple tool to determine whether any particular drug candidate targets the apicoplast. The attenuated form of the parasite also provides an intriguing hypothetical vaccine candidate – and one that would be relatively cheap to produce, DeRisi said. However, he cautioned, the history of malaria control is filled with failed efforts, and several past vaccines have fallen short. Only time and clinical trials will tell if this is a viable solution to the problem. "This parasite has clearly evolved to be an immune system escape artist," DeRisi said. "It's no surprise that the simple approaches have not worked."

UC Davis researchers develop computer model for testing heart-disease drugs

Wed, 31 Aug 2011 17:30:31 PDT

UC Davis researchers have developed an accurate computer model to test the effects of medications for arrhythmia, or abnormal heart rhythm, before they are used in patients. The new tool -- described in the Aug. 31 issue of the journal Science Translational Medicine -- will help scientists screen anti-arrhythmia medications early in the drug-development pipeline and eventually guide physicians in prescribing those interventions to patients who could benefit the most.......> Full story