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New Therapeutic Target for Asthma, COPD and Other Lung Disorders

Dr. Michael Croft, a researcher at the La Jolla Institute for Allergy & Immunology, and colleagues have discovered a molecule's previously unknown role as a major trigger for airway remodeling, which impairs lung function, making the molecule a promising therapeutic target for chronic asthma, chronic obstructive pulmonary disease (COPD) and several other lung conditions. A scientific paper on Dr. Croft's finding was published online on April 17, 2011, in Nature Medicine. The finding marks Dr. Croft's second major discovery with therapeutic potential for asthma. His previous finding, of a novel molecular mechanism driving lung inflammation, is the basis for a potential asthma treatment now in Phase II human clinical trials. "Dr. Croft's continued efforts to uncover the cellular pathways influencing asthma and other lung disorders have produced remarkable results," said Dr. Mitchell Kronenberg, La Jolla Institute president and chief scientific officer. "He is a researcher of the highest caliber and I believe his discoveries will someday improve the lives of millions of people around the world." In the Nature Medicine paper entitled, "The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling," Dr. Croft and colleagues showed that blocking LIGHT's interactions with its two receptors significantly inhibited the process of airway remodeling in mouse models of chronic asthma. Airway remodeling refers to inflammation-fueled structural changes in the lungs, including fibrosis, which can occur over time and result in declining lung function that strongly contributes to conditions such as COPD, chronic asthma, and several other respiratory disorders. Asthma affects more than 20 million Americans, including nine million children, and is the third-ranking cause of hospitalization among U.S.

FDA Approves Treatment Device for Recurrent Glioblastoma

On April 14, 2011, Novocure announced that the U.S. Food and Drug Administration (FDA) approved the NovoTTF-100A System (NovoTTF) for the treatment of adult patients with glioblastoma multiforme (GBM) brain tumors, following tumor recurrence after receiving chemotherapy. The portable, wearable device delivers an anti-mitotic, anti-cancer therapy as patients maintain their normal daily activities. The NovoTTF is a novel, first-in-class treatment option for patients and physicians battling glioblastoma. "Our device provides patients and physicians with a novel, non-invasive alternative to chemotherapy that is safe and effective," said Dr. Eilon Kirson, Novocure's Chief Medical Officer. "The device allows for continuous treatment without the usual, debilitating side effects that chemotherapies inflict on recurrent GBM patients and indirectly on their families." The NovoTTF-100A System is a portable, non-invasive medical device designed for continuous use throughout the day by the patient. The device has been shown in in vitro studies to slow and reverse tumor growth by inhibiting mitosis, the process by which cells divide and replicate. The NovoTTF-100A device, which weighs about six pounds (three kilograms), creates a low intensity, alternating electric field within the tumor that exerts physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cancer cell death prior to division. Novocure currently has US and European marketing approvals for the NovoTTF-100A. Results from a 237 patient randomized pivotal trial demonstrated that compared to patients treated with chemotherapy, NovoTTF-treated patients achieved comparable median overall survival times, had fewer side effects, and reported improved quality of life scores.

Analysis Indicates Human Speech Arose in Africa

An analysis of language from around the world suggests that human speech originated – just once – in central and southern Africa. Verbal communication then likely spread around the globe, evolving alongside migrating human populations, according to Dr. Quentin Atkinson, reporting in the April 15 issue of Science. The researcher from New Zealand studied the phonemes, or the perceptually distinct units of sound that differentiate words, used in 504 human languages today and found that the dialects containing the most phonemes are spoken in Africa while those with the fewest phonemes are spoken in South America and on tropical islands in the Pacific Ocean. The author notes that this pattern of phoneme usage around the world mirrors the pattern of human genetic diversity, which also declined as humans expanded their range from Africa to colonize other regions. In general, the areas of the globe that were most recently colonized incorporate fewer phonemes into the local languages whereas the areas that have hosted human life for millennia (particularly sub-Saharan Africa) still use the most phonemes. This decline in phoneme usage cannot be explained by demographic shifts or other local factors, and it provides strong evidence for an African origin of modern human languages – as well as parallel mechanisms that slowly shaped both genetic and linguistic diversity among humans. [Science abstract]

Potential New Target for Treatment of Neurofibromatosis Type 2

The proteins that provide cells with a sense of personal space could lead to a therapeutic target for neurofibromatosis type 2 (NF2), an inherited cancer disorder, according to researchers at The Wistar Institute and collaborating institutions. The findings, which appear in the April 12 issue of the journal Cancer Cell, could have profound implications for NF2 and related cancers, such as mesothelioma. The researchers describe, for the first time, that Merlin, the protein encoded by the NF2 gene interacts with a protein called angiomotin. This connection between Merlin and angiomotin also brings together two important information networks in cells, both of which have been implicated in numerous forms of cancer. It is a connection, the researchers say, between the sensors that detect interactions between cells and the signaling networks that drive cell division. "Angiomotin is required for movement of cells that form new blood vessels, so it is fascinating to see it so closely linked to Merlin, the product of the NF2 gene, loss of which leads to tumor formation," said Dr. Joseph Kissil, senior author of the study and associate professor in the Molecular and Cellular Oncogenesis Program of The Wistar Institute Cancer Center. "The discovery opens up a potential new method to treat NF2 by attacking the tumor cells directly and by starvation, a strategy already employed in certain cancer therapies. Drugs like Avastin, for example, target the growing blood vessels," Kissil said, "but what makes angiomotin a tempting target is that it is used by both blood vessels and the growing tumor cells that need the nutrients these blood vessels provide." NF2 is a genetic disorder caused by a mutation in both copies of a person's NF2 gene. It occurs in about one in every 30,000 people, and it is mostly hereditary.

Immunotherapy May Be Helpful in Wiskott-Aldrich Syndrome

In a novel approach that works around the gene defect in Wiskott-Aldrich syndrome, an inherited immune deficiency disorder, researchers used an alternative cell signaling pathway to significantly improve immune function in a 13-year-old boy with the disease. The study, at The Children's Hospital of Philadelphia, provides a proof-of-principle that immunotherapy, which harnesses elements of the body's immune system, may be used to treat this rare but often deadly disorder. "If this encouraging initial result holds up in further clinical studies, we may have a new treatment option for patients with Wiskott-Aldrich syndrome," said pediatric immunologist Dr. Jordan S. Orange, who holds the newly established Jeffrey Modell Endowed Chair in Pediatric Immunology Research at Children's Hospital. The immunotherapy study appears in the April 2011 issue of The Journal of Clinical Investigation. Wiskott-Aldrich syndrome (WAS) is a complex immunodeficiency disorder characterized by recurrent infections, eczema and thrombocytopenia (a low platelet count). Mutations in the WAS gene disable its ability to produce WAS protein (WASp), which crucially affects immune cells—particularly natural killer (NK) cells, a major component of the innate immune system. Without WASp, immune defenses are compromised, leaving WAS patients at risk for premature death from infection and cancers. This risk exists even for patients mildly affected by WAS. The only current cure for WAS is stem cell transplantation, a potentially risky procedure presently justified in severe cases. In addition, Dr. Orange recently contributed to a small experimental study of gene therapy for WAS led by European researchers, which achieved clinical benefits in two severely affected young boys.

NIH Completes Whole-Exome Sequencing of Melanoma

A team led by researchers at the National Institutes of Health is the first to systematically survey the landscape of the melanoma genome, the DNA code of the deadliest form of skin cancer. The researchers have made surprising new discoveries using whole-exome sequencing, an approach that decodes the 1-2 percent of the genome that contains protein-coding genes. The study appears in the April 15, 2011, early online issue of Nature Genetics. Melanoma is the most serious form of skin cancer and its incidence is increasing more quickly than that of any other cancer. A major cause is thought to be overexposure to the sun, particularly ultraviolet radiation, which can damage DNA and lead to cancer-causing genetic changes within skin cells. "It is now clear that genomic analysis will have a major impact on our ability to diagnose and treat cancer," said National Human Genome Research Institute Director Dr. Eric D. Green, who was not involved in the study. "This study represents a collaboration of basic science, clinical research, genome sequencing, and data analysis at its best." The researchers conducted a comprehensive genome analysis and explored the melanoma genome's functional components, especially gene alterations, or mutations. They studied advanced disease — the metastatic stage — when cells have the highest accumulation of gene mutations. "Melanoma is one of the most challenging solid cancers to work with because it has such a high rate of mutation," said senior author Dr. Yardena Samuels, investigator in the Cancer Genetics Branch of the NHGRI's Division of Intramural Research.

Antenna Transcriptome Characterized for Tobacco Hornworm

Insects use their antennae for smelling and thus for locating resources in their environment. Max Planck researchers now present the first complete analysis of genes involved in antennal olfaction of the tobacco hornworm Manduca sexta. Approximately 70 different receptors expressed in some 100 000 neurons allow these moths to detect a large number of odors and to perform odor-guided behaviors. This is the first essentially complete antennal transcriptome characterized in a non-model insect. Insects have a highly sensitive sense of smell. Extremely low concentrations of odor molecules in the air are sufficient to be detected by receptor neurons on their antennae. Specific proteins, so-called receptor proteins, expressed in these neurons recognize the odors. The odor molecules bind to the receptors and produce chemical and electrical signals that are processed in the insect brain and eventually affect the insect's behavior. Apart from the receptors, further proteins involved in olfaction, including enzymes and chemosensory proteins, come into play. Based on these molecular principles, all insects follow their innate and elementary survival formula: finding food, recognizing mates, and − in the case of females − identifying adequate oviposition sites that guarantee nutritious and easily digestible food for their offspring. Moths are popular research objects in addition to fruit flies. The genome of the silkworm Bombyx mori has been fully sequenced; however, this insect has been domesticated by humans for thousands of years, therefore its native conspecifics cannot be found anymore.

New Research Could Lead to Safer, More Effective Trypanosome Treatment

A safer and more effective treatment for 10 million people in developing countries who suffer from infections caused by trypanosome parasites could become a reality thanks to new research from Queen Mary, University of London published in the April 15 issue of the Journal of Biologicasl Chemistry. Scientists have uncovered the mechanisms behind a drug used to treat African sleeping sickness and Chagas disease, infections caused by trypanosome parasites which result in 60,000 deaths each year. The study investigated how the drug nifurtimox works to kill off the trypanosome. Co-author of the study, Dr. Shane Wilkinson from Queen Mary's School of Biological and Chemical Sciences, said: "Hopefully our research will lead to the development of anti-parasitic medicines which have fewer side effects than nifurtimox and are more effective. "What we've found is that an enzyme within the parasites carries out the process nifurtimox needs to be converted to a toxic form. This produces a breakdown product which kills the parasite. "This mechanism overturns the long-held belief that nifurtimox worked against the parasites by inducing oxidative stress in cells." Nifurtimox has been used for more than 40 years to treat Chagas disease (also known as American trypanosomiasis) and has recently been recommended for use as part of a nifurtimox-eflornithine combination therapy for African sleeping sickness (also called human African trypanosomiasis). Dr. Wilkinson and his colleagues Dr. Belinda Hall and Mr. Christopher Bot from Queen Mary's School of Biological and Chemical Sciences focused their research on the characterization of the breakdown product from nifurtimox. "The backbone of nifurtimox contains a chemical group called a nitro linked to a ring structure called a furan," Dr. Wilkinson explained.

Tiger-Parrots Occupy Own Perch on Evolutionary Tree

Researchers have found that the tiger-parrots of New Guinea‘s rainforests – named for their striped or barred plumage – are not, as has been widely accepted, closely related either to a group of rosella-like parrots found in Australia and Oceania, nor a similar group found in Asia and Africa. In press in Molecular Phylogenetics and Evolution, the scientists report that tiger-parrots instead occupy their own perch on the parrot evolutionary tree. Co-author, the Director of CSIRO’s Australian National Wildlife Collection (ANWC) Dr. Leo Joseph, said the findings will help improve our understanding of how parrots have evolved. “This research on tiger-parrots – and some other enigmatic Australian parrots such as the little-known Night Parrot of inland Australian deserts – sheds light on the bigger picture of parrot evolution for Australia and New Guinea,” Dr. Joseph said. “It has shown for the first time, for example, that tiger-parrots represent a very early branch of the parrot evolutionary tree in Australia and New Guinea. “The research team’s quest has been to understand the true places of parrots such as the Night Parrot and the tiger-parrots in the ecological and evolutionary history of parrots across the Australian continent. “During our research on these oddball parrots of Australia and New Guinea, we affirmed that the Australian parrots are far from one cohesive group. They appear, instead, to be made up of about five different main branches of the parrot evolutionary tree,” Dr Joseph said. “We have shown that the New Guinea tiger-parrots aren’t rosella-like parrots and that their resemblance in some aspects of their appearance to rosellas probably indicates some plumage characters that have been part of the evolution of parrots of Australia and New Guinea for a long time.

Circadian Rhythms Play Key Role in Plant Adaptation to Cold

Just as monarch butterflies depend on circadian cues to begin their annual migration, so do plants to survive freezing temperatures. All living things – humans, animals, plants, microbes – are influenced by circadian rhythms, which are physical, mental and behavioral changes that follow a 24-hour cycle. In the April 6, 2011 online edition of PNAS, Dr. Michael Thomashow, University Distinguished Professor of molecular genetics, along with MSU colleagues Dr. Malia Dong and Dr. Eva Farré, has identified that the circadian clock provides key input required for plants to attain maximum freezing tolerance. “The integration of cold-signaling pathways with the circadian clock may have been an important evolutionary event that has contributed to plant adaptation to cold environments,” Dr. Thomashow said. Dr. Thomashow, who is an elected member of the National Academy of Sciences for his contributions to the field of plant biology, has focused his research on the identification of stress response pathways involved in freezing and drought tolerance. Stresses, including extreme temperatures and water deficit, are major factors that limit the geographical locations where food and potential bioenergy crops can be grown. His research led to the identification of the C-repeat binding factor, or CBF response pathway, a stress pathway that can be found in many different plants and plays a major role in freezing and drought tolerance. Reducing abiotic stresses, such as extremes in temperature and drought, can help expand where crops can be grown and increase yields on an annual basis, Dr. Thomashow said.

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