BreakThrough Digest Medical News |
- Tweaking gene expression to repair lungs
- Study: Babies born by C-section at risk of developing allergies
- UCLA researchers further refine ‘NanoVelcro’ device to grab single cancer cells from blood
- Keck Medical Center of USC offers new treatment for chronic reflux disease
| Tweaking gene expression to repair lungs Posted: 24 Feb 2013 09:00 PM PST Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are on the rise, according to the American Lung Association and the National Institutes of Health. These ailments are chronic, affect the small airways of the lung, and are thought to involve an injury-repair cycle that leads to the breakdown of normal airway structure and function. For now, drugs for COPD treat only the symptoms.
“A healthy lung has some capacity to regenerate itself like the liver,” notes Ed Morrisey, Ph.D., professor of Medicine and Cell and Developmental Biology and the scientific director of the Penn Institute for Regenerative Medicine in the Perelman School of Medicine, University of Pennsylvania. “In COPD, these reparative mechanisms fail.” Morrisey is looking at how epigenetics controls lung repair and regeneration. Epigenetics involves chemical modifications to DNA and its supporting proteins that affect gene expression. Previous studies found that smokers with COPD had the most significant decrease in one of the enzymes controlling these modifications, called HDAC2. “HDAC therapies may be useful for COPD, as well as other airway diseases,” he explains. “The levels of HDAC2 expression and its activity are greatly reduced in COPD patients. We believe that decreased HDAC activity may impair the ability of the lung epithelium to regenerate.” Using genetic and pharmacological approaches, they showed that development of progenitor cells in the lung is specifically regulated by the combined function of two highly related HDACs, HDAC/1 and /2. Morrisey and colleagues published their findings in this week’s issue of Developmental Cell. By studying how HDAC activity, as well as other epigenetic regulators, controls lung development and regeneration, they hope to develop new therapies to alleviate the unmet needs of patients with asthma and COPD. HDAC1/2 deficiency leads to a loss of expression of the key transcription factor, a protein called Sox2, which in turn leads to a block in airway epithelial cell development. This is affected in part by deactivating a repressor of expression (derepressing) of two other proteins, Bmp4 and the tumor suppressor Rb1 – targets of HDAC1/2. In the adult lung, loss of HDAC1/2 leads primarily to increased expression of inhibitors of cell proliferation including the proteins Rb1, p16, and p21. This results in decreased epithelial proliferation in lung injury and inhibition of regeneration. Together, these data support a critical role for HDAC-mediated mechanisms in regulating both development and regeneration of lung tissue. Since HDAC inhibitors and activators are currently in clinical trials for other diseases, including cancer, such compounds could be tested in the future for efficacy in COPD, acute lung injury, and other lung diseases that involve defective repair and regeneration, says Morrisey. ### This work was funded by the National Heart, Lung and Blood Institute (HL071589, HL087825, HL100405, HL110942) and the Lung Repair and Regeneration consortium, funded by the NHLBI. Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise. The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year. The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital ? the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community. Contact: Karen Kreeger |
| Study: Babies born by C-section at risk of developing allergies Posted: 23 Feb 2013 09:00 PM PST For expectant moms who may contemplate the pros and cons of natural child birth or Caesarian section, a Henry Ford Hospital study suggests that C-section babies are susceptible to developing allergies by age two.
Researchers found that babies born by C-section are five times more likely to develop allergies than babies born naturally when exposed to high levels of common allergens in the home such as those from dogs, cats and dust mites. The study is being presented Sunday at the American Academy of Allergy, Asthma and Immunology annual meeting in San Antonio. “This further advances the hygiene hypothesis that early childhood exposure to microorganisms affects the immune system’s development and onset of allergies,” says Christine Cole Johnson, Ph.D., MPH, chair of Henry Ford Department of Health Sciences and the study’s lead author. “We believe a baby’s exposure to bacteria in the birth canal is a major influencer on their immune system.” Dr. Johnson says C-section babies have a pattern of “at risk” microorganisms in their gastrointestinal tract that may make them more susceptible to developing the antibody Immunoglobulin E, or IgE, when exposed to allergens. IgE is linked to the development of allergies and asthma. For its study Henry Ford researchers sought to evaluate the role of early exposure to allergens and how this exposure affects the association between C-section and the development of IgE. Researchers enrolled 1,258 newborns from 2003-2007, and evaluated them at four age intervals ? one month, six months, one year and two years. Data was collected from the baby’s umbilical cord and stool, blood samples from the baby’s mother and father, breast milk and household dust, as well as family history of allergy or asthma, pregnancy variables, household pets, tobacco smoke exposure, baby illnesses and medication use. ### The study was funded by Henry Ford Hospital and National Institute of Allergy and Infectious Diseases. Contact: David Olejarz |
| UCLA researchers further refine ‘NanoVelcro’ device to grab single cancer cells from blood Posted: 21 Feb 2013 09:00 PM PST Researchers at UCLA report that they have refined a method they previously developed for capturing and analyzing cancer cells that break away from patients’ tumors and circulate in the blood. With the improvements to their device, which uses a Velcro-like nanoscale technology, they can now detect and isolate single cancer cells from patient blood samples for analysis.
Circulating tumor cells, or CTCs, play a crucial role in cancer metastasis, spreading from tumors to other parts of the body, where they form new tumors. When these cells are isolated from the blood early on, they can provide doctors with critical information about the type of cancer a patient has, the characteristics of the individual cancer and the potential progression of the disease. Doctors can also tell from these cells how to tailor a personalized treatment to a specific patient. In recent years, a UCLA research team led by Hsian-Rong Tseng, an associate professor of molecular and medical pharmacology at the Crump Institute for Molecular Imaging and a member of both the California NanoSystems Institute at UCLA and UCLA’s Jonsson Comprehensive Cancer Center, has developed a “NanoVelcro” chip. When blood is passed through the chip, extremely small “hairs” ? nanoscale wires or fibers coated with protein antibodies that match proteins on the surface of cancer cells ? act like Velcro, traping CTCs and isolating them for analysis. CTCs trapped by the chip also act as a “liquid biopsy” of the tumor, providing convenient access to tumor cells and earlier information about potentially fatal metastases. Histopathology ? the study of the microscopic structure of biopsy samples ? is currently considered the gold standard for determining tumor status, but in the early stages of metastasis, it is often difficult to identify a biopsy site. By being able to extract viable CTCs from the blood with the NanoVelcro chip, however, doctors can perform a detailed analysis of the cancer type and the various genetic characteristics of a patient’s specific cancer. Improving the NanoVelcro device
Tseng’s team now reports that they have improved the NanoVelcro chip by replacing its original non-transparent silicon nanowire substrate inside with a new type of transparent polymer nanofiber-deposited substrate, allowing the device’s nanowires to better “grab” cancer cells as blood passes by them. Tseng and his colleagues were able to pick single CTCs immobilized on the new transparent substrate by using a miniaturized laser beam knife, a technique called laser micro-dissection, or LMD. The researchers’ paper on their improvement to the chip was published online Feb. 22 in the peer-reviewed journal Angewandte Chemie and is featured on the cover of the journal’s March 2013 print issue. “This paper summarizes a major milestone in the continuous development of NanoVelcro assays pioneered by our research group,” Tseng said. “We now can not only capture cancer cells from blood with high efficiency but also hand-pick single CTCs for in-depth characterization to provide crucial information that helps doctors make better decisions.” Testing the improvements on melanoma
Using the new assay on patients’ blood containing circulating melanoma cells (CMCs), Tseng’s team was able to isolate and preserve single CMCs. Melanoma is a deadly type of skin cancer that is prone to spreading quickly throughout the body. The ability to capture and preserve single CMCs allows doctors to analyze melanoma cells’ DNA structure, determine the genetic characteristics of the patient’s cancer and confirm that the circulating cells remain genetically similar to the tumor they came from. The preservation of single captured CMCs in this proof-of-concept study also allowed researchers to conduct an analysis ? called single-cell genotyping ? to find within the cell a specific target (BRAF V600E) for a drug called vemurafenib. BRAF V600E is a mutation in the BRAF protein that appears in approximately 60 percent of melanoma cases. Drugs that inhibit BRAF are able to slow and often reverse the growth of melanoma tumors. “With this technology, we are getting closer to the goal of a widely clinically applicable liquid biopsy, where we can sample cancer cells by a simple blood draw and understand the genes that allow them to grow,” said Dr. Antoni Ribas, a professor of medicine in the division of hematology?oncology, a Jonsson Cancer Center member and one of Tseng’s key collaborators. “With the NanoVelcro chips, we will be able to better personalize treatments to patients by giving the right treatment to stop what makes that particular cancer grow.” Dr. Roger Lo, another key Tseng collaborator and an assistant professor in UCLA’s department of medicine, division of dermatology, and department of molecular and medical pharmacology, was also optimistic about the new method. “This scientific advancement ? being able to capture the melanoma cells in transit in the blood and then perform genetic analysis on them ? will in principle allow us to track the genomic evolution of melanoma under BRAF-inhibitor therapy and understand better the development of drug resistance,” said Lo, who is also a member of the Jonsson Cancer Center. ### UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years. For more news, visit the UCLA Newsroom and follow us on Twitter. Contact: Shaun Mason |
| Keck Medical Center of USC offers new treatment for chronic reflux disease Posted: 21 Feb 2013 09:00 PM PST Clinical trial results published in the New England Journal of Medicine this week offer additional evidence that a new device may help relieve chronic heartburn symptoms that standard treatment cannot. The Keck Medical Center of USC was one of 14 U.S. and European medical centers to test the device prior to its March 2012 approval by the U.S. Food and Drug Administration.
John Lipham, M.D., associate professor of surgery at the Keck School of Medicine of USC, led clinical investigation of the device at USC as part of his ongoing work to find alternative ways to treat gastroesophageal reflux disease (GERD), or chronic heartburn. “These results show that there is another option for the millions of people suffering from chronic reflux,” Lipham said. “Currently, the Keck Medical Center of USC is one of only 30 sites in the country certified to implant the device.” The LINX Reflux Management System, manufactured by Minnesota-based Torax Medical, Inc., is like a bracelet made up of magnetic, titanium beads implanted around the end of the esophagus, where the lower esophageal sphincter is located. The lower esophageal sphincter is the valve that prevents reflux, and GERD develops when this valve is weakened. Implantation of the device is potentially an outpatient procedure that can be completed in 15 to 20 minutes, Lipham said. Lipham and his colleagues assessed 100 patients with GERD before and after surgery, finding that acid reflux decreased, reflux symptoms improved and the use of medication to manage those symptoms decreased for most patients. Severe regurgitation was eliminated in all patients. More than 9 in 10 patients reported satisfaction with their overall condition after having the procedure, compared to 13 percent before treatment while taking medication. Follow-up studies are still required to assess long-term safety. Lipham says the LINX device is best for patients with mild to moderate reflux that cannot be adequately controlled by medication or for patients who do not want to take medication to manage the disease. More than 60 million Americans experience heartburn at least once a month and some studies have suggested that more than 15 million experience heartburn symptoms every day, according to the American College of Gastroenterology. Surgical treatment of reflux disease had been limited to a procedure called a Nissen fundoplication, which involves recreating the esophageal sphincter. While fundoplication is recommended for those with severe reflux, it is a complicated procedure that prevents the ability to belch or vomit and often leads to bloating or gas problems. The most common adverse events experienced with the LINX included difficulty swallowing, pain when swallowing food, chest pain, vomiting, and nausea. It is important to note that patients with LINX will no longer be able to undergo magnetic resonance imaging (MRI) procedures. The magnetic beads interfere with the machine and can cause the device to be damaged and the patient to be injured. ### Funding for the clinical trial came from Torax Medical, ClinicalTrials.gov No. NCT00776997. Article cited:
Ganz, R.A., Peters, J.H., Horgan, S., Bemelman, W.A., Dunst, C.M., Edmundowicz, S.A., Lipham, J.C., Luketich, J.D., Melvin, W.S., Oelschlager, B.K., Schlack-Haerer, S.C., Smith, C.D., Smith C.C., Dunn, D., & Taiganides, P.A. (2013). Esophageal sphincter device for gastroesophageal reflux disease. New England Journal of Medicine, 368(8), 719-727. Published Feb. 21, 2013; doi:10.1056/NEJMoa1205544 Contact: Alison Trinidad |
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