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Keyword: m.d.

Anti-fibrotic effects of M10 in a mouse model of interstitial lung disease

Caption: Lung tissue isolated from mice that received bleomycin is characterized by extensive infiltration of inflammatory cells, thickening of the alveolar walls, and multiple fibrotic lesions with excessive amounts of extracellular matrix proteins (left). Lung tissue from mice receiving bleomycin + M10 shows significant reduction of cellular infiltrates, decreased thickness of alveolar septa, and reduced accumulation of extracellular matrix proteins (right). Images courtesy of Galina S. Bogatkevich, M.D., Ph.D. Reproduced from Translational Research (http://www.translationalres.com), Volume 170, April 2016, Pages 99–111, with permission from Elsevier.

Summary: Investigators at the Medical University of South Carolina report preclinical findings showing that the M10 peptide reduces collagen production and reverses fibrotic damage due to systemic sclerosis (SSc)–associated interstitial lung disease (ILD) in the April 2016 issue of Translational Research. ILD is one of the deadliest complications of SSc, a chronic autoimmune disease characterized by vasculopathy, autoimmunity, and excessive collagen production and deposition. Lung fibrosis carries a high risk of morbidity/mortality in SSc patients.

 

The results of preclinical studies by investigators at the Medical University of South Carolina (MUSC) reported in the April 2016 issue of Translational Research suggest that the M10 peptide could help protect against fibrotic damage in patients with systemic sclerosis, particularly in those who develop interstitial lung diseases (ILD), its deadliest complication.

Fibrotic diseases, which are characterized by excessive scarring due to overproduction by fibroblasts of collagen or extracellular matrix, account for more than 45% of U.S. deaths—more than cancer—and are estimated to cost $10 billion annually. Despite the prevalence of fibrotic diseases, only a handful of anti-fibrotic agents have been approved by the U.S. Food and Drug Administration, and none is available for systemic sclerosis.

In many ways, systemic sclerosis is the quintessential fibrotic disease, since its scarring can damage any part of the body. “Systemic sclerosis is often more than skin deep, affecting the gastrointestinal tract, the lungs, the heart, the kidneys, and the blood vessels, so it is a model for many other more prevalent fibrotic diseases,” says Richard M. Silver, M.D., Director of the Division of Rheumatology and Immunology at MUSC and a co-author on the article. “Whereas there may be 300,000 Americans with scleroderma/systemic sclerosis, millions of others suffer from fibrosis of these other organ systems.”

M10 is a ten-amino acid peptide formed from the natural cleavage of the receptor tyrosine kinase MET by the caspase 3. MET, also known as hepatocyte growth factor receptor, is thought to protect against injury and fibrosis, but the mechanisms by which it does so have remained unclear.

The MUSC investigators showed that M10 could protect against fibrotic injury in a bleomycin-induced model of ILD and that its anti-fibrotic effects are likely due to its modulation of the transforming growth factor beta 1 (TGF-?1) pathway. TGF-?1 is a cytokine that has been implicated in inflammation and fibrosis.

“We observed that treatment with M10 by intraperitoneal injection markedly improved bleomycin-induced lung fibrosis in mice, suggesting that the M10 peptide may have potential for use in the treatment of scleroderma-associated interstitial lung disease and other forms of pulmonary fibrosis, for example, idiopathic pulmonary fibrosis,” says Galina S. Bogatkevich, M.D., Ph.D., senior author on the Translational Research article. Lead authors for the article are Ilia Atanelishvili, M.S., of MUSC and Yuichiro Shirai, M.D., Ph.D., who holds a dual appointment at MUSC and the Nippon Medical School.

When instilled intratracheally, bleomycin induces fibrotic changes in the lungs, including peribronchial and interstitial infiltration of inflammatory cells, thickening of alveolar walls, and the development of numerous fibrotic lesions with excess deposition of extracellular matrix protein. Using this bleomycin-induced model of lung fibrosis, the MUSC investigators evaluated the anti-fibrotic effects of M10, using a scrambled peptide as a control. The scrambled peptide had the same ten amino acids as M10 but arranged in a different order. Fibrosis was quantitated using the Ashcroft scale, which ranges from 0 (normal) to 8 (totally fibrotic).

As expected, mice receiving bleomycin plus a scrambled peptide showed greater than eight times more lung fibrosis than controls receiving saline and scrambled peptide (Ashcroft scores, 5.63±1.72 vs. 0.69± 0.35). However, Ashcroft scores dropped to 1.67±1.01 when mice were administered both bleomycin and M10, suggesting the anti-fibrotic potential of this peptide.

Because M10 was given on the same day as bleomycin, its anti-fibrotic effects are considered preventive. To establish the therapeutic anti-fibrotic efficacy of M10, Bogatkevich and her MUSC colleagues are planning experiments in which M10 will be administered a week after the instillation of bleomycin, when fibrotic damage has already occurred. If these additional experiments suggest therapeutic efficacy, Bogatkevich hopes to find an industry partner to help take M10 forward into clinical trials.  

Many researchers speculate that there is a final common pathway to fibrosis in many different organ systems. If an anti-fibrotic agent is demonstrated to be effective in systemic sclerosis, which can affect many different organs, it could potentially hold promise for treating fibrotic disease that is confined to particular organ systems as well.

Bogatkevich and the other MUSC investigators also performed in vitro studies to assess the efficacy of M10 in decreasing abnormal collagen production/deposition and to shed light on the mechanism by which it does so. Skin and lung fibroblasts were obtained from three deceased patients with systemic sclerosis with confirmed lung involvement. As expected, these fibroblasts showed high levels of collagen production. Incubation of these fibroblasts with M10 reduced collagen expression in a dose-dependent manner. M10 likewise reduced collagen production induced in normal cells by administration of TGF-?1 without affecting baseline collagen levels.

These findings suggest that the anti-fibrotic effects of M10 may rely on its suppression of the TGF-?1 pathway. Indeed, protein interaction assays showed that M10 likely achieves such suppression by interacting with the Smad2 protein, thereby preventing it from binding to Smad3, which is necessary for the downstream inflammatory effects of the TGF-?1 pathway.
 

graphic for macular degenerationOne approach to treating retinal diseases such as age-related macular degeneration is transplantation of the cells under the retina, i.e., the retinal pigment epithelium (RPE), but life-long immune suppression drugs are required to prevent rejection. Researchers using induced pluripotent stem cells (iPSC) have demonstrated alternatives that do not trigger rejection, but that process uses viruses to introduce the desired reprogramming factors. Currently, the U.S. FDA has not allowed clinical trials using virally generated iPSC.

A team of Medical University of South Carolina (MUSC) scientists led by Lucian V. Del Priore, M.D., Ph.D., Pierre Gautier Jenkins Professor in the Department of Ophthalmology, has demonstrated a successful alternative to viral induction--exposing skin cells to human proteins—and reported on these results in the November 25, 2015 PLOS ONE. This alternative lays the groundwork for providing a safer way to generate RPE cells for transplantation.

“This works because ultimately the DNA creates a protein inside the cell, which then affects the cell’s behavior,” explains Del Priore. The efficiency is low; only about 1% of cells become transformed, he reports, but the research established that these cells can then be turned into RPE and that these cells function normally in the Petri dish. Specifically, the work demonstrated that the generated RPE can ingest outer segments from the retina, which is important in the normal maintenance of this delicate neural tissue. Work on this project involved a collaborative research team that included Ernesto Moreira, M.D.; Jie Gong, M.D., Ph.D.; Mark Fields, Ph.D., MPH; and Zsolt Ablonczy, Ph.D.

Another team led by Del Priore reported on a "chemical peel" of the substrate under the RPE, which is damaged by retinal disease as well. Successful transplantation depends upon a healthy substrate. The investigators’ successful rejuvenation of the tissue was reported in Translational Vision Science and Technology 2015 (Oct 30;4(5):10. 

Physicians in a discussionThroughout the nation, payers’ penalties to hospitals for readmissions are driving numerous initiatives to improve care transitions. South Carolina’s acute care facilities have come together to create a statewide quality improvement learning collaborative named Preventing Avoidable Readmissions Together (PART). Eligible participants include all acute care hospitals and home health organizations, nursing facilities, hospices, and other health care organizations. The results of PART’s initial 18 months (September 2012 to February 2014) are profiled in an article published ahead of print in Population Health Management (June 23, 2015) at http://online.liebertpub.com/doi/10.1089/pop.2014.0182). The authors include Patrick J. Cawley, M.D., Executive Director/CEO of MUSC Medical Center and Vice President for Clinical Operations at MUSC; and R. Neal Axon, M.D., Associate Professor in the Department Medicine at the Medical University of South Carolina.

The majority of the state’s acute care hospitals (92%) and hospital systems (90%) participated in collaborative events that included webinars and coaching calls, in-person meetings, and individualized peer consultations. The PART leadership team developed and distributed a resource guide to all interested organizations. Progress reports and outcomes analyses were also shared. At the completion of year one, 58% of participating hospitals completed a survey. Rates of implementation of the best practices that had been suggested were as follows: complete implementation of multidisciplinary rounds (58%), post-discharge telephone calls (58%), teach-back (32%), in-process implementation of high-quality transition records (53%), improved discharge summaries (45%), and timely follow-up appointments (39%). As for outcomes, a higher proportion of hospitals reported significant decreases in all-cause readmission rates for acute myocardial infarction, heart failure, and chronic obstructive pulmonary disease. The authors explain why certain readmission data should be interpreted with caution, and point out that the full effects of PART participation are probably not yet realized.

leddy and surgery team preparing prosthesisIn May 2015, an 8-year-old boy from Columbia, SC became the second child in the state to receive an extendible implant that replaced the leg bone that osteosarcoma had destroyed.  Orthopaedic oncologist Lee Leddy, M.D., Associate Professor in the Department of Orthopaedics at MUSC Health, performed the surgery, removing the cancerous bone (and its growth plate) and replacing it with a device designed to be lengthened over time to ensure that both legs will be of equal length. During follow-up visits every four to six weeks, the boy will place his leg into a doughnut-shaped magnet that will drive a gearbox to extend the prosthesis nine centimeters, the remainder of the boy’s projected growth.

Prior to this technology, options for a child whose growth plate had to be removed due to cancer were amputation; rotationplasty, in which the child’s ankle is substituted for the knee joint; or implants that required repeated surgeries to lengthen the prosthesis.  With this device, future operations are not necessary. More than 100 procedures have been completed in the U.S. with this device, but only two in South Carolina, both by Leddy at MUSC Health.

Leddy says this prosthesis is a dramatic improvement over the ways doctors previously met the challenges of limb salvage surgery in the skeletally immature patient. “Being able to reliably lengthen the extremity without surgery is a major advantage,” he says. “However, it is important to realize how critical the team approach is when treating these complex problems.”

The team of specialists who collaborated on these complex cases included musculoskeletal radiologists who interpreted radiographs and magnetic resonance imaging reports,  pathologists who evaluated biopsy tissues, sarcoma-trained surgical oncologists who helped resect the cancer and reconstruct the extremity, operating room nurses, oncologists who made recommendations regarding chemotherapy, and physical therapists who worked with the patients to help return them  to their active lives.

Leddy says that assuming a good response to chemotherapy and physical therapy, these patients can expect a full recovery. 

Photo provided by Sarah A. Pack

image accompanying chronic pancreatitisIn the last decade, total pancreatectomy with islet autotransplantation (TPIAT) has emerged as a means for treating selected patients with chronic pancreatitis (CP). This specialized procedure, undertaken in a complex group of patients, requires a multidisciplinary team of physicians including gastroenterologists, endocrinologists, GI surgeons, behavioral medicine specialists, and others. To establish the best standard of care, representatives from these disciplines gathered in 2014 near MUSC at an international symposium organized by David B. Adams, M.D., Professor in the Department of Surgery. This event led to a July 2014 workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Disease in which specialists focused on research gaps and the best management of TPIAT.  Common themes included the need to identify which patients best benefit from TPIAT and when to intervene with TPIAT, its current limitations, diabetes remission and the potential for improvement, opportunities to better address pain remission, GI complications, and unique features of children with CP considered for TPIAT.  A summary of these discussions published in the January 2015 Annals of Surgery was co-authored by Katherine A. Morgan, M.D., Chief of the Division of Gastrointestinal and Laparoscopic Surgery at MUSC.  A subsequent paper also authored by Morgan (in the April 2015 Journal of the American College of Surgeons) shares the results of a study on quality of life outcomes (physical and psychological) for TPIAT patients.

As a result of this initial collaboration, pancreatic specialists from various institutions and disciplines have formed a research consortium to further explore TPIAT.

MUSC is recognized as a leading institution in the management of CP and in the research and understanding of the best application of TPIAT.

Silhouette of joggersClinicians often underutilize exercise and pulmonary rehabilitation as a therapy for lung cancer patients and survivors, but investigators from MUSC Health have found that physical activity is safe, well-tolerated, and beneficial at every stage of lung cancer. Their findings are reported in the Journal of Thoracic Oncology (March 30, 2015). The researchers – Gerard A. Silvestri, M.D., MS, Professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the Medical University of South Carolina, and Brett Bade, M.D., a Fellow in the Division of Pulmonary, Critical Care, and Sleep Medicine – reviewed more than 100 studies that examined the effects of exercise on cancer patients.  “We found that physical activity reduces the risk of cancer development and the symptom burden as the disease progresses,” says Silvestri. The authors advised clinicians to consider physical activity early, counsel against inactivity, and encourage physical activity for patients in all stages of lung cancer and for survivors.  

For neuroendovascular surgeons treating intracranial aneurysms, two of the most difficult to treat are bifurcation aneurysms arising at the basilar apex or the carotid terminus.  Until recently, effective techniques that could be applied with acceptable risk were available only outside the U.S.  In June 2014, the U.S. Food and Drug Administration (USFDA) approved an investigational device exemption for the PulseRider® (Pulsar Vascular, San Jose, CA), a reconstruction device intended for wide-neck aneurysms at or near a bifurcation of the basilar tip or carotid terminus.  The first three U.S. cases were done by Alejandro M. Spiotta, M.D., Assistant Professor in the Department of Neurosciences, Raymond D. Turner, M.D., Associate Professor in the Department of Neurosciences, and M. Imran Chaudry, M.D., Associate Professor of Radiology at the Medical University of South Carolina (MUSC). They were able to achieve complete occlusion of the aneurysm without intraprocedural complications in all three cases. These cases are part of a multicenter clinical trial currently being conducted at eight select centers in the U.S. The trial is ongoing and patient enrollment is scheduled to end in late fall 2015. Dr. Spiotta and co-authors reported on these results in the January 5, 2015 issue of the Journal of Neurointerventional Surgery

ecigarette imageThe use of electronic nicotine delivery systems (ENDS), which include e-cigarettes, is on the rise, but authorities in cancer research and tobacco policy are not ready to recommend them as a safe way to quit smoking.  Twelve experts from cancer research institutions developed a national policy statement published January 8 in two prominent cancer journals, Clinical Cancer Research and the Journal of Clinical Oncology.  The authors, who include Graham W. Warren, M.D., PhD, Associate Professor of Radiation Oncology at the Medical University of South Carolina, caution that E-cigarettes are not regulated by the FDA and may be harmful, particularly to youth.  “E-cigarettes are a rapidly evolving product and we simply don't know if they help people quit smoking or if they increase the risk that people will start or continue smoking, such as when people start trying e-cigarettes in their youth,”  says Dr. Warren.

The authors recommend further research on these devices, regulation of ENDS, requiring FDA oversight and warning labels on products and advertisements, prohibiting marketing to youth, and prohibiting ENDS use in places where cigarette smoking is prohibited.  

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