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For many of the millions of patients treated annually in hospitals for upper gastrointestinal (GI) bleeding, there is little value in placing a nasogastric (NG) tube in patients to determine the source of that bleeding or size of a lesion, report investigators in an article published online ahead of print on January 9, 2017 by the Journal of Investigative Medicine.

Study authors, including Don C. Rockey, M.D., Medical of University of South CarDr. Don C. Rockeyolina (MUSC) Department of Medicine chair and professor of gastroenterology, position the research as improving patient care by doing less when possible, in terms of procedures or treatments that don't provide significant benefit to patients and are costly and uncomfortable.

"Placing a tube through the nose and down into the stomach makes sense if we are talking about delivering nutrition to a patient or to get an idea of what is in someone's stomach, but the value of placing this tube for patients who have an upper GI bleed has been unclear," Rockey said. "Our goal was to examine that value, and our results suggest that for millions of patients with an upper GI bleed, placing this tube had little clinical benefit and produces unnecessary cost and discomfort for all involved. If it doesn't help the patient or the clinician trying to diagnose the cause of this kind of bleed, we don't need it as a standard of care when there is no value."

The single-blind, randomized, prospective, non-inferiority study compared NG placement (with aspiration and lavage) to no NG placement (control) and demonstrated that NG tube placement in patients with typical upper GI bleeding had no impact on outcomes. In addition, the placement of NG tubes was often unsuccessful or associated with patient discomfort.

Screen Shot of New Medical Video Center

The MUSC Health Medical Video Center is now available online at MUSCHealth.org/medical-video. It profiles cutting-edge surgical procedures and innovative treatments available at MUSC Health and is intended for a health care audience. Its initial areas of focus are cardiology, oncology, neuroscience, and pediatrics. The site contains educational (and explicit) surgical video and photography.

Predicting speech fluency after stroke. Brain images showign features of damage to grey-matter and white-matter regions of brain, reflecting their importance in predicting speech fluency.

Image Caption: Predicting speech fluency after stroke. These are features of gray-matter cortical regions (left) and white-matter tracts (right), reflecting their importance in predicting speech fluency scores. Regions/connections are marked in red when they strongly influence speech fluency, in blue when their influence is moderate, and are left uncolored when the influence is weak or non-existent. Image used courtesy of Dr. Leonardo Bonilha and Dr. Grigori Yourganov of the Medical University of South Carolina, who own the copyright for the image. Published in the June 22 issue of the Journal of Neuroscience (doi:10.1523/JNEUROSCI.4396-15.2016).

Loss or impairment of the ability to speak is one of the most feared complications of stroke—one faced by about 20% of stroke patients. Language, as one of the most complex functions of the brain, is not seated in a single brain region but involves connections between many regions.

In an article published in the June 22, 2016 issue of the Journal of Neuroscience (doi:10.1523/JNEUROSCI.4396-15.2016), investigators at the Medical University of South Carolina (MUSC) and the University of South Carolina (USC) report that mapping all of the brain’s white matter connections after stroke, in addition to imaging the areas of cortical tissue damage, could better predict which patients will have language deficits and how severe those deficits will be. The totality of the brain’s connections is referred to as the connectome.

“Imaging the connectome of patients after stroke enables the identification of individual signatures of brain organization that can be used to predict the nature and severity of language deficits and one day could be used to guide therapy,” said MUSC Health neurologist Leonardo Bonilha M.D., Ph.D., senior author on the Journal of Neuroscience article, whose laboratory focuses on connectome imaging, particularly as it relates to language loss after stroke. Grigori Yourganov, Ph.D., is the first author on the article. Julius Fridriksson, Ph.D., Chris Rorden, Ph.D., and  Ezequiel Gleichgerrcht, Ph.D, aphasia researchers at USC who recently received NIH funding to establish a Center for the Study of Aphasia Recovery and who are long-time collaborators of the Bonilha laboratory, are also authors on the article.

This study is the one of the first to use whole-brain connectome imaging to examine how disruptions to white matter connectivity after stroke affect language abilities. White matter fiber tracts are the insulated wires that connect one area of the brain to others. White matter is named for the myelin sheaths (insulation) that cover the many axons (wires) that make up the fiber tracts.

“If you have two brain areas and both of them have to work together in order to carry out a function and the stroke lesion takes out axons that connect those brain areas—the two areas are intact but the communication between them is disrupted and so there is dysfunction,” said Yourganov.

Currently, structural magnetic resonance imaging (MRI) is used after stroke to assess lesions in the cortical tissue—the brain’s grey matter. However, the extent of cortical damage often does not correlate with the severity of language deficits.

“Stroke patients sometimes have significant impairments beyond the amount of cortical damage,” said Bonilha. “It is also hard to predict how well a patient will recover based on the cortical lesion alone.”

Could connectome-based imaging be a useful complement for assessing damage to the brain’s connections after stroke and for guiding rehabilitative therapy?

The study led by Bonilha took an important first step toward answering these questions. The study, which enrolled 90 patients at MUSC and USC with aphasia due to a single stroke occurring no less than six months prior, assessed four areas related to speech/language using the Western Aphasia Battery—speech fluency, auditory comprehension, speech repetition, and oral naming—as well as a summary score of overall aphasia. Within two days of behavior assessment, each of the patients underwent imaging studies—both T1- and T2- weighted MRI, typically used after stroke to map cortical damage, and diffusion imaging, used for connectome mapping. The team then used a type of machine learning algorithm—support vector regression (SVR)—to analyze the imaging results and make predictions about each patient’s language deficits.  In essence, an algorithm was created that could derive the WAB score from either a feature relevant to imaging of the grey matter damage by structural MRI or a feature relevant to connectome imaging of the brain’s white matter fiber tracts. The team used 89 of the 90 patients as training sets for SVR and then used the algorithm to predict language defect/preservation in the 90th patient. This was done for each of the 90 patients and, in each patient, for both features identified via structural MRI and connectome imaging.

The accuracy of the algorithm’s prediction of WAB score for each patient was then assessed by comparing it to the WAB score determined via behavioral testing. Connectome-based analysis was as accurate as cortical lesion mapping for predicting WAB scores. In fact, it was better at predicting auditory comprehension scores than was lesion-based imaging using structural MRI and only slightly less accurate at predicting speech fluency, speech repetition, and naming scores.

The study demonstrates that damage to the white matter fiber tracts that connect the brain’s regions plays a role beyond cortical damage in language impairment after stroke. Furthermore, this study also discloses that connections in the brain’s parietal region are particularly important for language function, especially fluency. This region is less likely to sustain damage after stroke, even in patients who experience aphasia, suggesting that damage or preservation of the brain’s connections in this region could play a key role in determining who will experience aphasia and who will have the best chances for recovery. The integrity of these connections could not be mapped with conventional structural MRI but can now be assessed through connectome-based analysis.

The study findings also suggest that connectome-based analysis could be used to inform a more individualized approach to stroke care. Because the algorithms developed using these study patients as the training set are generalizable to a broader stroke population, connectome-based analysis could one day be used to identify the distinctive features of each patient’s stroke—which connections have been lost and which preserved—and then the algorithm could be used to predict the type and severity of language impairment and the potential for recovery. This information could then be used to direct rehabilitative therapy to improve outcomes. 

“By mapping much more accurately the individual pattern of brain structural connectivity in a stroke survivor, we can determine the integrity of neuronal networks and better understand what was lesioned and how that relates to language abilities that are lost,” said Bonilha. “This is, broadly stated, a measure of post-stroke brain health. It is the individual signature pattern that could also be used to inform about the personalized potential for recovery with therapy and guide treatments to focus on the deficient components of the network.”

 

Summary: Investigators at the Medical University of South Carolina report impressive 90-day outcomes in patients with large-vessel ischemic stroke who underwent thrombectomy using a direct-aspiration, first pass technique.

In an article published online April 16, 2016 by the Journal of Neurointerventional Surgery (doi: 10.1136/neurintsurg-2015-012211), investigators at the Medical University of South Carolina (MUSC) report promising 90-day outcomes for stroke patients with large-vessel clots who underwent thrombectomy or clot removal using the direct-aspiration, first pass technique (ADAPT).  Approximately 58% of stroke patients with a large-vessel clot removed using the technique achieved a good outcome at 90 days, defined as a Modified Rankin Score (mRS) of 0 to 2.

ADAPT aims to remove the clot in its entirety with a large-diameter aspiration catheter in a single pass. In contrast, stent retrievers, currently considered standard of care, frequently fragment the clot for removal and can require several passes.

ADAPT was developed by MUSC Health neuroendovascular surgeons M. Imran Chaudry, M.D., Alejandro M. Spiotta, M.D., Aquilla S. Turk, D.O., and Raymond D. Turner, M.D., all co-authors on the April 2016 Journal of Neurointerventional Surgery article. MUSC Health neurosurgery resident Jan Vargas, M.D., is first author on the article.

“The goal in ADAPT is to take the largest-bore catheter available up to the blood clot and put suction where it’s blocked and pull it out of the head to reestablish flow in that blood vessel,” said Turk. If the first-pass attempt is unsuccessful, stent retrievers can still be used to remove the clot.

In the article, the investigators report the results of a retrospective study of 191 consecutive patients with acute ischemic stroke who underwent ADAPT at MUSC Health. In 94.2% of patients, blood vessels were successfully opened—by direct aspiration alone in 145 cases and by the additional use of stent retrievers in another 43 cases. Good outcomes at 90 days (mRS, 0-2) were achieved in 57.7% of patients who were successfully revascularized with aspiration alone and in 43.2% of those who also required a stent retriever. The average time required to reopen the blocked blood vessels was 37.3 minutes—29.6?minutes for direct aspiration alone and 61.4 minutes for cases that also required stent retrievers. Patients presented for thrombectomy on average 7.8 hours after stroke onset.

These results confirm the promise of ADAPT, which was first described by the MUSC Health team in a seminal 2014 article in the Journal of Neurointerventional Surgery. Since the publication of that article, a number of single-center series studies have reported impressive recanalization times (the time it takes to open the blood vessel) and good neurological outcomes with ADAPT using a large-bore catheter, suggesting that it could offer an alternative approach to stent retrievers for mechanical thrombectomy.

Stent retrievers have been considered standard of care for stroke patients since the publication in the October 2015 issue of Stroke of a scientific statement on thrombectomy by the American Heart Association. That statement recommended rapid clot removal in addition to tissue plasminogen activator (tPA), a clot-busting drug that can minimize stroke complications if administered in a tight time window. The recommendation was based on the promising findings of five large clinical trials comparing treatment with tPA alone versus treatment with tPA plus thrombectomy using stent retrievers in large-vessel clots: MR CLEAN, EXTEND-IA,  ESCAPE, SWIFT PRIME, and REVASCAT.

A definitive answer as to whether ADAPT could likewise become standard of care for stroke patients with large-vessel clots will require clinical trials comparing the efficacy of the direct aspiration technique versus stent retrievers in this population of stroke patients.

The MUSC Health neuroendovascular surgery team is currently running the COMPASS trial (COMParison of ASpiration vs Stent retriever as first-line approach; Clinicaltrials.gov identifier NCT02466893) in conjunction with colleagues Dr. J. Mocco of Mount Sinai and Dr. Adnan Siddiqui of the University of Buffalo. The trial is randomizing patients to either ADAPT or a stent retriever as the initial thrombectomy technique. The trial, scheduled to enroll 270 patients, has enrolled 90 patients in the past year at ten sites in the United States.

Image Caption: Left: Frontal view of the skull showing occlusion of the right internal carotid artery (ICA) beginning at the level of the vertical petrous potion (arrow). Right: Frontal view of the skull after thrombectomy shows the revascularization of the ICA and the distal arteries supplying the right side of the brain.

In an article published online ahead of print on May 25, 2016 in Nature (doi: 10.1038/ nature17965), MUSC investigators report that, during sensory stimulation, increases in blood flow are not precisely “tuned” to local neural activity, challenging the long-held view that vascular and local neural responses are tightly coupled.

Many brain-imaging techniques that rely on changes in the flow and oxygenation of blood—including functional magnetic resonance imaging (fMRI)—assume that vascular changes reflect a proportional change in local neural activity.

“Because there isn’t enough blood to send everywhere in the brain at the same time with the optimal levels of oxygen and glucose needed to support neural activity, it is widely accepted that the brain has a built-in Communication between neurons and blood vessels in the brainauto-regulatory mechanism for increasing blood flow to regions with increased activity,” says Prakash Kara, Ph.D., Associate Professor in the Department of Neurosciences at MUSC and senior author on the Nature article.

But how precise is this auto-regulation? With resolution typically at about one millimeter, the fMRI signal represents the blood flow averaged across many blood vessels. Using micron-scale resolution two-photon imaging in an animal model, the MUSC team studied blood flow in single vessels simultaneously with neural activity.

In higher mammals, the neurons in the visual cortex are organized into columns, each of which specializes in responding to a specific stimulus orientation. For example, neurons responding to a “horizontal” stimulus reside in one column and those to “vertical” in another. When the specialized neurons in one of these columns respond to a horizontal stimulus, for example, it would be expected that the blood vessels in the vicinity would likewise respond by dilating and increasing blood flow locally if vascular and neural responses are indeed congruent.

Instead, Kara and colleagues showed that, while blood flow did increase with neural activity, it also increased in response to certain sensory stimuli that did not evoke local neural activity.

To account for this “surplus dilation” and the resultant increase in blood flow, Kara and colleagues have devised a hypothesis. “The blood vessel dilation triggered by local, selective neural activity does not remain entirely local,” says Kara. “From a vessel deep within the brain, the dilation propagates up along the vessel walls into a surface vessel and then down into other vessels that enter neighboring columns.”

Thus, there appears to be no tight correlation between blood flow and local neural activity, and so hemodynamic imaging techniques such as fMRI may only reveal a “blurred” representation of the underlying neural activity.

The news for fMRI could then be mixed. The good news is that the strongest vascular response matched the strongest nearby neural activity, suggesting that fMRI has much to tell us about the general function of an area of the brain. The bad news is that precisely mapping neuronal circuitry could be forever out of fMRI’s reach.

But Kara cautions that much more work is needed, particularly on the generalization of this principle of "surplus dilation” and blood flow occurring in response to other forms of sensory stimuli. "Our team has just taken the first step, albeit an important one, in untangling the spatial precision of neurovascular coupling using very high-resolution imaging," says Kara.

Image Caption: Communication between neurons and blood vessels in the brain. Illustration by Emma Vought of the Medical University of South Carolina.

  The Structure of the Myo1c-Neph1 Complex

 

 

 

 

 

 

 

 

 

 Summary: Researchers at the MUSC used small-angle X-ray scattering to determine the full structure of the motor protein Myo1c and it complex with Neph1, a protein crucial for kidney filtration. Their findings suggest that Myo1c uses the actin cytoskeleton as a “track” for Neph1 transport—a finding with translational relevance for glomerular diseases such as diabetic nephropathy, as movement of Neph1 to and from the surface membrane triggers the injury/recovery response.

The motor protein Myo1c binds to Neph1, a protein crucial for ensuring effective filtration by the kidney, and serves as one mode of its cellular transport, according to findings by investigators at the Medical University of South Carolina (MUSC) and their collaborators report in an article in press at Molecular and Cellular Biology.

Neph1 is essential for the maintenance of podocytes—neuron-like cells with long finger-like projections that wrap around the glomerular capillaries, serving as the final barrier between the blood and the urine. When podocyte structure fails, the kidney is no longer able to act as an effective filter, and excessive protein escapes the capillaries into the urine. The resulting proteinuria can lead to kidney failure over time. Faulty podocyte structure and filtration also characterize diabetic nephropathy and glomerular diseases (e.g., focal and segmental glomerular sclerosis), which were once considered orphan diseases but have become more prevalent in recent years as sedentary lifestyles and diets high in processed foods have become commonplace.

The MUSC investigators and their collaborators used small-angle X-ray scattering (SAXS) to determine the full structure of Myo1c and its complex with Neph1. The crystallographic structure of two of Myo1c’s three segments had previously been determined but never that of the entire protein or the complex it forms with another protein.

 “Having a 3D crystal structure is more like a snapshot of the protein in three-dimensional space but of more physiological relevance is understanding how the proteins behave in solution,” says senior author Deepak Nihalani, Ph.D., an Associate Professor in the College of Medicine, Division of Nephrology, at MUSC. “We did a solution-based structure where we could actually get the structure of the entire protein and study that structure in complex with a cargo protein (Neph1).”

Nihalani’s team sent solutions of purified Myo1c to Brookhaven National Laboratory for SAXS analysis, examined the resulting SAXS intensity profiles to determine the structure of Myo1c in solution, and used molecular modeling to fill in the gaps of the 3D crystal structure. They also showed that Neph1 binds to the C tail region of Myo1c.

These findings suggest that Myo1c uses the actin cytoskeleton as a “track” for cellular transport of its Neph1 cargo (bound to its C tail). The movement of Neph1 through cellular space is known to be linked to the injury/recovery response. When injury occurs, Neph1 and other surface proteins are dislodged into the cytoplasm and must find their way back to the surface of the cell membrane to trigger the events needed for recovery.

As a means of transport for Neph1, Myo1c likely plays an important role in the injury/recovery response as well. However, it is unclear whether Myo1c favors renal protection or injury since it is not yet known in which direction Myo1c transports Neph1.

If it carries Neph1 from the surface into the cytoplasm and perinuclear space, it could be associated with more severe glomerular disease. In that case, Myo1c could be an attractive therapeutic target, as inhibiting it would prevent these proteins from leaving the cell membrane, an event that triggers the injury response. Over time, the inflammation associated with the injury response can lead to renal damage. If instead it ferries Neph1 back to the cell membrane, it could be essential in recovery after injury.

“These are early findings, but they show that Myo1c is critical to the transport of Neph1. Understanding whether that transport contributes to protection or injury could have translational importance for the treatment of glomerular diseases,” says Nihalani.

To solve that mystery, Nihalani and his collaborators have developed a mouse model in which Myo1c is knocked out in the podocytes and are conducting experiments to better understand the effects of Myo1c knockout on the injury/recovery response. They also hope to study whether Myo1c forms complexes with other proteins key for the maintenance of healthy renal function.

Image Caption: The Structural Domain of the Myo1c-Neph1 Complex. Image courtesy of  Dr. Deepak Nihalani. Reproduced from Molecular and Cellular Biology (10.1128/MCB.00020-16), with permission of the American Society of Microbiology.

Nurse practitioner Kelli GarberMUSC Health School-Based Nurse Practitioner Kelli Garber led a special live event for Nurse's Week on the free case-sharing app Figure 1, answering questions about telehealth from health care workers worldwide.

If you missed the live event, you can view the transcript here (free Figure 1 registration required).

Read more about her work with school-based telehealth here.

On May 10, MUSC Health’s School-Based Telehealth Nurse Practitioner Kelli Garber led a live event for Nurses Week on Figure 1, a free case-sharing app (iOS and Android)  used by over a million  health care professionals. Through the Center for Telehealth’s school-based telehealth program, Garber provides care to children in rural Williamsburg County and other areas of the state. Read more about her work here. During this special live event, known as a Figure 1 on 1, Garber answered questions in real time from health care workers worldwide bout her important work and her passion for nursing. Download the free app (Android or iOS) to view a transcript of the event. Or you can also access Figure 1 on the web (figure1.com) but will need to create a free account to view the event.

Nonocarriers to help prevent kindney rejection after transplant

 

Congratulations to ToleRaM Nanotech, LLC  for winning a National TechConnect Innovation Award, which is meant to recognize innovative technology that has the potential to make a difference in a special sector, such as medicine. Only 15% of submitted entries receive the prestigious award.

ToleRaM Nanotech is a start-up company that grew out of a collaboration among MUSC Health transplant surgeon Satish Nadig, M.D., Ph.D,  biomedical engineer and nanotechnologist Ann-Marie Broome, Ph.D., MBA, and immunologist Carl Atkinson, Ph.D.

ToleRaM Nanotech, LLC was developed to use novel graft targeting nanoparticles to attenuate both acute and chronic rejection after transplant. Learn more by reading Progressnotes article Special Delivery.

 

Dr. Vincent Pellegrini, Chair of the Department of Orthpaedics, leading a revision hip replacementFigure 1 Logo

Join Dr. Vincent Pellegrini, Chair of the Department of Orthopedics at MUSC Health, on April 26 at 8 pm as he leads a virtual grand rounds on revision hip replacement on the free case-sharing app Figure 1 (http://figure1.com, app available on iOS and Android). Annotated surgical photos highlighting key moments in this complex surgery will drop one by one, with Dr. Pellegrini available live online to answer questions and respond to comments. Follow @MUSChealth on the app to participate in this event and see photographs from other complex and innovative surgeries at MUSC Health.

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.
 

Placement of a single, coated, self-expanding metallic stent achieved similar rates of resolution of benign pancreatobiliary strictures as placement of multiple plastic stents, the current standard of care, and required fewer sessions of endoscopic retrograde cholang­iopancreatography, according to the results of a randomized controlled trial led by an endoscopist at the Medical University of South Carolina and reported in the March 22 JAMA.

Pictured above: MUSC Health endoscopist Gregory A Coté, M.D., performing ERCP

Placement of a single covered, self-expanding metallic stent (cSEMS) via endoscopic retrograde cholang­iopancreatography (ERCP) resolved benign obstructions of the pancreatic and biliary ducts as well as placement of multiple plastic stents, the current standard of care, and required fewer ERCP sessions, according to the results of a randomized controlled trial reported in the March 22, 2016 issue of the Journal of the American Medical Association. These findings will change practice in the opinion of Gregory A. Coté, M.D., an endoscopist at the Digestive Disease Center at the Medical University of South Carolina, lead author of the article, and the national principal investigator for the eight-center study. B. Joseph Elmunzer, M.D., of the MUSC Digestive Disease Center is also a co-author.

“For appropriately selected patients who are presenting the first time with a blockage, many endoscopists will change their strategy and use these newer stents, in an effort to reduce the total procedures that are required,” says Coté.

For now, the use of cSEMS (pictured below right) in benign biliary strictures would be off-label, as they have been approved by the U.S. Food and Drug Administration only for the treatment of malignant pancreatobiliary strictures, such as those which develop in the setting of unresectable pancreatic cancer.

Left untreated, benign biliary strictures can lead to jaundice, cholangitis (i.e., infection of the bile duct), and secondary biliary cirrhosis. Benign strictures most often occur after liver transplantation and gallbladder surgery or as a result of chronic pancreatitis. ERCP is preferred to surgery in these patients because it is less invasive.

ERCP is an endoscopic procedure in which a camera is introduced through the mouth and advanced first to the proximal duodenum and then, using endoscopy and fluoroscopy, into the pancreatic and bile ducts.  Although highly effective, three to four ERCP sessions are typically required to fully stretch the blockage and minimize the chance of recurrence once the stents are removed.  Because ERCP is not without its risks—complications include pancreatitis, infections, bowel perforation, and bleeding—minimizing the number of sessions needed to successfully treat the stricture benefits patients. Coté designed the trial to determine whether using the larger cSEMS could successfully treat benign strictures with fewer ERCP sessions. cSEMS are coated to prevent in-growth of tumor or other tissue and to facilitate removal.

The primary endpoint of the trial, which enrolled 112 patients, was the rate of benign stricture resolution after no more than 12 months of stenting. cSEMS were found to be noninferior to plastic stents for achieving stricture resolution and they did so more quickly (181 vs. 225 days) and with fewer ERCP sessions (2.14 vs. 3.24). It should be noted that the study had careful enrollment criteria; patients with small (<6 mm) bile ducts and those with intact gall bladders were excluded. “We were careful not to cross the gall bladder insertion into the bile duct in patients who still have their gall bladder because you don’t want to block the gall bladder and potentially create a new problem,” says Coté.

The procedure can be performed by anyone proficient in ERCP but best results will likely be seen when it is performed by a high-volume provider (2-3 ERCPs per week) who is comfortable placing and removing cSEMS.

“We can’t universally change practice based on these findings, but, in appropriately selected patients with benign pancreatobiliary strictures, deployment of cSEMS via ERCP should be first-line treatment,” says Coté.

Aberrant phenotypes in zebrafish after Tuba knockdown

Image Caption: Aberrant phenotypes resulting from Tuba knockdown in zebrafish. Image courtesy of Dr. Joshua Lipschutz.

Summary: Zebrafish help investigators at the Medical University of South Carolina shed light on the mechanisms underlying cilia dysfunction in polycystic kidney disease and other ciliopathies

In an article published online ahead of print on February 19, 2015 in the Journal of Biological Chemistry (JBC), investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center report findings from in vitro and in vivo studies that elucidate the mechanisms underlying the impaired ciliogenesis and abnormal kidney development characteristic of polycystic kidney disease (PKD). Depletion of dynamin-binding protein or Tuba, a guanine nucleotide exchange factor, disrupted renal ciliogenesis in cell culture and led to abnormal kidney morphology in a Tuba knockdown zebrafish model of PKD.

Currently, no drug has been approved by the U.S. Food and Drug Administration to treat autosomal dominant PKD, which affects a half million Americans and more than 12 million people worldwide. The disease is characterized by the development of fluid-filled cysts in both kidneys, leading to end-stage renal disease, usually around age 50 to 60. In PKD, it is speculated that dysfunctional cilia are unable to detect the presence of urine flow, triggering reactivation of developmental pathways, which lead to the uncontrolled production of cysts that eventually destroy the kidney.

Cilia, the finger-like protrusions on most epithelial cells, were not so long ago thought to be as irrelevant to cell biology as the appendix is to physiology, a vestigial remnant of a long ago evolutionary past.  Today, they are recognized as essential chemo-mechanical sensors that monitor and regulate what crosses into and out of a cell. Dysfunctional cilia are now known to be implicated in not only PKD but a wide range of diseases affecting the eyes, ears, heart, and other organs. Understanding how cilia become dysfunctional in these diseases could provide insight into how to better treat or prevent them.  

“How are cilia made? If you know that, you can figure out what goes wrong in ciliopathies, including polycystic kidney disease,” says nephrologist Joshua H. Lipschutz, M.D., the senior author on the article, who holds a dual appointment at MUSC and the Ralph H. Johnson VA Medical Center. 

Much must go right for ciliogenesis to occur. Proteins necessary for ciliogenesis are manufactured in the endoplasmic reticulum before traveling to the trans-Golgi network to be sorted into “zip-coded packages” or vesicles for transport to the cilia. Lipschutz and others previously showed that the exocyst, a protein targeting complex, plays a crucial role in receiving these “zip-coded packages” containing ciliary proteins.  The GTPase Cdc42 regulates the exocyst, which is the mailbox where these “packages” are received in the kidney.  Renal ciliogenesis occurs only when the packaged proteins are delivered to the Cdc42-activated exocyst complex. Depleting either the exocyst or Cdc42 disrupts renal ciliogenesis.

In the JBC article, Lipschutz and his MUSC coauthors go a step further—showing in cell culture and a zebrafish model that depletion of Tuba, a guanine nucleotide exchange factor required for Cdc42 activation, also disrupts renal ciliogenesis. Tuba is thought to ensure that the Cdc42/exocyst mailbox is in place at the base of the cilia and ready to receive the packaged proteins. Without Tuba, Cdc42 is not appropriately activated, and the exocyst is mislocalized, so the undelivered packages continue to pile up, perhaps playing a role in the uncontrolled production of renal cysts in PKD.

When grown in a collagen gel, Madin-Darby canine kidney (MDCK) cells form into cysts, and the orientation of proteins, called polarity, are abnormal following Tuba knockdown.  Specifically, apical proteins that would normally face the urinary space are mislocalized throughout the cell. 

In zebrafish, injection of low doses of both Tuba and Cdc42 antisense morpholinos, which had no effect when administered separately, led to severe phenotypes similar to those seen following knockdown of other ciliary proteins. This is called genetic synergy and provides further evidence that both Tuba and Cdc42 are part of the same pathway. Because knockdown of Tuba in zebrafish affects cilia in a number of organs, including the brain, a variety of aberrant phenotypes were seen in the Tuba knockdown zebrafish model.

Lipschutz, who directs the zebrafish core at MUSC along with co-author Seok-Hyung Kim, Ph.D., is well aware of the advantages of the zebrafish for research—its genome is well characterized, it can be bred rapidly and inexpensively, and its transparent body enables easy visualization of aberrations under microscopy. However, the next step in this line of research will be to study the effects of Tuba depletion in the kidneys of mice, since murine kidneys are more like human kidneys than those of zebrafish.

Once the pathways underlying impaired ciliogenesis in PKD are more fully understood, therapeutic interventions can be designed to disrupt those pathways.  As Lipschutz notes, “We do this research to help our patients. Further elucidating the pathways that underlie impaired ciliogenesis is an essential step in beginning to develop treatment options for PKD and other ciliopathies.”

Accumulation of DihydroceramidesSummary: Sphingosine kinase inhibitors are a new category of drugs that act on specific enzymes involved in sphingolipid metabolism to reduce the formation of a pro-cancer, pro-inflammatory lipid signaling molecule known as sphingosine-1 phosphate (S1P). Preclinical studies led by immunologist Christina Voelkel-Johnson, Ph.D., of the Medical University of South Carolina showed that a first-in-class sphingosine kinase 2 inhibitor slowed growth of aggressive prostate cancer cells.

A first-in-class sphingosine kinase 2 inhibitor slowed the growth of castration-resistant prostate cancer cells, in part by inhibiting the enzyme dihydroceramide desaturase (DEGS), but did not kill them, according to the results of preclinical in vitro and in vivo studies published in the December 2015 issue of Molecular Cancer Therapeutics by researchers at the Medical University of South Carolina (MUSC) and others.

Christina Voelkel-Johnson, Ph.D., Associate Professor of Microbiology and Immunology at MUSC, led the study, which was funded by a pilot grant from MUSC Hollings Cancer Center. Co-authors include Charles D. Smith, Ph.D., who developed the compound and led an earlier phase 1 trial at MUSC Hollings Cancer Center; oncologist Michael Lilly, M.D., a prostate cancer specialist; and Richard Drake, Ph.D., director of the Proteomics Core at MUSC, who has developed techniques to use MALDI imaging mass spectrometry to measure sphingolipid levels.

Sphingosine kinase inhibitors are a new category of drugs that reduce the generation of sphingosine-1-phosphate. This lipid signaling molecule promotes cancer cell growth and survival, thereby supporting the development of resistance to chemotherapy and radiation by cancer cells.

The study reported in Molecular Cancer Therapeutics showed that the compound YELIVA™ (ABC294640; RedHill Biopharma Ltd.; Tel Aviv, Israel) slowed prostate cancer cell proliferation by inhibiting sphingosine kinase 2, but also that it did something unexpected. “By inhibiting a second sphingolipid enzyme (DEGS), the compound increases levels of another class of lipids - dihydroceramides - which may contribute to the growth suppressive effects of the drug,” says Voelkel-Johnson. This study is the first to show activity for this compound against DEGS and to potentially link inhibition of DEGS to slowing the growth of castration-resistant prostate cancer cells. Treatment with YELIVA™ (ABC294640) increased dihydroceramide levels even in the absence of sphingosine kinase 2. 

The MUSC team conducted both in vitro and in vivo studies with YELIVA™ (ABC294640) in castration-resistant prostate cancer, relying on the MUSC Lipidomics Shared Resource for measurement of sphingolipid levels and the MUSC Proteomics Center for MALDI imaging mass spectrometry.

 In vitro studies conducted with castration-resistant mouse prostate cancer cells (TRAMP-C2) showed that treatment with YELIVA™ (ABC294640) reduced expression of the androgen receptor and the oncogene c-Myc, both important therapeutic targets for prostate cancer. Although many existing prostate cancer therapies target the androgen receptor, none directly target c-Myc.

To test in vivo response, one million TRAMP-C2 cells were injected under the skin of mice with an intact immune system, which were then treated with YELIVA™ (ABC294640) three days later. MALDI imaging mass spectrometry showed the presence of YELIVA™ (ABC294640) within murine tumors and confirmed in vitro findings of increased dihydroceramide levels.

“The significance of these findings is that this compound might be a novel therapeutic for advanced prostate cancer,” says Voelkel-Johnson, who believes that combination regimens of YELIVA™ (ABC294640) and focal radiation in this difficult-to-treat patient population deserve further study.

See full EurekAlert! release at http://www.eurekalert.org/pub_releases/2016-01/muos-anc012816.php

Image Caption:

The signal for ABC294640 is detected only when the drug but not the vehicle was administered (upper panel). The intensity for two different dihydroceramides is shown in the middle panel (dhC16-cer) and lower panel (dhC18-cer). A color bar indicates the signal intensity. Adapted with permission from the American Association for Cancer Research : Venant H, et al. The Sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides In vitro and In vivo. Molecular Cancer Therapeutics; 2015 Dec; 14(12):2744-52. doi: 10.1158/1535-7163.MCT-15-0279.

Figure 1 Live Event wth Dr. Satish Nadig January 27 at 8 pm

MUSC Health transplant surgeon Satish N. Nadig, M.D., Ph.D., will lead a virtual ground rounds on kidney transplant on January 27 at 8pm EST on Figure 1 (https://figure1.com/), a case-sharing app for healthcare professionals. Download the free app on iOS or Android to follow along in real time.

During the live event, 10-12 preloaded  photos of a recent kidney transplant surgery at MUSC Health will drop one at a time, and Dr. Nadig will be available virtually to answer questions from those in attendance. The transcript of the event will then  be posted to the app.

To learn more about Figure 1, see http://abcnews.go.com/Health/figure-app-instagram-doctors/story?id=30160402.

Localization of GM allotypes on an IgG(?) molecule. Copyright ©2013 Pandey and Li; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0). Published online 2013 Feb 20. doi:  10.1186/2162-3619-2-6Janardan Pandey, Ph.D.,  an immunogeneticist specializing in immunoglobulin GM genes at the Medical University of South Carolina, helped monitor for immune responses that could limit the effectiveness of the broadly neutralizing antibody VRC01 in a phase 1 trial of that antibody in HIV-infected individuals led by a team at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The results of the trial were reported in an article in the December 23 issue of Science Translational Medicine, on which Pandey was a co-author. 

Pandey's expertise as an immunogeneticist specializing in immunoglobulin GM genes was needed for the trial because the VRC01 antibody is built on the immunoglobulin GM3 platform. “If you give VRC01 antibodies to a person without the gene, they could make antibodies against the VRC01 antibodies, which could reduce their effectiveness,” says Pandey. Fortunately, that did not prove an issue in the phase 1 trial, which showed that a single infusion of the VRC01 antibody could suppress the blood plasma level of HIV in infected individuals not taking antiretroviral therapy.

Broadly neutralizing antibodies such as VRC01 are of increasing interest to HIV investigators. They have been isolated from patients with chronic HIV infection who have begun to produce antibodies that are effective at killing many different strains of HIV, but too late in the course of their disease to have a preventive benefit. VRC01, for example, has been shown to neutralize 91% of 200 HIV types from around the world.

In the phase 1 trial conducted at the VRC, 15 HIV-infected patients on antiretroviral therapy (ART) received two infusions of VRC01 28 days apart and eight not on ART received a single infusion. Plasma HIV levels were reduced more than tenfold after VRC01 infusion in six of the eight patients not on ART. In the two people in this group who began the study with the lowest viral loads, the antibody suppressed HIV to extremely low levels for approximately 3 weeks—as long as VRC01 was present at therapeutic concentrations. In the other four people whose HIV levels declined, their viral load fell substantially but did not reach undetectable levels. No decrease was observed in patients whose plasma levels of HIV had already been reduced through ART. VRC01 infusion did not affect the quantity of HIV in blood cells in any of the 23 study patients.

“This is a very promising first step for an HIV treatment approach using broadly neutralizing antibodies, and the first good news for some time for people infected with HIV,” says Pandey.

The next step—preventing blood cells from serving as a reservoir of HIV virus—will likely require new strategies, possibly used in combination. One of these, antibody-dependent cell-mediated cytotoxicity (ADCC), involves binding antigens on the surface of infected cells with antibodies that make them attractive to natural killer cells that can then recognize and destroy them. “We have to make the antibody in a way that it will attract natural killer cells and then they can kill the virally infected cells,” says Pandey. Another involves using an adeno-associated virus to deliver genetic instructions for building protective antibodies.

Reference

RM Lynch et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Science Translational Medicine. December 23, 2015; 7(319): 319ra206.

Image Caption:

Published online 2013 Feb 20. Exp Hematol Oncol. 2013; 2: 6. doi:  10.1186/2162-3619-2-6
Copyright
©2013 Pandey and Li; licensee BioMed Central Ltd.

 


 

 

 

Nursing motherIn the October 2015 issue of Pediatrics, two MUSC Children’s Hospital faculty members—vitamin D researcher Bruce W. Hollis, Ph.D., and neonatologist Carol L. Wagner, M.D.—reported clinical trial findings definitively showing that sufficient vitamin D can be transmitted via breast milk to meet the needs of the exclusively breastfed infant, provided that the mother is adequately supplemented.

Breastfeeding is encouraged by the medical community in part because breast milk meets all nutritional needs of the child, with the glaring exception of vitamin D. Why such an essential vitamin would be missing from breast milk has always been puzzling. Many physicians erroneously believe that vitamin D simply cannot be transmitted via breast milk. To prevent deficiency in exclusively breastfed babies, the American Academy of Pediatrics recommends that they be supplemented with 400 IU/d of vitamin D3, delivered via liquid drops. Unfortunately, the drops can be difficult to administer and not all mothers adhere to this directive, leaving some infants vulnerable to rickets or fractures.

The study results reported by Hollis and Wagner suggest that a more natural and effective way to supplement the child would be to adequately supplement the nursing mother.  At the time the study was designed, the Institute of Medicine (IOM) recommended that adults, even nursing mothers, receive 400 IU/d of vitamin D3; the IOM has since increased the recommended dose to 600 IU/d. The study randomized mother/infant dyads to either 400 IU/d of vitamin D3 each or 6,400 IU/d for the mother and none for the infant. The infants in both arms of the trial achieved vitamin D sufficiency, and no adverse effects were reported for mothers receiving the 6,400/IU day dose.  The results suggest that adequate maternal supplementation—6,400 IU/d of vitamin D3 vs. the current IOM recommendation of 600 IU/d—offers a safe and effective alternative to direct infant supplementation.

It is now accepted that our immune system is capable of mounting an attack against cancer. However, tumors have devised ways to elude detection and to render tumor reactive or “effector” T cells indolent. Cancer immunotherapies such as adoptive T cell transfer (ACT) seek to reinvigorate and reinforce tumor-reactive cells so that they can effectively target tumor.

In ACT therapy, exhausted T cells in the vicinity of a tumor are harvested; expanded, conditioned, and sometimes genetically reengineered to better recognize and target the tumor; and then reinfused. T cell growth factors, such as interleukin (IL) 2 and IL-15, are often administered to promote proliferation of the reinfused T cells that have been trained to target the patient’s tumor. IL-15 is a more recently discovered cytokine and seems to promise some advantages over IL-2, which is toxic at therapeutic doses and which can stimulate regulatory T cells that blunt the effect of effector T cells.  One limitation of translating this therapy to the clinic is that preconditioning with chemotherapy or radiation is required for best results. Chemotherapy and radiation are expensive, associated with substantial adverse effects, and require hospital admission.T cells expressing IL-2 receptor alpha outcompete host cells for IL-2

In an article published in the October 28, 2015 issue of Science Translational Medicine, senior author Mark P. Rubinstein, Ph.D., and his colleagues in the Department of Surgery and the Department of Microbiology and Immunology at the Medical University of South Carolina and his collaborators at the University of California San Diego report the surprising finding that curative responses were achieved with ACT in a mouse model of melanoma without lymphodepletion when IL-2 but not IL-15 was co-administered. These findings are important because they suggest that low-dose IL-2 could be used as an alternative to chemotherapy and radiation as a preconditioning regimen for ACT therapy.

Host cells are thought to outcompete the reinfused or “donor” cells for T cell growth factors such as IL-2 and IL-15. Chemotherapy and radiation knock down the number of host cells so that the donor cells can more effectively compete for IL-2 or IL-15.  Rubinstein and his colleagues found that curative responses were achieved with IL-2 without lymphodepletion when the effector T cells were engineered to express elevated levels of IL-2 receptor alpha (IL-2R?). The presence of IL-2R? on the surface of the effector T cells enabled them to outcompete host cells for IL-2. This suggests that, if the effector T cells harvested from patients are engineered to express high levels of IL-2R?, then low doses of IL-2 may be adequate to achieve significant clinical response, making preconditioning with chemotherapy or radiation unnecessary.

The study authors also describe a novel mechanism that helps account for the ability of IL-2 to mediate curative responses in the absence of chemotherapy or radiation. They found that, in T cells expressing IL-2R?, IL-2 does not degrade as expected after being taken up by the effector T cell. Instead, IL-2R? rescues IL-2 from being degraded, thereby enabling IL-2 to be recycled so it can continue to optimize effector T cell response. “The ability of IL-2R? to sustain IL-2 signaling provides a molecular mechanism to explain how IL-2 therapy may be particularly useful clinically,” says Rubinstein. “This mechanism could provide a novel way to enhance the tumor-killing potential of T cells transferred to patients in the absence of prior chemotherapy or radiation.”

 The lead researchers in the Rubinstein laboratory for this study were Ee Wern Su, Ph.D.,and Caitiln Moore. Ms. Moore is currently in medical school at MUSC. For a complete list of authors, please view the article's abstract.

sub-cutaneous icd imageThe clinical promise of the subcutaneous implantable cardioverter-defibrillator (S-ICD System®; Boston Scientific, Natick, MA), the first ICD in which the leads are placed under the skin of the chest and are not connected to the heart or vasculature, was confirmed by longer-term (median of 22-month) safety and efficacy data reported in the April 28, 2015 issue of the Journal of the American College of Cardiology (JACC). The S-ICD was approved by the FDA in September 2012 to provide an electric shock to the heart (defibrillation) when the patient’s heart is beating chaotically (ventricular fibrillation) or abnormally fast (ventricular tachyarrhythmia). Because the S-ICD is not implanted in the vasculature or heart, major complications, such as device/lead displacement or failure and pneumothorax, are very rare. Because the S-ICD lacks pacing capacity, it is contraindicated in patients who require a pacemaker or pacing therapy. The JACC article, coauthored by MUSC cardiologist Michael Gold, M.D., Ph.D., is a pooled analysis of 882 patients implanted with the S-ICD who were either participants in the investigational device exemption (IDE) study that led to FDA approval or members of the European EFFORTLESS S-ICD registry, created to evaluate the long-term efficacy and safety of the S-ICD.  Of the 111 events of ventricular fibrillation/tachyarrhythmia reported in the study, 90% (100) were terminated with one shock and 98% (109) within the five shocks available with the S-ICD.  This is similar to reported shock termination rates with traditional ICDs. Device-related complications occurred in 11.1% of patients at three years, with generator pocket infections and inappropriate shocks due to oversensing being the more prominent. Rates of both decreased as providers gained experience with the S-ICD, infection control techniques were implemented, and dual zone programming was favored. The infection rate was reduced more than 3-fold in the latter half of these trials and supraventricular arrhythmias by about 70%. Improvement in this technology will occur in future iterations of the device that should be available in the summer of 2015.  MUSC, the leading center in South Carolina for implantation of this device, participated in many of the early clinical studies that led to the approval of the S-ICD.

intracranial stenosisAggressive medical management is the treatment of choice for patients with severe atherosclerotic stenosis (70%-90% ) of the arteries in their brain, according to the results of the 27-site VISSIT trial (NCT00816166) reported by Zaidat et al in the March 24 issue of JAMA. These patients are at extremely high risk of recurrent stroke, and it was hoped that reopening the artery via an endovascular intervention and using a stent to hold it open would reduce that risk. According to MUSC Health stroke neurologist Marc I. Chimowitz, MBChB, who led the earlier 50-site SAMMPRIS trial (NCT00576693) in the same population of patients, “The VISSIT trial confirms the findings from the SAMMPRIS trial that intracranial stenting for symptomatic intracranial arterial stenosis is associated with an unacceptably high risk of stroke and that aggressive medical therapy is the treatment of choice for these patients.” Aggressive medical therapy is defined as dual antiplatelet therapy, intensive risk factor management (systolic blood pressure <140 mm Hg, low-density lipoprotein <70 mg/dL), and a lifestyle modification program. Both SAMMPRIS and VISSIT were stopped early because patients in the endovascular intervention and stenting arm of the trials (who also received aggressive medical management) had a much higher-than-expected rate of both ischemic and hemorrhagic stroke and those in the aggressive medical management arm had a lower-than-expected rate. In an editorial accompanying the JAMA article by the VISSIT investigators, Chimowitz notes that some had questioned the SAMMPRIS results, attributing the increased rate of stroke to the two-pass endovascular intervention it used (on the first pass,  angioplasty was performed to widen the artery and on the second pass the stent was deployed). These critics speculated that a balloon-mounted stent, which could widen the artery and deploy the stent on a single pass, would be less likely to increase the risk of stroke. Balloon-mounted stents were used in the endovascular therapy arm of the VISSIT trial, and even higher rates of stroke were seen than in SAMMPRIS, definitively establishing aggressive medical management as the safest and most effective treatment in these patients and drawing into real question whether stents will have a role in even limited subgroups of these patients in the foreseeable future.

Statins can lower low-density lipoprotein cholesterol (LDL-C) levels by 25%-50%, but for many patients that is not enough to reach target levels, leaving them at residual risk for cardiovascular events. Some patients experience muscle aches when taking statins and must discontinue therapy or take a suboptimal dose. The search has been on for agents that can provide additional benefit in patients already taking statins or that can provide an alternative therapeutic option for those who do not tolerate them, but with largely disappointing results.

That is why the dramatic reduction in LDL-C levels achieved by proprotein convertase subtilisin–kexin type 9 (PC3K9) inhibitors are being met with such excitement. The interim results of the Osler-1 and -2 trials (NCT01439880 and NCT01854918) and the Odyssey Long Term trial (NCT01507831) were published online on March 15 in the New England Journal of Medicine (Osler: http://dx.doi.org/10.1056/NEJMoa1500858; Odyssey: http://dx.doi.org/10.1056/NEJMoa1501031). The results showed a more than 60% decrease in LDL-C levels (from a median of 119-120 mg/dL to 48 mg/dL; P<.001) and a significant decrease in cardiovascular events in patients taking the PC3K9 inhibitor evolocumab (Amgen; Osler) or alirocumab (Sanofi/Regeneron; Odyssey) in addition to standard therapy vs those receiving standard therapy alone. Those decreases were maintained over time.  The FDA has scheduled a target action date for evolocumab and alirocumab for August and July, respectively, and could approve both for certain indications as early as September of this year.

“PCSK9 inhibitors are the most exciting thing going on right now in the field of lipids. They are rocking the lipid world,” says MUSC Health cardiologist Pamela B. Morris, M.D., who is the principal investigator for the MUSC site of two trials of these inhibitors: GAUSS III, which is testing the efficacy of evolocumab in patients who have been verified as being statin intolerant, and FOURIER (NCT01764633), which is seeking to definitively establish whether the dramatic decreases in LDL-C seen with evolocumab indeed reduce the risk for cardiovascular events long term in patients already receiving statin therapy.

Side effects of PCSK9 inhibitors include  minor injection-site reactions and a few cases of memory deficit that were at first thought to due to excessively low LDL-C levels; the Osler interim results showed that this was not the case.

PCSK9 inhibitors are monoclonal antibodies that must be subcutaneously injected, and it is still being assessed whether better efficacy and patient adherence can be achieved with a smaller dose every two weeks or a larger dose once a month.

If approved, PCSK9 inhibitors will offer a promising new treatment option for patients who could not take statins or who did not reach target LDL-C levels despite taking the highest dose of statins they could tolerate.

How They Work: The body clears LDL-C via LDL receptors on the surface of liver cells, which bind to LDL-C and target it for degradation. Depending of the body’s needs, the LDL receptor is then itself degraded or is recycled (as many as 200 times) to clear more LDL-C. PCSK9 binds to the LDL-C/LDL receptor complex and targets the receptors for degradation rather than recycling. When PCSK9 levels are decreased, more LDL-C receptors are recycled to the cell surface to clear LDL-C. Indeed, patients with a loss-of-function PCSK9 mutation tend to have very low levels of LDL-C and very low rates of cardiovascular disease, an observation that helped spark interest in PCSK9 inhibitors. 

baby earCongenital cytomegalovirus (CMV) infection, the most frequently transmitted intrauterine infection, is the leading nongenetic cause of hearing loss, accounting for 21% of cases at birth and 24% at 4 years of age. It is also the leading viral cause of mental retardation. An article in the March 5, 2015 issue of the New England Journal Medicine co-authored by Sandra L. Fowler, M.D., MSc, Director of Pediatric Infectious Diseases at MUSC Children’s Hospital, and other members of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG), reported the results of a double-blinded, randomized, placebo-controlled trial of oral valganciclovir in neonates with symptomatic CMV infection (NCT00466817).1 A 2003 trial by the CASG of intravenous (IV) ganciclovir in neonates with CMV infection and central nervous system involvement showed that 6 weeks of ganciclovir therapy resulted in better hearing at 6 months but suggested that those gains were not durable.2 The recently completed CASG trial randomized neonates to either 6 weeks or 6 months of treatment with oral valganciclovir, a prodrug of ganciclovir, and assessed changes at 6, 12, and 24 months in better-ear and overall hearing and performance on a neurodevelopmental test, particularly as it related to linguistic and communication ability. No significant differences in hearing were noted between the two groups at 6 months, but improved hearing was 3 times as likely at 12 months and 2.6 times as likely at 24 months in study patients receiving 6 months vs 6 weeks of therapy. Those receiving 6 months of therapy also scored higher on the Bayley III assessment of neurodevelopment in the language-composite component and the receptive-communication scale, with low average results vs the borderline results seen in neonates receiving only 6 weeks of therapy. Neutropenia (i.e., a reduced number of neutrophils), which can be a concern in neonates taking IV ganciclovir, posed less of an issue with the oral administration of valganciclovir over the course of 6 months. According to Fowler, these results represent “a big step forward in our ability to improve outcomes in infants with congenital CMV and will establish a new standard of care. Our next step will be to determine whether infants who are asymptomatically infected with CMV—but still at risk for developing hearing loss—will benefit from antiviral therapy, as well.”

Dr. Robert StuartDr. Azizul Haque

The body’s own immune system could be a potent weapon in the war on cancer if the cloaking mechanisms tumor cells use to elude it could be deactivated. In an article published in the February 15 issue of the Journal of Immunology, one of those cloaking mechanisms was identified in B cell tumors by a team of MUSC immunologists led by Azizul Haque, PhD (above right), MUSC Health hematologist/oncologist Robert Stuart, M.D. (above left), and their colleagues at the University of Indiana and German Research Center for Environmental Health. They reported that overexpression of the c-MYC protein, one of the most commonly activated genes in human cancers that is implicated in the cancer-related deaths of about 100,000 people worldwide, is linked to the ability of B cell tumors to “hide” from the immune system.1 Specifically, they showed for the first time that overexpression of the c-MYC protein in Burkitt’s lymphoma interferes with human leucocyte antigen (HLA) class II antigen presentation. T cells can mount an immune response against antigens only if they can “see” them; they “see” them when TCRs (T cell receptors) on their surface recognize antigen fragments bound to HLA class II molecules on the surface of antigen-presenting cells. When tumor antigen is not presented properly due to c-MYC overexpression, it remains invisible to the T cells. The article also provided evidence that treatment of c-MYC-overexpressing cells with a c-MYC inhibitor decreased c-MYC expression and partially restored HLA class II-mediated antigen presentation. These results suggest that c-MYC inhibitors could help “unmask” B cell lymphomas and promote a more robust immune response. According to Haque, “This study uncovers a mechanism by which c-MYC impairs immune detection of malignant tumors, which could be targeted in future treatments for B cell lymphomas and other malignancies.” The article by Haque and colleagues was highlighted in the “In This Issue” section of the Journal of Immunology, reserved for the top 10% of articles published in the journal.

References

1 God JM, Cameron, C, Figueroa J, Amria S, Hossain A, Kempkes B, Bornkamm GW, Stuart RK, Blum JS, Haque A. Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors. The Journal of Immunology 2015;194:1434–1445.

The novel anticoagulant dabigitran can reduce the risk of stroke in patients with atrial fibrillation and, unlike warfarin, the most commonly prescribed anticoagulant, does not require injection, special dietary restrictions, or continuous monitoring of the patient’s international normalized ratio. However, these clinical benefits come at a cost - dabigatran is associated with almost twice the rate of gastrointestinal (GI) bleeding as warfarin in patients with atrial fibrillation (Hernandez et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern. Med.).The risk is greatest among African Americans, those with chronic kidney disease, and those who are also receiving antiplatelet therapy. As for any medication, the benefits must be weighed against the risks, and it remains controversial whether the risks associated with dabigatran outweigh the risks. According to Don Rockey, M.D., a noted gastroenterologist and Chair of the Department of Medicine at the Medical University of South Carolina, ?In patients with GI bleeding, the appropriate use of anticoagulants, now more than ever before, has become a major clinical challenge." In a recent commentary in Nature Reviews of Gastroenterology & Hepatology (2015 Jan 20. doi:10.1038/ nrgastro.2015.7. [Epub ahead of print]), Rockey provides guidance on how to minimize and best manage GI complications in patients with cardiovascular disease who are taking dabigatran.

Rockey suggests a collaborative team approach, with team members including at least a cardiologist and primary care physician with addition of a gastroenterologist if the patient has a history of GI bleeding. Concomitant medications that cause bleeding should be used in the lowest dose possible (e.g., no more than 81 mg aspirin). He suggests the use of proton pump inhibitors in patients at high risk of GI bleeding, such as those with a history of GI bleeding, those aged 65 years or over, those with multiple comorbidities, and those prescribed concomitant aspirin, antiplatelet agents, or nonsteroidal anti-inflammatory drugs. Patients who develop GI bleeding while taking dabigatran or other novel anticoagulants should be managed by a gastroenterology team, and endoscopy should be considered early not only to identify sources of bleeding but also to stop bleeding. In Rockey’s experience, anticoagulants do not directly cause bleeding but exacerbate bleeding from existing lesions, so locating and addressing those lesions can help minimize GI bleeding.

Use of these novel anticoagulants is likely to increase, and so it is paramount that clinicians understand the increased risk of GI bleeding associated with them and the best management for that bleeding.

Two recent recognitions by prestigious national organizations testify to the spirit of entrepreneurialism at the Medical University of South Carolina (MUSC).

In December 2014, MUSC took the No. 4 spot in the category of universities on the Patent Power 2014 Scorecard (available online), a roundup of the companies and universities with the strongest patent portfolios. The Scorecard is published by the International Electrical and Electronics Engineers (IEEE) association, the world’s largest professional association for the advancement of technology. The top three universities include No. 1 Massachusetts Institute of Technology (MIT), followed by University of California and Harvard University. The formula to determine overall “Pipeline Power” starts with the number of U.S. patents an organization receives during the preceding year and weights that based on metrics that reflect the growth, impact, originality, and generality of the organization’s patent portfolio. MUSC’s debut appearance in the top tier of the annual listing spotlights the overall strength of its patent portfolio, which is managed by MUSC Foundation for Research Development (FRD), the university’s technology transfer office. "This ranking is an acknowledgement of the cutting-edge research being performed at MUSC and captured in FRD's patent portfolio. It highlights why MUSC is a great choice for industry partnerships,” said FRD Associate Director Jesse Goodwin. To search a database of currently available technologies, visit http://musc.technologypublisher.com/

Also in December, Bärbel Rohrer, Ph.D., Professor of Ophthalmology at MUSC’s Storm Eye Institute, was named a fellow of the National Academy of Inventors (NAI).  Only 414 American inventors currently hold this distinction. NAI fellows are named inventors on U.S. patents and are nominated by their peers for outstanding contributions to innovation in areas such as patents and licensing, innovative discovery and technology, significant impact on society, and support and enhancement of innovation.

Rohrer, who specializes in diseases of the retina, holds two U.S. patents and five international patents, with an additional 23 applications pending. Her intellectual property provided the foundation for three start-up companies, with a major pharmaceutical company acquiring her first company and her co-founding the next two companies. To learn more about one of those companies, MitoChem, read “Four MUSC Start-Up Companies That Are Changing Care” in the Research section of the MUSC Health Year in Review.

To learn more about research and clinical innovation at MUSC, subscribe to Progressnotes, MUSC’s quarterly medical magazine.

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