Citations

Abstract Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. TROY expression increases with glial tumor grade and inversely correlates with patient survival. TROY stimulates GBM cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. Conversely, knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. In this study, we demonstrated that PPF decreases TROY protein expression in glioma cells, and subsequently suppress activation downstream signaling effectors including AKT, NF-κB, and Rac1. PPF treatment of glioma cells also suppressed glioma cell migration and invasion, demonstrated by transwell migration assay and reduced membrane ruffling. Finally, PPF treatment increased vulnerability of glioma cells to Temozolomide (TMZ) and radiation. In summary, this study demonstrates that PPF provides a pharmacologic approach to target TROY to inhibit glioma cell invasion and reduce therapeutic resistance to TMZ and radiation. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran. Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5366. doi:10.1158/1538-7445.AM2015-5366

Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications.

Background The International Classification of Headache Disorders provides criteria for the diagnosis and subclassification of migraine. Since there is no objective gold standard by which to test these diagnostic criteria, the criteria are based on the consensus opinion of content experts. Accurate migraine classifiers consisting of brain structural measures could serve as an objective gold standard by which to test and revise diagnostic criteria. The objectives of this study were to utilize magnetic resonance imaging measures of brain structure for constructing classifiers: (1) that accurately identify individuals as having chronic vs episodic migraine vs being a healthy control; and (2) that test the currently used threshold of 15 headache days/month for differentiating chronic migraine from episodic migraine. Methods Study participants underwent magnetic resonance imaging for determination of regional cortical thickness, cortical surface area, and volume. Principal components analysis combined structural measurements into principal components accounting for 85% of variability in brain structure. Models consisting of these principal components were developed to achieve the classification objectives. Tenfold cross validation assessed classification accuracy within each of the 10 runs, with data from 90% of participants randomly selected for classifier development and data from the remaining 10% of participants used to test classification performance. Headache frequency thresholds ranging from 5‐15 headache days/month were evaluated to determine the threshold allowing for the most accurate subclassification of individuals into lower and higher frequency subgroups. Results Participants were 66 migraineurs and 54 healthy controls, 75.8% female, with an average age of 36 +/− 11 years. Average classifier accuracies were: (1) 68% for migraine (episodic + chronic) vs healthy controls; (2) 67.2% for episodic migraine vs healthy controls; (3) 86.3% for chronic migraine vs healthy controls; and (4) 84.2% for chronic migraine vs episodic migraine. The classifiers contained principal components consisting of several structural measures, commonly including the temporal pole, anterior cingulate cortex, superior temporal lobe, entorhinal cortex, medial orbital frontal gyrus, and pars triangularis. A threshold of 15 headache days/month allowed for the most accurate subclassification of migraineurs into lower frequency and higher frequency subgroups. Conclusions Classifiers consisting of cortical surface area, cortical thickness, and regional volumes were highly accurate for determining if individuals have chronic migraine. Furthermore, results provide objective support for the current use of 15 headache days/month as a threshold for dividing migraineurs into lower frequency (ie, episodic migraine) and higher frequency (ie, chronic migraine) subgroups.

Medicine is increasingly focused on team‐based practice as interprofessional cooperation leads to better patient care. Thus, it is necessary to teach teamwork and collaboration with other health care professionals in undergraduate medical education to ensure that trainees entering the workforce are prepared to work in teams. Gross anatomy provides an opportunity to expose students to interprofessional education (IPE) early in their training. The purpose of this study is to describe an IPE experience and report if the experience has lasting influence on the participating students. The Readiness for Interprofessional Learning Scale (RIPLS) questionnaire was administered to first year medical (MD) and physical therapy (PT) students at Mayo Medical School and Mayo School of Health Sciences. Results demonstrated an openness on the part of the students to IPE. Interprofessional education experiences were incorporated into gross anatomy courses in both medical and PT curricula. The IPE experiences included a social event, peer‐teaching, and collaborative clinical problem‐solving sessions. These sessions enhanced gross anatomy education by reinforcing previous material and providing the opportunity to work on clinical cases from the perspective of two healthcare disciplines. After course completion, students again completed the RIPLS. Finally, one year after course completion, students were asked to provide feedback on their experience. The post‐curricular RIPLS, similar to the pre‐curricular RIPLS, illustrated openness to IPE from both MD and PT students. There were however, significant differences in MD and PT perceptions of roles and responsibilities. One‐year follow‐up indicated long‐term retention of lessons learned during IPE. Anat Sci Educ 8: 317–323. © 2015 American Association of Anatomists.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurologic disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurologic deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurologic function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurologic disease, we propose the IgM may act late in the cascade of neuronal stress and/or death by a broad mechanism.

Summary Objective Patients with suspected mesial temporal lobe ( MTL ) epilepsy typically undergo inpatient video–electroencephalography ( EEG ) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography ( EC oG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory EC oG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. Methods Ambulatory EC oG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal EC oG activity. EC oG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. Results Eighty‐two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. Significance About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory EC oG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory EC oG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video‐ EEG monitoring, and can contribute to treatment decisions.

Positioning‐related injuries caused during surgery under anesthesia are most likely multifactorial. Pathologic mechanical forces alone (overstretching and/or ischemia from direct compression) may not fully explain postsurgical neuropathy with recent evidence implicating patient‐specific factors or perioperative inflammatory responses spatially and even temporally divorced from the anatomical region of injury. The aim of this introductory article is to provide an overview of anatomic considerations of these mechanical forces on soft and nervous tissues along with factors that may compound compression or stretch injury. Three subsequent articles will address specific positioning‐related anatomic considerations of the (1) upper extremities, (2) lower extremities, and (3) central nervous system and soft tissues. Clin. Anat. 28:678–682, 2015. © 2015 Wiley Periodicals, Inc.