Rabbit Elastase Aneurysm: Imaging and Histology Correlates for Inflammation and Healing.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage remains a devastating event with poorly understood pathophysiology. Previous studies have suggested that aneurysm wall inflammation may play a part in the development and potential rupture of aneurysms. The rabbit elastase aneurysm model is a well-established model, which produces aneurysms closely mimicking human cerebral aneurysms in flow dynamics and histopathology. The primary aim of this study was to correlate inflammatory changes after aneurysm formation using sequential vessel wall imaging with histopathologic analysis. A secondary aim was to evaluate the potential effect of gender and anti-inflammatory treatment with aspirin on this inflammatory response. METHODS: Twenty-seven New Zealand rabbits underwent surgery to create an aneurysm using elastase infusion at the right common carotid artery origin. Vessel wall imaging and histopathologic analysis was obtained at different time points after aneurysm creation. The rabbits were also randomized by gender and to treatment groups with or without aspirin. RESULTS: Histopathologic analysis revealed 3 distinct phases after aneurysm formation. These phases were an initial inflammatory phase, followed by a regeneration phase, and finally a connective tissue deposition phase. Vessel wall imaging demonstrated 2 distinct imaging patterns. No appreciable differences were seen in histology or imaging when comparing gender or treatment with aspirin. CONCLUSIONS: Inflammatory changes induced by the rabbit elastase aneurysm model can be correlated with histopathologic findings and observed on noninvasive vessel wall imaging. This may provide a method to study the inflammatory pathway as it pertains to aneurysmal development and subsequent rupture.

A systematic review and quality analysis of pediatric traumatic brain injury clinical practice guidelines.

BACKGROUND: Traumatic brain injuries (TBI) are a significant cause of mortality and morbidity for children globally. Adherence to evidence-based treatment guidelines have been shown to improve TBI outcomes. To inform the creation of a pediatric TBI management guideline for a low and middle income country context, we assessed the quality of available clinical practice guidelines (CPGs) for the acute management pediatric TBI. METHODS: Articles were identified and retrieved from MEDLINE, EMBASE, Cochrane Library, LILACS, Africa-Wide Information and Global Index Medicus. These articles were screened by four reviewers independently. Based on the eligibility criteria, with the exception of literature reviews, opinion papers and editor's letters, articles published from 1995 to November 11, 2016 which covered clinical recommendations, clinical practice or treatment guidelines for the acute management of pediatric TBI (within 24 hours) were included for review. A reference and citation analysis was performed. Seven independent reviewers from low, middle and high income clinical settings with knowledge of pediatric TBI management appraised the guidelines using the AGREE II instrument. Scores for the CPGs were aggregated by domain and overall assessment was determined. RESULTS: We screened 2372 articles of which 17 were retained for data extraction and guideline appraisal. Except for one CPG from a middle income country, the majority (16/17) of the guidelines were developed in high income countries. Seven guidelines were developed specifically for the pediatric population, while the remaining CPGs addressed the acute management of TBI in both adult and pediatric populations. The New Zealand Guideline Group (NZGG, 2006) received the highest overall assessment score of 46/49 (93.88%) followed by the Scandinavian Neurotrauma Committee (SNC, 2016) with a score of 45/49 (91.84%) followed by the Scottish Intercollegiate Guideline Network (SIGN, 2009) and Brain Trauma Foundation (BTF 2012) both with scores of 44/49 (89.80%). CPGs from Cincinnati Children's Hospital (CCH 2006) and Sao Paulo Medical School Hospital/Brazilian Society of Neurosurgery (USP/BSN, 2001) received the lowest score of 27/49 (55.10%) subsequently followed by the Appropriateness Criteria (ACR, 2015) with 29/49 (59.18%). The domains for scope and purpose and clarity of presentation received the highest scores across the CPGs, while applicability and editorial independence domains had the lowest scores with a wider variability in score range for rigor of development and stakeholder involvement. CONCLUSIONS: To our knowledge, this is the first systematic review and guideline appraisal for pediatric CPGs concerning the acute management of TBI. Targeted guideline creation specific to the pediatric population has the potential to improve the quality of acute TBI CPGs. Furthermore, it is crucial to address the applicability of a guideline to translate the CPG from a published manuscript into clinically relevant local practice tools and for resource limited practice settings.

Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers.

Neurofibromin 1-mutant (NF1-mutant) cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While combined MEK and mTORC1 suppression causes regression of NF1-deficient malignancies in animal models, the potential toxicity of cotargeting these 2 major signaling pathways in humans may necessitate the identification of more refined, cancer-specific signaling nodes. Here, we have provided evidence that MAPK-interacting kinases (MNKs), which converge on the mTORC1 effector eIF4E, are therapeutic targets in NF1-deficient malignancies. Specifically, we evaluated primary human NF1-deficient peripheral nervous system tumors and found that MNKs are activated in the majority of tumors tested. Genetic and chemical suppression of MNKs in NF1-deficient murine tumor models and human cell lines potently cooperated with MEK inhibitors to kill these cancers through effects on eIF4E. We also demonstrated that MNK kinases are important and direct targets of cabozantinib. Accordingly, coadministration of cabozantinib and MEK inhibitors triggered dramatic regression in an aggressive genetically engineered tumor model. The cytotoxicity of this combination required the suppression of MNK-induced eIF4E phosphorylation and was not recapitulated by suppressing other cabozantinib targets. Collectively, these studies demonstrate that combined MNK and MEK suppression represents a promising therapeutic strategy for these incurable Ras-driven tumors and highlight the utility of developing selective MNK inhibitors for these and possibly other malignancies.