RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1).

MOAP-1 is a pro-apoptotic tumor suppressor molecule with a growing set of known interacting partners. We have demonstrated that during death receptor-dependent apoptosis, MOAP-1 is recruited to TNF-R1 or TRAIL-R1, followed by RASSF1A and Bax association. MOAP-1/Bax association promotes Bax conformational change resulting in the translocation of Bax into the mitochondrial membrane, mitochondrial membrane insertion and dysregulation resulting in several hallmark events that execute apoptosis. Although a role in apoptosis is established, it is currently unknown how MOAP-1 is regulated and how it links to Bax to promote apoptosis. In this study, we demonstrate robust association with RACK1, a versatile scaffolding protein that responds to activation of protein kinase C. Furthermore, we can demonstrate that RACK1 functions to bring the E3 ligase, TRAF2, to MOAP-1 in order to undergo a K63-dependent ubiquitination. Furthermore, RACK1 associates with MOAP-1 via electrostatic associations similar to those observed between MOAP-1/RASSF1A and MOAP-1/TNF-R1. These events illustrate the complex nature of MOAP-1 regulation and characterizes the important role of the scaffolding protein, RACK1, in influencing MOAP-1 biology.

Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-ß, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis.

CT imaging, classification, and complications of acute pancreatitis.

Acute pancreatitis is an increasingly common condition and can result in significant morbidity and mortality. Contrast enhanced computed tomography (CECT) is the primary initial imaging modality in the characterization of acute pancreatitis. In this article, we provide sample CECT technical acquisition parameters for pancreatic imaging. We also review the classification systems for acute pancreatitis and give examples of common and uncommon complications of acute pancreatitis.

Injection augmentation and endoscopic repair of type 1 laryngeal clefts: development of a management algorithm.

OBJECTIVES: To describe indications for injection augmentation (IA), endoscopic repair (ER) and conservative methods for the management of type 1 laryngeal cleft (LC1) and propose a management algorithm. We also aimed to compare success of IA and ER and determine independent predictors of treatment failure. METHODS: Retrospective study of patients diagnosed with LC1 at a Pediatric Otolaryngology referral centre between 2004 and 2016. All had pre-operative instrumental swallowing evaluation (VFSS/FEES), and were managed with a combination of conservative measures, IA and/or ER. We collected demographics, symptoms, comorbidities, VFSS/FEES results, and operative details. The primary outcome was symptom resolution by parental report. The secondary outcome was predictors of treatment failure. RESULTS: 88 patients were included in the analysis, with mean age 26 ± 25 months. Most presented with choking events (68%) or recurrent pneumonias (48%). In total, there were 55 IA performed and 45 ER. Of the patients who received IA, 19 required subsequent ER. 95% had symptom improvement, 67% had complete resolution. IA had a 56% long-term success rate, whereas that for ER was 85%. Tube feeding at initial evaluation was an independent predictor of treatment failure (HR 11.33 [1.51-84.97], p = 0.018). CONCLUSIONS: LC1 can be effectively managed with a combination of IA and ER with favorable results. Failure to respond to IA does not preclude ER, and both have their role in management. Patients who are tube fed have a higher probability of treatment failure. We propose a management algorithm that includes reasoning for conservative approaches, and reduces exposure to general anesthesia.

Difficulties in Residency: An Examination of Clinical Rotations and Competencies Where Family Medicine Residents Most Often Struggle.

BACKGROUND AND OBJECTIVES: Remediation in residency is expensive; however, most research has focused on general approaches to remediation, with minimal investigation into whether there are patterns to the competencies or rotations that are most difficult for residents. Acquiring this information may improve future physician training and potentially reduce the frequency of resource-intensive remediation. We aimed to determine the competencies and rotations most challenging for family medicine residents, as defined by the number of assessments with flags (one or more competencies indicated as less than satisfactory). METHODS: A secondary data analysis of archived resident files from a large Canadian family medicine residency program was conducted. Residents from six cohorts were reviewed (N=393) and flags on the in-training evaluation reports (ITERs) and summative periodic progress reports were recorded and summarized with descriptive statistics. RESULTS: One hundred forty-one residents (36%) received at least one flag during training. Rotations where learners received the most flags were: internal medicine (average 1.52±4.82 flags), urban family medicine (average 1.48±4.18), and obstetrics (average 1.07±3.80). For residents having at least one flag, competencies causing most difficulty included: professionalism (21.4%), clinical decision making (17.8%), and teamwork and communication (15.5%). CONCLUSIONS: The file review identified coronary care unit, internal medicine, obstetrics, and general surgery as those rotations (adjusted for length) where family medicine residents most often struggled. Furthermore, deficient clinical knowledge was not one of the main reasons that residents are flagged. These findings may inform programs about where to target resident supports and resources.

Dysphagia in healthy children: Characteristics and management of a consecutive cohort at a tertiary centre.

OBJECTIVE: Whereas the literature is replete with reports on complex children with dysphagia (DP), the parameters characterizing non-neurologically impaired (NNI) children have been underreported, leaving a substantial knowledge gap. We set to characterize a consecutive cohort of NNI children, their management, and outcomes. METHODS: We undertook a retrospective case series. Children (<18 years old) attending a tertiary multidisciplinary swallowing clinic were eligible. Patients with neuro-developmental, neuromuscular, or syndromic abnormalities were excluded. Primary outcomes included demographics, co-morbidities, presentations, McGill score, swallowing and airway abnormalities (and their predictors). Secondary outcomes were interventions and management response. RESULTS: From 171 consecutive patients (37-month period), 128 were included (69 males, median age 6.6 months (0.5-124.2)). Significant clinical presentations included recurrent pneumonias (20), cyanotic spells (14) and life-threatening events (10). Swallowing assessments revealed laryngeal penetration (67), aspiration (25). Other investigations included overnight oximetry (77), airway (70), and gastrointestinal endoscopy (24); revealing laryngomalacia (29), laryngeal mobility disorder (8), and subglottic stenosis (8). Non-surgical interventions involved oral diet modifications (85) and enteral nutrition (15). Surgical interventions included supraglottoplasties (18), endoscopic laryngeal cleft repair (14), and injection (19). 119 patients received intervention and at last follow-up (median 5.2 months (0.3-88.8)) 94 had improved. Of those treated 116 were on an unmodified oral diet, and 24 on a modified diet. ALTE and snoring predicted airway abnormalities, recurrent pneumonia predicted swallowing abnormalities, and age and airway lesions predicted the McGill score. CONCLUSION: a significant proportion of NNI children with DP harbor airway and swallowing abnormalities warranting endoscopic and instrumental assessment.