Increased Expression of the Δ133p53ß Isoform Enhances Brain Metastasis.

The Δ133p53ß isoform is increased in many primary tumors and has many tumor-promoting properties that contribute to increased proliferation, migration and inflammation. Here we investigated whether Δ133p53ß contributed to some of the most aggressive tumors that had metastasized to the brain. Δ133p53ß mRNA expression was measured in lung, breast, melanoma, colorectal metastases and, where available, the matched primary tumor. The presence of Δ133p53ß expression was associated with the time for the primary tumor to metastasize and overall survival once the tumor was detected in the brain. Δ133p53ß was present in over 50% of lung, breast, melanoma and colorectal metastases to the brain. It was also increased in the brain metastases compared with the matched primary tumor. Brain metastases with Δ133p53ß expressed were associated with a reduced time for the primary tumor to metastasize to the brain compared with tumors with no Δ133p53ß expression. In-vitro-based analyses in Δ133p53ß-expressing cells showed increased cancer-promoting proteins on the cell surface and increased downstream p-AKT and p-MAPK signaling. Δ133p53ß-expressing cells also invaded more readily across a mock blood-brain barrier. Together these data suggested that Δ133p53ß contributes to brain metastases by making cells more likely to invade the brain.

Reduction of lithium induced interstitial fibrosis on co-administration with amiloride.

Long-term administration of lithium is associated with chronic interstitial fibrosis that is partially reduced with exposure to amiloride. We examined potential pathways of how amiloride may reduce interstitial fibrosis. Amiloride was administered to a rat model of lithium induced interstitial fibrosis over a long term (6 months), as well as for short terms of 14 and 28 days. Kidney cortical tissue was subjected to RNA sequencing and microRNA expression analysis. Gene expression changes of interest were confirmed using immunohistochemistry on kidney tissue. Pathways identified by RNA sequencing of kidney tissue were related to 'promoting inflammation' for lithium and 'reducing inflammation' for amiloride. Validation of candidate genes found amiloride reduced inflammatory components induced by lithium including NF-κB/p65Ser536 and activated pAKTSer473, and increased p53 mediated regulatory function through increased p21 in damaged tubular epithelial cells. Amiloride also reduced the amount of Notch1 positive PDGFrß pericytes and infiltrating CD3 cells in the interstitium. Thus, amiloride attenuates a multitude of pro-inflammatory components induced by lithium. This suggests amiloride could be repurposed as a possible anti-inflammatory, anti-fibrotic agent to prevent or reduce the development of chronic interstitial fibrosis.

Comparison of Four Classroom-Based Strategies for Middle School Students With ADHD: A Pilot Randomized Controlled Trial.

Middle school students with ADHD often experience negative academic outcomes. To intervene, schools frequently provide services through special education or section 504. These services include strategies, such as breaks, prompting, and sensory proprioception to remove the impact of construct-irrelevant variance. Student plans rarely include strategies, such as selfmanagement, designed to teach students skills to increase independent functioning. The purpose of this study was to compare the effectiveness of four strategies on engagement, disruptive behavior, and time to initiate tasks. Fifteen sixth and seventh grade students were randomized daily to one of four conditions. Results indicated large statistically significant differences. Social validity data indicated that students found prompting and self-management helpful, but preferred breaks and sensory proprioception. This study builds on a growing empirical base that supports the prioritization of strategies to teach skills over strategies to remove the impact of ADHD on performance.

Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy.

INTRODUCTION: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition. METHODS: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy. RESULTS: On whole exome sequencing, we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a ß-strand to cause an unstable structure and likely significant changes in protein function. CONCLUSIONS: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.

Adhesion G-protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development.

Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders. Developmental Dynamics 246:275-284, 2017. © 2016 Wiley Periodicals, Inc.

Impact of early extubation and reintubation on the incidence of bronchopulmonary dysplasia in neonates.

OBJECTIVE: The objective of this study was to assess rates of bronchopulmonary dysplasia (BPD) and BPD/death in infants first extubated between day of life (DOL) 1 to 3 versus 4 to 7, 8+, and impact of reintubation. STUDY DESIGN: We included infants with gestational age ≤ 28 weeks, birth weight ≤ 1,000 g, and intubation on DOL 1. Proportional hazards regression modeled time to BPD and BPD/death, adjusting for potential confounders. RESULTS: Of 262 infants, 101 (38.55%), 41 (15.65%), and 120 (45.80%) were extubated between DOL 1 to 3, 4 to 7, and 8+, respectively. Extubation between DOL 4 to 7 and DOL 1 to 3 was associated with an increased hazard of developing BPD (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.0-2.8; p < 0.05). Extubation on DOL 8+ was associated with a significantly increased hazard compared with extubation between DOL 1 to 3 (HR, 16.9; 95% CI, 10.5-27.1; p < 0.0001) and DOL 4 to 7 (HR, 10.0; 95% CI, 6.1-16.3; p < 0.0001). Similar results were noted with BPD/death. Reintubation did not affect BPD and BPD/death. CONCLUSIONS: Delaying extubation beyond the first 3 and 7 days was associated with an increased risk of BPD and BPD/death. Reintubation did not impact outcomes.

Constitutional telomerase mutations are genetic risk factors for cirrhosis.

UNLABELLED: Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004). CONCLUSION: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis.

Dextromethorphan protects male but not female mice with brain ischemia.

The non-competitive N-methyl-D-aspartate receptor antagonist dextromethorphan is protective against some types of brain injury. Unilateral carotid ligation in postnatal day 12 CD1 mice produces ischemic brain injury. To evaluate the neuroprotective potential of dextromethorphan against ischemic injury in the immature brain, seven litters of postnatal day 12 CD1 mice received either dextromethorphan or vehicle after a unilateral carotid ligation. Only the male pups were protected, and brain injury was unchanged in the female pups treated with dextromethorphan. These results suggest that dextromethorphan neuroprotection against ischemic injury in the immature brain is sex-dependent.

Sturge-Weber syndrome associated with other abnormalities: a medical record and literature review.

OBJECTIVE: To develop hypotheses regarding the relationship between Sturge-Weber syndrome (SWS) and other abnormalities in a subset of patients. DESIGN: We retrospectively reviewed medical records in a group of 28 patients with SWS, noting the main features of SWS and accompanying unexpected abnormalities. We also conducted a literature review of abnormalities associated with SWS. RESULTS: Twenty-eight medical records of patients with SWS were reviewed. Of this number, we found 8 (29%, 2 female) patients who manifested other abnormalities. Our review of the literature uncovered 15 additional cases with associated abnormalities. CONCLUSIONS: We hypothesize that the abnormalities associated with SWS suggest testable insights regarding pathogenesis and that chromosome 17p1-p13 may be a candidate region for genes involved with SWS. We also propose that some patients with SWS may have disorders of cholesterol biosynthesis or carbohydrate glycosylation.