St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Abstract: MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway.

Abstract: Although Streptococcus pneumoniae is a major cause of meningitis in humans, the mechanisms underlying its traversal from the circulation across the blood-brain barrier (BBB) into the subarachnoid space are poorly understood. One mechanism might involve transcytosis through microvascular endothelial cells. In this study we investigated the ability of pneumococci to invade and transmigrate through monolayers of rat and human brain microvascular endothelial cells (BMEC). Significant variability was found in the invasive capacity of clinical isolates. Phase variation to the transparent phenotype increased invasion as much as 6-fold and loss of capsule approximately 200-fold. Invasion of transparent pneumococci required choline in the pneumococcal cell wall, and invasion was partially inhibited by antagonists of the platelet-activating factor (PAF) receptor on the BMEC. Pneumococci that gained access to an intracellular vesicle from the apical side of the monolayer subsequently were subject to three fates. Most opaque variants were killed. In contrast, the transparent phase variants were able to transcytose to the basal surface of rat and human BMEC in a manner dependent on the PAF receptor and the presence of pneumococcal choline-binding protein A. The remaining transparent bacteria entering the cell underwent a previously unrecognized recycling to the apical surface. Transcytosis eventually becomes a dominating process accounting for up to 80% of intracellular bacteria. Our data suggest that interaction of pneumococci with the PAF receptor results in sorting so as to transcytose bacteria across the cell while non-PAF receptor entry shunts bacteria for exit and reentry on the apical surface in a novel recycling pathway.

Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study

Abstract: Summary Background Therapy for ependymoma includes aggressive surgical intervention and radiotherapy administered by use of methods that keep the risk of side-effects to a minimum. We extended this treatment approach to include children under the age of 3 years with the aim of improving tumour control. Methods Between July 11, 1997, and Nov 18, 2007, 153 paediatric patients (median age 2·9 years [range 0·9–22·9 months]) with localised ependymoma were treated. 85 patients had anaplastic ependymoma; the tumours of 122 were located in the infratentorial region, and 35 had received previous chemotherapy. Patients received conformal radiotherapy after definitive surgery (125 patients had undergone gross total, 17 near total, and 11 subtotal resection). Doses of 59·4 Gy (n=131) or 54·0 Gy (n=22) were prescribed to a 10 mm margin around the target volume. Disease control, patterns of failure, and complications were recorded for patients followed over 10 years. Overall survival, event-free survival (EFS), cumulative incidence of local recurrences, and cumulative incidence of distant recurrences were assessed. Variables considered included tumour grade, tumour location, ethnic origin, sex, age when undergoing conformal radiotherapy, total radiotherapy dose, number of surgical procedures, surgery extent, and preradiotherapy chemotherapy. Findings After a median follow-up of 5·3 years (range 0·4–10·4), 23 patients had died and tumour progression noted in 36, including local (n=14), distant (n=15), and combined failure (n=7). 7-year local control, EFS, and overall survival were 87·3% (95% CI 77·5–97·1), 69·1% (56·9–81·3), and 81·0% (71·0–91·0), respectively. The cumulative incidences of local and distant failure were 16·3% (9·6–23·0) and 11·5% (5·9–17·1), respectively. In the 107 patients treated with immediate postoperative conformal radiotherapy (without delay or chemotherapy), 7-year local control, EFS, and overall survival were 88·7% (77·9–99·5), 76·9% (63·4–90·4), and 85·0% (74·2–95·8), respectively; the cumulative incidence of local and distant failure were 12·6% (5·1–20·1), and 8·6% (2·8–14·3), respectively. The incidence of secondary malignant brain tumour at 7 years was 2·3% (0–5·6) and brainstem necrosis 1·6% (0–4·0). Overall survival was affected by tumour grade (anaplastic vs differentiated: HR 3·98 [95% CI 1·51–10·48]; p=0·0052), extent of resection (gross total vs near total or subtotal: 0·16 [0·07–0·37]; p vs white: 3·0 [1·21–7·44]; p=0·018). EFS was affected by tumour grade (anaplastic vs differentiated: 2·52 [1·27–5·01]; p=0·008), extent of resection (gross total vs near total or subtotal: 0·20 [0·11–0·39]; p vs female: 2·19 [1·03–4·66]; p=0·042). Local failure was affected by extent of resection (gross total vs near total or subtotal: 0·16 [0·067–0·38]; p vs female: 3·85 [1·10–13·52]; p=0·035), and age ( vs ≥3 years: 3·25 [1·30–8·16]; p=0·012). Distant recurrence was only affected by tumour grade (anaplastic vs differentiated: 4·1 [1·2–14·0]; p=0·017). Interpretation Treatment of ependymoma should include surgery with the aim of gross-total resection and conformal, high-dose, postoperative irradiation. Future trials might consider treatment stratification based on sex and age. Funding American Cancer Society and American Lebanese Syrian Associated Charities (ALSAC).

Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression.

Abstract: CYP2B6 metabolizes many drugs, and its expression varies greatly. CYP2B6 genotype-phenotype associations were determined using human livers that were biochemically phenotyped for CYP2B6 (mRNA, protein, and CYP2B6 activity), and genotyped for CYP2B6 coding and 5'-flanking regions. CYP2B6 expression differed significantly between sexes. Females had higher amounts of CYP2B6 mRNA (3.9-fold, P G substitution that resulted in an Lys139Glu change. Many CYP2B6 splice variants (SV) were observed, and the most common variant lacked exons 4 to 6. A nonsynonymous SNP in exon 4 (15631G>T), which disrupted an exonic splicing enhancer, and a SNP 15582C>T in an intron-3 branch site were correlated with this SV. The extent to which CYP2B6 variation was a predictor of CYP2B6 activity varied according to sex and ethnicity. The 1459C>T SNP, which resulted in the Arg487Cys substitution, was associated with the lowest level of CYP2B6 activity in livers of females. The intron-3 15582C>T SNP (in significant linkage disequilibrium with a SNP in a putative hepatic nuclear factor 4 (HNF4) binding site) was correlated with lower CYP2B6 expression in females. In conclusion, we found several common SNPs that are associated with polymorphic CYP2B6 expression.