Abstract Brain tumors represent the most common solid tumors in childhood and account for significant morbidity and mortality. The lack of advances in treatment of the brain tumors is hindered by our lack of knowledge about the molecular pathogenesis of these malignancies as well as the availability of brain-permeable therapies. Personalised medicine approaches have the potential to enhance diagnostic, prognostic and / or therapeutic information. The TARGET study is a feasibility pilot study which focused on the development of genomic platforms, high throughput drug screening (HTS), and PDX models in order to identify personalised therapies for patients with aggressive pediatric tumors. In the pilot phase 59 patients were enrolled of which 28 were brain tumor patients (47%). In 28 curated cases molecular analysis identified a reportable somatic anomaly (SNVs, gene fusions, CNVs) in 82% (23/28), of which 78% (18/23) had actionable molecular aberrations. Four cases had a reportable germline predisposition variant and in 1 case, the genomic findings changed the primary diagnosis. Fresh tissue collection permitted in vitro HTS (112 single agents) in 58% of cases to date. Four PDX models have been established with additional 8 currently still being evaluated. This feasibility study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing may be useful to guide the management of aggressive pediatric brain tumors. Citation Format: Maria Tsoli, Carol Wadham, Mark Pinese, Tim Failes, Swapna Joshi, Emily Mould, Julia Yin, Velimir Gayevski, Amit Kumar, Warren Kaplan, Paul Ekert, Laura Franshaw, Andrew Gifford, Martin Weber, Michael Rodriguez, Chelsea Mayoh, Richard Cohn, Greg Arndt, Richard Lock, Vanessa Tyrrell, Murray Norris, Michelle Haber, Loretta Lau, Dong Anh Khuong Quang, Marie Wong, Toby Trahair, Glenn M. Marshall, Mark J. Cowley, David S. Ziegler. Integrated genomics: drug screening and personalized xenograft development approach to identify precision treatments for aggressive pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-137.
Pramipexole (PRA) is a preferential D3R agonist that, in rats and humans, modifies prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating. The ability to use similar PPI measures across species, and the relative ease of genetic manipulations in mice, suggests that molecular studies of the D3R regulation of sensorimotor gating might be best pursued in mice. Here, we evaluate the effects of PRA on PPI and locomotion in C57BL/6J mice, the background strain for many gene knockout mouse models. Male C57BL/6J mice were tested for PPI and locomotor activity after injection of PRA. No significant effects of PRA on PPI were observed at any dose (0.1–10.0 mg/kg), but a significant reduction in startle magnitude was observed after 10 mg/kg PRA. In contrast, the D1/2 agonist, apomorphine (5 mg/kg) significantly reduced PPI in these mice. At doses of PRA that did not alter startle magnitude (0.3, 1, 3 mg/kg), significant decreases in the amount of locomotor and investigatory behavior were observed. Distinct from findings in rats and humans, it seems that either: (i) PRA does not activate D3Rs in C57BL/6J mice, or (ii) D3R agonists are not sufficient to alter PPI in this mouse strain.
Einleitung: Der Bedarf nach einem stabilen Außenknöchelersatz zur Vermeidung von Luxationen insbesondere bei geplanten Beinverlängerungen bei Fibulaaplasie ist gegeben. Bisherige Techniken konnten nicht überzeugen.
Several autopsy protocols have been suggested for investigating sudden unexpected deaths in infancy (SUDI). The aim of this study is to provide data on the utility of such post-mortem investigations from a large paediatric autopsy series to inform future policy.
Methods:
Retrospective analysis of >1500 consecutive post-mortem examinations carried out by specialist paediatric pathologists at a single centre during a 10-year period according to a common autopsy protocol that included the use of detailed ancillary investigations. SUDI was defined as the sudden unexpected death of an infant aged from 7 to 365 days. All data capture and cause of death classification were carried out according to defined criteria.
Results:
Of 1516 paediatric post-mortem examinations, 546 presented as SUDI. In 202 infants (37%), death was explained by the autopsy findings. The other 344 cases (63%) remained unexplained. Of the explained deaths, over half (58%) were infective, most commonly due to pneumonia (22%). The component of the post-mortem examination that primarily determined the final cause of death was histological examination in 92 infants (46%), macroscopic examination in 61 (30%), microbiological investigations in 38 (19%) and clinical history in 10 (5%).
Conclusion:
This constitutes the largest single-institution autopsy study of SUDI. Ten years on from the Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) SUDI studies, the ascertainment of a cause of death at autopsy has improved. However, with almost two thirds of SUDI remaining unexplained, alternative and/or additional diagnostic techniques are required to improve detection rates of identifiable causes of death at autopsy.
This chapter discusses the pathophysiological basis and pathology of twin reversed arterial perfusion (TRAP) sequence, briefly discussing prenatal diagnosis and treatment in relation to our understanding of the pathophysiology of the condition and largely focusing on the treatment options. Numerous pregnancy complications may develop, either due to consequences of the abnormal development of the acardiac fetus, or due to secondary effects on the pump twin. The abnormalities present in the affected acardiac twin represent a wide spectrum, ranging from the fetus comprising an amorphous mass of tissue through to a relatively well-formed fetus with trunk, arms, and legs. TRAP sequence is essentially a defect of monozygotic duplication requiring the presence of interfetal placental vascular anastomoses; it is therefore a complication affecting monochorionic multiple pregnancies. Since "pump" twin mortality and morbidity is well reported, several strategies have been described for antenatal intervention in TRAP sequence to improve the outcome.
Recent studies have shown that CC chemokines act on monocytes, lymphocytes, eosinophils and basophils, but not neutrophils, with distinct target cell selectivities, possibly explaining the selective attraction and activation of these cell types in different types of chronic inflammation and allergic disease. Functional and desensitization studies on basophils and eosinophils indicate the expression of at least three distinct G-protein-coupled CC chemokine receptors (three on basophils and two on eosinophils), which exert partially selective and partially overlapping ligand specificities and also appear to mediate distinct functions despite similar signal transduction pathways. Functional studies with all known six human CC chemokines show that each cytokine has a distinct spectrum of bioactivities and target cell profile. Interestingly, overall sequence homologies between the chemokines are not predictive for the cell function or cell type that a particular chemokine will preferentially activate, and thus discrete sequence motifs may be important for activating the different CC chemokine receptors. Using different chemokine mutants and hybrids between chemokines, the functional importance of selected individual amino acids and short motifs are now being analysed. These structure-function studies could also lead to antagonists that have more disease-selective anti-inflammatory properties than currently available drugs.
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