Next generation sequencing is informing phenotype: a TP53 example.

The increased availability of next generation sequencing (NGS) and multi gene panel testing has resulted in more frequent TP53 testing of families that do not meet classic testing criteria. We investigated testing criteria, family history and result outcome in a cohort of Irish probands undergoing TP53 full sequencing. All TP53 test requests processed through the national genetic testing laboratory between 2012 and 2014 were retrospectively reviewed. Personal and family cancer histories were collected, including tumour type and age at diagnosis, from two adult cancer genetic services in Ireland. Association between Li Fraumeni syndrome (LFS) or Li Fraumeni like syndrome (LFL) criteria and test result was examined. One hundred and 35 TP53 test requests were identified. Family history data and test results were available on 123 of the TP53 test requests (118 female; 5 male). 59/123 (48%) did not meet classic LFS or LFL criteria. Two individuals from this group harboured pathogenic TP53 mutations, giving a 3% mutation detection rate in those not meeting testing criteria. Both were female and had a personal history of early onset bilateral breast cancer with no reported LFS cancers in the family. 64/123 (52%) met LFS or LFL criteria and were all TP53 negative. 37/64 (57.8%) met Chompret criteria, 19/64 (29.7%) met Eeles and 7/64 (10.9%) met Eeles and Chompret and 1/64 (1.6%) met Classic LFS criteria. Stringent testing criteria miss germline mutations in TP53. Broadening the criteria for TP53 testing may improve our understanding of the phenotype and penetrance in the association syndrome.

An Irish outbreak of New Delhi metallo-ß-lactamase (NDM)-1 carbapenemase-producing Enterobacteriaceae: increasing but unrecognized prevalence.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) may cause healthcare-associated infections with high mortality rates. New Delhi metallo-ß-lactamase-1 (NDM-1) is among the most recently discovered carbapenemases. AIM: To report the first outbreak of NDM-1 CPE in Ireland, including microbiological and epidemiological characteristics, and assessing the impact of infection prevention and control measures. METHODS: This was a retrospective microbiological and epidemiological review. Cases were defined as patients with a CPE-positive culture. Contacts were designated as roommates or ward mates. FINDINGS: This outbreak involved 10 patients with a median age of 71 years (range: 45-90), located in three separate but affiliated healthcare facilities. One patient was infected (the index case); the nine others were colonized. Nine NDM-1-producing Klebsiella pneumoniae, an NDM-1-producing Escherichia coli and a K. pneumoniae carbapenemase (KPC)-producing Enterobacter cloacae were detected between week 24, 2014 and week 37, 2014. Pulsed-field gel electrophoresis demonstrated similarity. NDM-1-positive isolates were meropenem resistant with minimum inhibitory concentrations (MICs) ranging from 12 to 32 µg/mL. All were tigecycline susceptible (MICs ≤1 µg/mL). One isolate was colistin resistant (MIC 4.0 µg/mL; mcr-1 gene not detected). In 2015, four further NDM-1 isolates were detected. CONCLUSION: The successful management of this outbreak was achieved via the prompt implementation of enhanced infection prevention and control practices to prevent transmission. These patients did not have a history of travel outside of Ireland, but several had frequent hospitalizations in Ireland, raising concerns regarding the possibility of increasing but unrecognized prevalence of NDM-1 and potential decline in value of travel history as a marker of colonization risk.

Extragonadal teratomas of the adult abdomen and pelvis: a pictorial review.

Teratomas comprise a spectrum of tumours that have striking imaging appearances and are commonly considered when evaluating a mass in the female pelvis. A subgroup of these tumours located in an extragonadal abdominopelvic location, in contrast, are extremely rare and can affect both sexes. Extragonadal teratomas can occur at all ages, are particularly unusual in adults and can cause confusion in the differential diagnosis, especially in children. Familiarity with the imaging features of the spectrum of teratomas within the abdominal cavity is therefore of great importance, as radiological diagnosis can guide treatment, prevent delays in diagnosis and avoid sequelae. This article summarizes the radiological appearances of these rare extragonadal tumours in adults in relation to their pathology, malignant potential, location and behaviour. Although uncommon, teratomas should be considered in the differential diagnosis of extragonadal abdominal masses, particularly in young adults.

Tail-end troubles: imaging of soft-tissue buttock tumours.

Primary soft-tissue buttock tumours are relatively common entities, although they are infrequently reported in the literature. The buttock can be a difficult anatomical site to treat soft-tissue tumours due to the proximity of the sciatic nerve and the propensity of tumours at this site to extend into the pelvis and perineum. Therefore, the radiologist plays an important role in the multidisciplinary assessment of these lesions. Cross-sectional imaging, principally magnetic resonance imaging, is used to determine the exact location and extension of the tumour. Furthermore, certain tumours have characteristic imaging appearances that can help to establish a suitably ordered differential diagnosis. From our prospectively maintained database at The Royal Marsden Hospital, including 225 cases that were treated at the Sarcoma Unit over a 30 year period, we present examples of benign and malignant primary soft-tissue buttock tumours and describe the pertinent imaging characteristics, with emphasis on computed tomography and magnetic resonance imaging findings.

Towards structural biology in the genus Mytilus: on-line homology modeling with Geno3D.

Seven structures from the genus Mytilus exist in the protein data bank (PDB) but > 1000 Mytilus protein sequences are known. Sequences (NCBI) were used as targets for on-line homology modeling with Geno3D as an alternative route to structure. Quality comparators include root mean square deviation (RMSD) of target from template, chain geometry and Ramachandran diagram analysis. We modeled 17 Mytilus structures for mainly stress-response proteins relevant to biomonitoring. These model files are available as a first step towards a structural resource for Mytilus. Analysis suggests that they are structurally plausible with low RMSDs relative to targets. Ramachandran analysis suggests a small percentage of disallowed dihedral angles (in the range 0-6.86% for 15 of 17 models).

Glycogen synthase kinase-3 (GSK-3) is regulated during Dictyostelium development via the serpentine receptor cAR3.

Glycogen synthase kinase-3 (GSK-3) is required during metazoan development to mediate the effects of the extracellular signal wingless/Wnt-1 and hence is necessary for correct cell type specification. GSK-3 also regulates cell fate during Dictyostelium development, but in this case it appears to mediate the effects of extracellular cAMP. By direct measurement of GSK-3 kinase activity during Dictyostelium development, we find that there is a rise in activity at the initiation of multicellular development which can be induced by cAMP. The timing of the rise correlates with the requirement for the Dictyostelium homologue of GSK-3, GSKA, to specify cell fate. We show that loss of the cAMP receptor cAR3 almost completely abolishes the rise in kinase activity and causes a mis-specification of cell fate that is equivalent to that seen in a gskA- mutant. The phenotype of a cAR3(-) mutant however is less severe than loss of gskA and ultimately gives rise to an apparently wild-type fruiting body. These results indicate that in Dictyostelium extracellular cAMP acts via cAR3 to cause a rise in GSKA kinase activity which regulates cell type patterning during the initial stages of multicellularity.