Maturation- and aging-related differences in electrophysiological correlates of error detection and error awareness

The error-related negativity (ERN/Ne) as well as the early and late error positivity (Pe) are electrophysiological correlates known to reflect error detection and error awareness. Despite much evidence on age differences in mastering response conflicts, the development and the functional distinctiveness of these components across the lifespan is still unclear. Here we investigated maturation- and aging-related differences in the ERN/Ne, the early and late Pe during a response conflict task in a lifespan sample that included 45 children, 42 adolescents, 39 younger and 34 older adults. Lifespan age differences were characterized by marked declines of all three components in older age, whereas clear maturation effects from childhood to adolescence were only observed for error detection reflected in the ERN/Ne component. Furthermore, using regression analyses, we examined functional relationships of the error monitoring components to behavioral indicators of task performance. Across all age groups, both the ERN/Ne and the early Pe were related to response accuracy, but only the early Pe was further associated with performance in a covariate task indicative of perceptual processing and attention capacities. Our results suggest that the ERN/Ne, the early and late Pe reflect distinct but complementary processes of error monitoring across the lifespan

Chiasma

Newspaper reporting on events at the Boston University School of Medicine in the 1960s

Genomic Annotation of Bacteriophages Clayda5, GShelby23, Santhid, and Wrigley

We annotated the genomes of four recently discovered Actinobacteriophages. Clayda5 and GShelby23 were isolated on Microbacterium foliorum NRRL B-24224. Clayda5 is a lytic, cluster EB phage, one of only 47 discovered to date. It has 10 base pair 3’ sticky overhanging ends and a GC content is 67.2%. It has 70 protein-coding genes and two tRNA genes in its 39,894 bp genome. Clayda5 was purified from soil collected in Hull, IA. GShelby23 was isolated from soil collected in Storm Lake, IA. It is a cluster EM phage, one of only six discovered to date. Its genome is circularly permuted and 53,603 bp long. Its GC content is 64.8%. Santhid and Wrigley are phages that infect Gordonia terrae 3612. Santhid is a cluster DY phage, one of only five discovered to date. It was isolated from soil collected in Orange City, IA. Its genome is 39,295 bp long and includes 60 protein-coding genes. Its GC content is 67.7% and has 10 base pair 3’ sticky overhanging ends. Wrigley was isolated using an enrichment protocol from soil collected in Johnston, IA. It is a cluster CY phage, one of only 17 discovered to date. It is a temperate phage whose genome is 51,878 bp long and includes 81 protein-coding genes. It has 10 base pair 3’ sticky overhanging ends and a GC content of 66.3%.

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988

Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance

INTRODUCTION: Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells. METHODS: BM aspirates from 32 carcinoma patients were screened for the presence of micrometastatic cells positive for epithelial cell adhesion molecule and positive for cytokeratins, using optimized immunodetection methods. A comparison with data obtained for 46 control BM aspirates and a correlation with the clinical status of patients were performed. RESULTS: We developed a sensitive and efficient immunomagnetic protocol for the enrichment of BM micrometastases. This method was used to divide 32 breast carcinoma patients into three categories according to their epithelial cell adhesion molecule status. These categories were highly correlated with the recently revised American Joint Committee on Cancer staging system for breast cancer, demonstrating the clinical relevance of this simple and reliable immunomagnetic technique. We also evaluated immunocytochemical detection of cytokeratin-positive cells and cytomorphological parameters. Immunocytochemistry-based methods for the detection of BM micrometastases did not provide any information about the clinical status of patients, but helped to refine the immunomagnetic data by confirming the presence of micrometastases in some cases. We also tested a new density gradient centrifugation system, able to enrich the tumor fraction of BM specimens by twofold to threefold as compared with standard Ficoll methods. CONCLUSION: These improved methods for the detection of micrometastatic cells in patient BM should help clinicians to predict the clinical status of breast cancer patients at the time of surgery or treatment

N-Glycans and Glycosylphosphatidylinositol-Anchor Act on Polarized Sorting of Mouse PrPC in Madin-Darby Canine Kidney Cells

The cellular prion protein (PrPC) plays a fundamental role in prion disease. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein with two variably occupied N-glycosylation sites. In general, GPI-anchor and N-glycosylation direct proteins to apical membranes in polarized cells whereas the majority of mouse PrPC is found in basolateral membranes in polarized Madin-Darby canine kidney (MDCK) cells. In this study we have mutated the first, the second, and both N-glycosylation sites of PrPC and also replaced the GPI-anchor of PrPC by the Thy-1 GPI-anchor in order to investigate the role of these signals in sorting of PrPC in MDCK cells. Cell surface biotinylation experiments and confocal microscopy showed that lack of one N-linked oligosaccharide leads to loss of polarized sorting of PrPC. Exchange of the PrPC GPI-anchor for the one of Thy-1 redirects PrPC to the apical membrane. In conclusion, both N-glycosylation and GPI-anchor act on polarized sorting of PrPC, with the GPI-anchor being dominant over N-glycans