Laurie A. Steiner

OBJECTIVE: Our goal was to identify trends in patient demographics and indications for and complications related to neonatal exchange transfusion over a 21-year period in a single institution using a uniform protocol for performing the procedure. METHODS: A retrospective chart review of 107 patients who underwent 141 single- or double-volume exchange transfusions from 1986-2006 was performed. Patients were stratified into 2 groups, 1986-1995 and 1996-2006, on the basis of changes in clinical practice influenced by American Academy of Pediatrics management guidelines for hyperbilirubinemia. RESULTS: There was a marked decline in the frequency of exchange transfusions per 1000 newborn special care unit admissions over the 21-year study period. Patient demographics and indications for exchange transfusion were similar between groups. A significantly higher proportion of patients in the second time period received intravenous immunoglobulin before exchange transfusion. There was a higher proportion of patients in the 1996-2006 group with a serious underlying condition at the time of exchange transfusion. During that same time period, a lower proportion of patients experienced an adverse event related to the exchange transfusion. Although a similar percentage of patients in both groups experienced hypocalcemia and thrombocytopenia after exchange transfusion, patients treated from 1996-2006 were significantly more likely to receive calcium replacement or platelet transfusion. No deaths were related to exchange transfusion in either time period. CONCLUSIONS: Improvements in prenatal and postnatal care have led to a sharp decline in the number of exchange transfusions performed. This decline has not led to an increase in complications despite relative inexperience with the procedure.

Erythropoiesis is dependent on the activity of transcription factors, including the erythroid-specific erythroid Kruppel-like factor (EKLF). ChIP followed by massively parallel sequencing (ChIP-Seq) is a powerful, unbiased method to map trans-factor occupancy. We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts. We correlated these results with the nuclear distribution of EKLF, RNA-Seq analysis of the transcriptome, and the occupancy of other erythroid transcription factors. In progenitor cells, EKLF is found predominantly at the periphery of the nucleus, where EKLF primarily occupies the promoter regions of genes and acts as a transcriptional activator. In erythroblasts, EKLF is distributed throughout the nucleus, and erythroblast-specific EKLF occupancy is predominantly in intragenic regions. In progenitor cells, EKLF modulates general cell growth and cell cycle regulatory pathways, whereas in erythroblasts EKLF is associated with repression of these pathways. The EKLF interactome shows very little overlap with the interactomes of GATA1, GATA2, or TAL1, leading to a model in which EKLF directs programs that are independent of those regulated by the GATA factors or TAL1.

Objective Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A ( ARID1A ), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models. Design Mice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53 , were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes. Results Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a , leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a -mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation. Conclusions ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a -deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.