Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation.

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Wnt/ß-catenin signalling is dispensable for adult neural stem cell homeostasis and activation.

Adult mouse hippocampal neural stem cells (NSCs) generate new neurons that integrate into existing hippocampal networks and modulate mood and memory. These NSCs are largely quiescent and are stimulated by niche signals to activate and produce neurons. Wnt/ß-catenin signalling acts at different steps along the hippocampal neurogenic lineage, but whether it has a direct role in the regulation of NSCs remains unclear. Here, we used Wnt/ß-catenin reporters and transcriptomic data from in vivo and in vitro models to show that adult NSCs respond to Wnt/ß-catenin signalling. Wnt/ß-catenin stimulation instructed the neuronal differentiation of proliferating NSCs and promoted the activation or differentiation of quiescent NSCs in a dose-dependent manner. However, deletion of ß-catenin in NSCs did not affect either their activation or maintenance of their stem cell characteristics. Together, these results indicate that, although NSCs do respond to Wnt/ß-catenin stimulation in a dose-dependent and state-specific manner, Wnt/ß-catenin signalling is not cell-autonomously required to maintain NSC homeostasis, which reconciles some of the contradictions in the literature as to the role of Wnt/ß-catenin signalling in adult hippocampal NSCs.

Cutaneous complications in hematopoietic cell transplant recipients: impact of biopsy on patient management.

The utility of cutaneous biopsies in directing the management of post-hematopoietic cell transplantation (HCT) eruptions remains uncertain. We retrospectively analyzed 439 consecutive HCT procedures for malignant hematologic disorders performed at our institution between January 2005 and December 2012; 192 patients underwent 430 cutaneous biopsies. The clinical and dermatopathologic diagnosis differed in 240 cases (56%). Biopsy results led to a change in therapy in 69 (16%) episodes. Seventeen of 69 management changes occurred in response to a clinical diagnosis of graft-versus-host disease and resulted in augmentation of systemic immunosuppression. The management was modified with similar frequencies with respect to concordance or discordance between the clinical and histopathologic diagnosis (P = .51). We used classification and regression tree (CART) analysis, a decision-modeling technique, to predict the biopsy yield as expressed by impact on clinical management in the allogeneic and autologous setting. The models were cross-validated and then tested against a validation subset, and they maintained a high negative predictive value and high specificity. Although skin biopsies may not be mandatory for either diagnostic or therapeutic reasons, in carefully chosen circumstances, this procedure can yield extremely important data. We believe a prospective study should be undertaken to evaluate current practice data and to validate our decision tree models.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission: have the indications changed?

PURPOSE OF REVIEW: Many improvements in chemotherapy and supportive care, as well as greater understanding of immunology and procuring graft sources, have led to more acute myeloid leukemia patients proceeding to hematopoietic cell transplantation, now the most common indication for this procedure. RECENT FINDINGS: As treatment-related mortality rates have been reduced, more practitioners and patients are amenable to use of this modality if the risk : benefit ratio appears justified. Clinical factors initially were used to identify patients at highest risk for relapse using conventional approaches, a strategy supplanted by one based on the genetic alterations of the leukemia cells. More recently, molecular factors are used to identify such candidates; the issue of which first remission acute myeloid leukemia patients receive hematopoietic cell transplantation is referred to as risk stratification. SUMMARY: With significant improvements in donor : recipient matching and a more varied graft source, greater numbers of patients can proceed to alternative donor hematopoietic cell transplantation. Advancing age appears to be less of a barrier and outcomes are reasonable in patients with good performance status and few comorbidities. The most interesting aspect of the moving target of which patients to take to hematopoietic cell transplantation is to define those with favorable-risk disease and avoid the procedure, while using the armamentarium at hand to identify those at higher and highest risk for relapse as the group most likely to benefit. The field, however, still awaits the data that demonstrate improved outcome in these poor-risk patients using the hematopoietic cell transplantation approach.

The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function.

PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that its RNA/NXF1-binding activity is required for the nuclear export of some canonical mitochondrial-related mRNAs and mitochondrial homeostasis. Genome-wide investigations reveal that the nuclear export function is not strictly linked to promoter-binding, identifying in turn novel regulatory targets of PGC-1α in non-homologous end-joining and nucleocytoplasmic transport. These findings provide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, aging and neurodegeneration.

Acute Myeloid Sarcoma: An Unusual Cause of Diarrhea.

A 62-year-old man with a past medical history of hypothyroidism was admitted for diarrhea and abdominal pain for three weeks. Initial workup for diarrhea was negative. His condition deteriorated after hospitalization. He underwent sigmoidoscopy which showed rectosigmoid mucosal ulceration. Pathology showed leukemic cells infiltration of the mucosa. The patient underwent bone marrow biopsy which confirmed the diagnosis of acute myeloid leukemia (AML). He received induction chemotherapy and his symptoms improved.

Cytomegalovirus associated colonic pseudotumor: a consequence of iatrogenic immunosuppression in a patient with primary brain tumor receiving radiation and temozolomide.

We report the case of a patient with primary brain tumor who developed cytomegalovirus associated colonic pseudotumor as an opportunistic infection while receiving chemotherapy with Temozolomide and radiation. This case highlights the potential for severe opportunistic infections in this patient population after severe immunosuppression.

Combining Volumetric Capnography And Barometric Plethysmography To Measure The Lung Structure-function Relationship.

Tools to measure lung and airways volume are critical for pulmonary researchers interested in evaluating the impact of disease or novel therapies on the lung. Barometric plethysmography is a classic technique to evaluate the lung volume with a long history of clinical use. Volumetric capnography utilizes the profile of exhaled carbon dioxide to determine the volume of the conducting airways, or dead space, and provides an index of airways homogeneity. These techniques may be used independently, or in combination to evaluate the dependence of airways volume and homogeneity on lung volume. This paper provides detailed technical instructions to replicate these techniques and our representative data demonstrates that the airways volume and homogeneity are highly correlated to lung volume. We also provide a macro for the analysis of capnographic data, which can be modified or adapted to fit different experimental designs. The advantage of these measures is that their advantages and limitations are supported by decades of experimental data, and they can be made repeatedly in the same subject without expensive imaging equipment or technically advanced analysis algorithms. These methods may be particularly useful for investigators interested in perturbations that change both the functional residual capacity of the lung and airways volume.

Novel transplant strategies in adults with acute leukemia.

Autologous and allogeneic hematopoietic cell transplantation (HCT) is regularly used as a curative treatment option for patients with various disorders, including acute leukemia in adults. The past decade has witnessed dramatic improvements in the reduction of treatment-related mortality (TRM), in part attributable to improved supportive care but also due to better graft selection and donor-to-recipient matching regimens, and the emergence of reduced-intensity conditioning in place of myeloablative conditioning. Despite these advances, HCT remains plagued by the risk of relapse or failure due to graft-versus-host disease, infectious complications, and TRM. This article reviews new approaches that may improve overall patient outcome.