Evaluating Ac and Lu Radioimmunoconjugates against Antibody-Drug Conjugates for Small-Cell Lung Cancer.

Interest in the use of Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported preclinical solid tumor study using Ac RICs. In an effort to compare Ac RICs to other current antibody conjugates, a variety of RICs are tested against intractable small-cell lung cancer (SCLC).

Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations.

Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high-throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development.

A molecular signature for purified definitive endoderm guides differentiation and isolation of endoderm from mouse and human embryonic stem cells.

Embryonic definitive endoderm (DE) generates the epithelial compartment of vital organs such as liver, pancreas, and intestine. However, purification of DE in mammals has not been achieved, limiting the molecular "definition" of endoderm, and hindering our understanding of DE development and attempts to produce endoderm from sources such as embryonic stem (ES) cells. Here, we describe purification of mouse DE using fluorescence-activated cell sorting (FACS) and mice harboring a transgene encoding enhanced green fluorescent protein (eGFP) inserted into the Sox17 locus, which is expressed in the embryonic endoderm.

Deconstructing pancreas development to reconstruct human islets from pluripotent stem cells.

There is considerable excitement about harnessing the potential of human stem cells to replace pancreatic islets that are destroyed in type 1 diabetes mellitus. However, our current understanding of the mechanisms underlying pancreas and islet ontogeny has come largely from the powerful genetic, developmental, and embryological approaches available in nonhuman organisms. Successful islet reconstruction from human pluripotent cells will require greater attention to "deconstructing" human pancreas and islet developmental biology and consistent application of conditional genetics, lineage tracing, and cell purification to stem cell biology.

Foxh1 and Foxa2 are not required for formation of the midgut and hindgut definitive endoderm.

The definitive endoderm forms during gastrulation and is rapidly transformed into the gut tube which is divided along the anterior-posterior axis into the foregut, midgut, and hindgut. Lineage tracing and genetic analysis have examined the origin of the definitive endoderm during gastrulation and demonstrated that the majority of definitive endoderm arises at the anterior end of the primitive streak (APS). Foxh1 and Foxa2 have been shown to play a role in specification of the APS and definitive endoderm.

Dynamic expression of thyrotropin-releasing hormone in the mouse definitive endoderm.

Thyrotropin-releasing hormone (TRH) is a well-characterized regulator of the hypothalamic-pituitary-thyroid endocrine axis. Here, we describe the expression of Trh during early embryonic development in the mouse. We find Trh to be highly expressed during postimplantation stages in the mouse embryo, with expression first observed in the epiblast at embryonic day (E) 6.

Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties.

Hematopoietic stem cells (HSCs) execute self-renewal divisions throughout fetal and adult life, although some of their properties do alter. Here we analyzed the magnitude and timing of changes in the self-renewal properties and differentiated cell outputs of transplanted HSCs obtained from different sources during development. We also assessed the expression of several "stem cell" genes in corresponding populations of highly purified HSCs.

Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect.

The regulation of HSC proliferation and engraftment of the BM is an important but poorly understood process, particularly during ontogeny. Here we show that in mice, all HSCs are cycling until 3 weeks after birth. Then, within 1 week, most became quiescent.