Our findings replicate those of other recent studies and also show, for the first time, that the prenatal stress-associated difference in newborn mean telomere length is due to a shift in the overall telomere distribution.

Objectives Retrospective cohort study of a United States based-group of metastatic neuroendocrine tumor (NET) patients who underwent peptide receptor radionuclide therapy (PRRT). Methods Twenty-eight patients from a single United States NET Center were treated with PRRT. Toxicities were assessed using CTCAE v4.03. Progression was determined by RECIST 1.1. Univariate and multivariate Cox regression was performed to identify potential predictors of progression free survival (PFS) and overall survival (OS). Results The median age of NET diagnosis was 56 years, 50% of the patients were male, 46% of NET primaries were located in the pancreas, 71% of tumors were non-functional, 25% were WHO grade III, and 20% had at least a 25% hepatic tumor burden. Anemia (36%) was the most common post-PRRT toxicity, followed by leukopenia (31%), nephrotoxicity (27%), and thrombocytopenia (24%). Median PFS was 18 months, and median OS was 38 months. Having a WHO grade III NET or receiving systemic chemotherapy prior to PRRT where found to be to independent predictors of shorter PFS and OS. Conclusions PRRT is an effective therapy in a United States population. PFS and OS were better in WHO grade I/II NETs and when PRRT was sequenced prior to systemic chemotherapy.

Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer, however, remains unclear. Here, we demonstrate that menin was overexpressed in colorectal cancer and that inhibition of menin synergized with small-molecule inhibitors of EGFR (iEGFR) to suppress colorectal cancer cells and tumor xenografts in vivo in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for colorectal cancer growth, and promoted its expression. Moreover, the iEGFR gefitinib activated endoplasmic reticulum calcium channel inositol trisphosphate receptor 3 (IP3R3)-mediated release of calcium, which directly bound menin. Combined inhibition of menin and iEGFR-induced calcium release synergistically suppressed menin-mediated expression of SKP2 and growth of colorectal cancer. Together, these findings uncover a molecular convergence of menin and the iEGFR-induced, IP3R3-mediated calcium release on SKP2 transcription and reveal opportunities to enhance iEGFR efficacy to improve treatments for colorectal cancer. Significance: Menin acts as a calcium-responsive regulator of SKP2 expression, and small molecule EGFR inhibitors, which induce calcium release, synergize with Menin inhibition to reduce SKP2 expression and suppress colorectal cancer.

Conditions during early life can have dramatic effects on adult characteristics and fitness. However, we still know little about the mechanisms that mediate these relationships. Telomere shortening is one possibility. Telomeres are long sequences of DNA that protect the ends of chromosomes. They shorten naturally throughout an individual's life, and individuals with short telomeres tend to have poorer health and reduced survival. Given this connection between telomere length (TL) and fitness, natural selection should favor individuals that are able to retain longer telomeres for a greater portion of their lives. However, the ability of natural selection to act on TL depends on the extent to which genetic and environmental factors influence TL. In this study, we experimentally enlarged broods of Tree Swallows ( Tachycineta bicolor ) to test the effects of demanding early‐life conditions on TL, while simultaneously cross‐fostering chicks to estimate heritable genetic influences on TL. In addition, we estimated the effects of parental age and chick sex on chick TL. We found that TL is highly heritable in Tree Swallow chicks, and that the maternal genetic basis for TL is stronger than is the paternal genetic basis. In contrast, the experimental manipulation of brood size had only a weak effect on chick TL, suggesting that the role of environmental factors in influencing TL early in life is limited. There was no effect of chick sex or parental age on chick TL. While these results are consistent with those reported in some studies, they are in conflict with others. These disparate conclusions might be attributable to the inherent complexity of telomere dynamics playing out differently in different populations or to study‐specific variation in the age at which subjects were measured.

A major focus of our pediatric cancer research is the discovery of chemical probes to further our understanding of the biology of leukemia harboring fusion proteins arising from chromosomal rearrangements, and to develop novel specifically targeted therapies. The NUP98-NSD1 fusion protein occurs in a highly aggressive subtype of acute myeloid leukemia after rearrangement of the genes NUP98 and NSD1. The methyltransferase activity of NSD1 is retained in the fusion, and it gives rise to abnormally high levels of methylation at lysine 36 on histone 3, enforcing oncogene activation. Therefore, inhibition of the methyltransferase activity of NUP98-NSD1 may be considered a viable therapeutic strategy. Here, we report the development and validation of a highly sensitive and robust luminescence-based assay for NSD1 and other methyltransferases that use S-adenosylmethionine (SAM) as a methyl donor. The assay quantifies S-adenosylhomocysteine (SAH), which is produced during methyl transfer from SAM. SAH is converted enzymatically to adenosine monophosphate (AMP); in the process, adenosine triphosphate (ATP) is consumed and the amount of ATP remaining is measured using a luminescent assay kit. The assay was validated by pilot high-throughput screening (HTS), dose-response confirmation of hits, and elimination of artifacts through counterscreening against SAH detection in the absence of NSD1. The known methyltransferase inhibitor suramin was identified, and profiled for selectivity against the histone methyltransferases EZH2, SETD7, and PRMT1. HTS using the luminescent NSD1 assay described here has the potential to deliver selective NSD1 inhibitors that may serve as leads in the development of targeted therapies for NUP98-NSD1-driven leukemias.

Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1–383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.

◥Menin serves both tumor suppressor and promoter roles in a highly tumor-specific manner. In colorectal cancer, menin is overexpressed and plays a critical role in regulating transcription of SKP2, and combined treatment with a menin inhibitor and smallmolecule EGFR inhibitor (EGFRi) leads to synergistic killing of colorectal cancer cells. However, the full spectrum of menin function in colorectal cancer remains uncertain. Herein, we demonstrate that menin inhibition increases glycolysis in colorectal cancer cells. This menin inhibitor-induced increase in glycolysis occurs in an mTOR-independent manner and enhances the sensitivity of colorectal cancer cells to EGFRis. In addition, we show that EGFRis induce autophagy in colorectal cancer cells, which is important for cell survival in the setting of combined treatment with an EGFRi and menin inhibitor. Inhibition of autophagy with chloroquine further sensitizes colorectal cancers to treatment with the combination of an EGFRi and menin inhibitor. Together, these findings uncover a novel role for menin in colorectal cancer as a repressor of glycolysis and demonstrate that menin inhibitor-induced increases in glycolysis sensitize colorectal cancer cells to EGFRis. In addition, these findings illustrate the importance of autophagy as a protective mechanism against EGFRis, especially in the presence of menin inhibition. Ultimately, these data open the possibility of using menin-mediated regulation of glycolysis to potentially improve treatment modalities for colorectal cancer.

No abstract