Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%–90.7%,95% CI) and 97.4% (92.3%–100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

The let-7 microRNA (miRNA) regulates stemness in animals ranging from worms to humans. However, the cause of the dramatic vulval rupturing phenotype of let-7 mutant C. elegans has remained unknown. Consistent with the notion that miRNAs function by coordinately tuning the expression of many targets, bursting may result from joint dysregulation of several targets, possibly in the epidermis. Alternatively, overexpression of LET-60/RAS, a key vulva development gene and a phylogenetically conserved target of let-7, may be responsible. Here, we show that let-7 functions in the vulval-uterine system to ensure vulval integrity but that regulation of most targets of let-7, including LET-60/RAS, is dispensable. Using CRISPR-Cas9 to edit endogenous let-7 target sites, we found that regulation of LIN-41/TRIM71 alone is necessary and sufficient to prevent vulval rupturing. Hence, let-7 does not function to reduce gene expression noise broadly, but to direct vulval development through extensive regulation of a single, defined target.

lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) is well known for being a conserved target of the let-7 (lethal 7) microRNA (miRNA), a regulatory relationship found in animals evolutionarily as distant as Caenorhabditis elegans and humans. It has thus been studied extensively as a model for miRNA-mediated gene silencing. In contrast, the developmental and molecular functions of LIN41 have historically received less attention. However, LIN41 proteins are now emerging as important regulators of cell proliferation and differentiation in stem and progenitor cells. Moreover, LIN41's functions appear to involve two distinct molecular activities; namely, protein ubiquitylation and post-transcriptional silencing of mRNAs. Thus, LIN41 is ready for a scientific life of its own.