Faculty Bibliography

BACKGROUND:Graft-versus-host Disease (GvHD) prophylaxis after allogeneic hematopoietic stem-cell transplantation (HSCT) is an ongoing effort but relative effects of different policies are not systematically explored. METHODS:We systematically reviewed 30-year evidence on GvHD prophylaxis and quantified the relative effect of different policies using a network meta-analysis. We searched PubMed and the Cochrane Library for randomized studies on the topic. The primary outcome of interest was grade II-IV acute GvHD over 0 or I (with odds ratio OR <1 denoting benefit). FINDINGS/RESULTS:Thirty-three eligible studies that enrolled 3,440 patients (published up to June 2014), provided data on seven immunosuppressive drugs namely cyclosporin A (CsA), methotrexate (MTX), anti-thymocyte globulin (ATG), mycophenolate mofetil (MMF), tacrolimus, sirolimus or corticosteroids and their combinations to calculate 14 direct and 21 indirect effects. The majority of trials (32/33) referred to myeloablative conditioning and sibling transplants (25/33). Tacrolimus/MTX (OR 0.44; 95% 0.27-0.70, number needed to treat to benefit, i.e. to avert a case of II-IV GvHD, NNTB = 5) and ATG/CsA/MTX (OR 0.45; 95%CI 0.26-0.78; NNTB = 5) were superior over CsA/MTX. ATG/CsA/MTX did not differ from tacrolimus/MTX (indirect evidence). Sirolimus-based prophylaxis outperformed CsA/MTX (OR 0.10; 95%CI 0.02-0.49, NNTB = 4) and marginally outperformed tacrolimus/MTX (OR 0.22; 95%CI 0.05-1.11). Add-on corticosteroids had no benefit over CsA/MTX. CONCLUSIONS:Tacrolimus/MTX and ATG/CsA/MTX were the outperformers over CsA/MTX, but sirolimus-based regimens showed also potential. More randomized data are needed for reduced-intensity conditioning, as well as for MMF and sirolimus-containing regimens.

It has been postulated that chromatin modifications can persist through mitosis and meiosis, thereby securing memory of transcriptional states. Whether these chromatin marks can self-propagate in progeny independently of relevant trans-acting factors is an important question in phenomena related to epigenesis. "Adaptive cellular memory" displayed by yeast cells offers a convenient system to address this question. The yeast GAL genes are slowly activated by Gal4 when cells are first exposed to galactose, but their progeny, grown in glucose media, exhibit a fast activation mode upon re-exposure to this sugar. This "galactose memory" persists for several generations and was recently proposed to involve chromatin modifications and perinuclear topology of the GAL genes cluster. Here, we perform a heterokaryon assay demonstrating that this memory does not have a chromatin basis but is maintained by cytoplasmic factor(s) produced upon previous galactose induction. We show that Gal3, the cytoplasmic rate-limiting factor that releases the Gal4 activator, is dispensable for preserving galactose memory. Instead, the important memory determinant is a close Gal3 homolog, the highly expressed Gal1 galactokinase, the residual activity of which preserves memory in progeny cells by rapidly turning on the Gal4 activator upon cells' re-exposure to galactose.