Key Points• UTX regulates migration and hematopoiesis.• Female UTX-KO mice show key features of myelodysplastic syndrome with chromosomal instability.Regulated migration of hematopoietic stem cells is fundamental for hematopoiesis. The molecular mechanisms underlying stem cell trafficking are poorly defined. Based on a short hairpin RNA library and stromal cell-derived factor-1 (SDF-1) migration screening assay, we identified the histone 3 lysine 27 demethylase UTX (Kdm6a) as a novel regulator for hematopoietic cell migration. Using hematopoietic stem and progenitor cells from our conditional UTX knockout (KO) mice, we were able to confirm the regulatory function of UTX on cell migration. Moreover, adult female conditional UTX KO mice displayed myelodysplasia and splenic erythropoiesis, whereas UTX KO males showed no phenotype. During development, all UTX KO female and a portion of UTX KO male embryos developed a cardiac defect, cranioschisis, and died in utero. Therefore, UTY, the male homolog of UTX, can compensate for UTX in adults and partially during development. Additionally, we found that UTX knockdown in zebrafish significantly impairs SDF-1/CXCR4-dependent migration of primordial germ cells. Our data suggest that UTX is a critical regulator for stem cell migration and hematopoiesis. (Blood. 2013;121(13):2462-2473

NLM proteins (NOD26-like major intrinsic proteins) from plants contain amino acid sequence signatures which can be found in aquaporins including plant plasma membrane intrinsic proteins and tonoplast intrinsic proteins and glycerol permeases such as the Escherichia coli GlpF and the yeast FPS1 proteins. Heterologous expression of two members of the NLM subgroup from Arabidopsis thaliana (AtNLM1 and AtNLM2) in baker's yeast demonstrated the glycerol permease activity in addition to the previously described aquaporin activity of AtNLM1. The transport was non-saturable up to 100 mM extracellular glycerol concentration. Longer-chain sugar alcohols did not compete with the transport of radiolabelled glycerol and hexoses were also not transported through the pore. ß

AIM:To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase (TS) gene expression in a rectal cancer patient cohort treated according to a standardized recommended neoadjuvant treatment regimen. METHODS:Formalin fixed, paraffin embedded pretherapeutical tumor biopsies (n = 22) and posttherapeutical resection specimens (n = 40) from patients with rectal adenocarcinoma (clinical UICC stage Ⅱ/Ⅲ) receiving standardized neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan realtime PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system. RESULTS:Responders (patients with high tumor regression) showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies (81.2% vs 16.7%; P < 0.05) as well as in the post-therapeutical resection specimens (75.8% vs 14.3%; P < 0.01). High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a

Persistent positive lymph node status and high intratumoral TS expression after preoperative CT/RT are predictive of an unfavorable prognosis in rectal cancer UICC stage II/III.

Pre-operative 5-fluorouracil (5-FU)-based chemoradiotherapy in locally advanced rectal cancer (UICC-II/III) may significantly reduce local tumour mass. Response to pre-operative treatment, however, varies significantly. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are thought to be important predictors for the efficiency of 5-FU-based treatment. The aim of this study was to determine the correlation between TS-, TP-, and DPD-gene expression and the response to 5-FU-based long-term pre-operative chemoradiotherapy assessed by histopathological tumour regression. Additionally, the predictive value of intra-tumoural TS-, TP-, and DPD-gene expression in pre-operative rectal tumour biopsies was assessed by correlation with the histopathological regression grade. Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection. Results were compared with standardized histopathological tumour regression analysis. There was a significant association between low TS-gene expression in pre-operative tumour biopsies and tumour response (p = 0.02). TS- and TP-gene expression was significantly lower in resection specimens of responders than of non-responders (p = 0.02) when microdissection was used. Statistical significance was even higher when TS and TP were combined (p = 0.0001). For the DPD gene, no significance was found at all. In conclusion, this study shows that TS gene expression in a pretreatment biopsy predicts the response of local rectal cancer to neo-adjuvant 5-FU-based chemoradiotherapy in a high percentage. Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied.