As an approach to understanding how mammals regulate H₂O₂ toxicity, intracellular concentration to prevent its we analyzed the genome-wide mRNA profile changes of human cells after treatment with a non-toxic H₂O₂ concentration. We identified a large and essentially late H₂O₂ response of induced and repressed genes that unexpectedly comprise few or no antioxidants but mostly apoptosis and cell cycle control activities. The requirement of the p53 regulator for regulating about a third of this H₂O₂ stimulon and the lack of an associated enhancement of total cellular H₂O₂ scavenging activity further suggest that H₂O₂ elicits a stress antiproliferative/repair response that does not increase antioxidant defenses. We conclude that mammalian antioxidant defenses are constitutive, a finding that contrasts with the oxidant-inducibility of such defenses in microorganisms. This finding might be important in understanding the role of H₂O₂ as a key signaling molecule in mammals.

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown.

PURPOSE: This study is an analysis of frequency and relationship regarding two undifferentiated carcinoma of nasopharyngeal type (UCNT)-associated paraneoplastic syndromes (PNS): leukemoid reaction (LR) and fever of unknown origin (FUO) with bone marrow invasion (BMI) and metastatic pattern. PATIENTS AND METHODS: A consecutive UCNT patient cohort (N = 255) with locally advanced (n = 142) or metastatic (n = 113) disease receiving chemotherapy alone or in combination with radiotherapy was studied. All patients had a complete baseline work-up that included bone marrow biopsy. RESULTS: UCNT has distinctive features among head and neck squamous cell cancers (HNSCC). These include early subclinical dissemination, with 70% of metastases appearing within 18 months of first symptoms. Metastases are common in bone (65% v 25% in HNSCC), liver (29% v 23%), and lung (18% v 84%), and BMI is observed in 25% of UCNT patients with metastases. Metastases likelihood is related to lymph node involvement, with 64% of patients with metastases having N3 disease. Involved lymph nodes in contrasted CT scans revealed hypodensity in 26% of UCNT patients versus 79% in patients with other HNSCC. Hypercalcemia was observed in one case. LR was identified in 41 patients (16%); in 26 of the 41 patients (64%) it was observed concomitant with N3 and/or metastatic disease. FUO was found in 23 patients (9%) and was associated in four instances with BMI and in 17 with LR (in four instances with both). Brain metastases or meningeal carcinomatosis were not observed despite the high rate of skull base compromise. Paraneoplastic signs were observed in 47 of 255 cases (18.5%) and were more frequent in patients with metastases. However, PNS were observed in 15 patients with negative metastases work-up. CONCLUSION: The PNS described could help in the diagnosis and follow-up of UCNT patients because they may be the first manifestation of the disease or may reappear with relapse. BMI is a frequent finding in patients with metastases and is unrelated to PNS.

The Kidd (JK) blood group locus encodes a urea transporter that is expressed on human red cells and on endothelial cells of the vasa recta in the kidney. Here, we report the identification in human erythroblasts of a novel cDNA, designated HUT11A, which encodes a protein identical to the previously reported erythroid HUT11 urea transporter, except for a Lys⁴⁴→ Glu substitution and a Val-Gly dipeptide deletion after proline 227, which leads to a polypeptide of 389 residues versus391 in HUT11. Genomic typing by polymerase chain reaction and transcript analysis by ribonuclease protection assay demonstrated that HUT11A encodes the true Kidd blood group/urea transporter protein, which carries only 2 Val-Gly motifs. Upon expression at high levels inXenopus oocytes, the physiological Kidd/urea transporter HUT11A conferred a rapid transfer of urea (which was insensitive top-chloromercuribenzene sulfonate or phloretin), a high water permeability, and a selective uptake of small solutes including amides and diols, but not glycerol and meso-erythritol. However, at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport and small solutes uptake were absent and the urea transport was poorly inhibited byp-chloromercuribenzene sulfonate, but strongly inhibited by phloretin. These findings show that, at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability, and that the observed water permeability is a feature of the red cell urea transporter when expressed at unphysiological high levels.