Although a number of target genes for the tumor suppressor p53 have been described, the mechanism of p53-dependent apoptosis is incompletely understood. Thus, it is essential to identify and characterize additional target genes that could mediate apoptosis. In the study reported here, we isolated a p53-regulated gene named NDRG1 (N-Myc down-regulated gene 1). Its expression is induced by DNA damage in a p53-dependent fashion. The promoter region of the NDRG1 gene contains a p53 binding site that confers p53-dependent transcriptional activation via a heterologous reporter. RNA interference and inducible gene expression approaches suggest that NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis. This report further supports the notion that p53 controls a network of genes that are required for its apoptotic function.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

Objectives To describe the use of a xenotransfusion protocol, the outcome of xenotransfusion in recipient cats and to assess owner memory of the xenotransfusion. Materials and Methods Cats administered xenotransfusions in two hospitals between January 2016 and July 2018 were included. Adherence to xenotransfusion protocol, cause of anaemia, blood type, packed cell volume (PCV), transfusion volume, transfusion reactions, PCV 12 hours after transfusion and survival to discharge were recorded. Owners of surviving cats were questioned to assess if they remembered that a xenotransfusion had been performed. Results Forty‐nine cats underwent the xenotransfusion protocol. The most common causes of anaemia were surgical blood loss (n = 17), immune‐mediated haemolytic anaemia (n = 14) and neoplasia (n = 14). Median PCV before transfusion was 10%. Six cats (12%) had febrile non‐haemolytic transfusion reactions. Median PCV 12 hours after transfusion was 25%. Ten cats (20%) died or were euthanased within 24 hours of xenotransfusion. A delayed haemolytic transfusion reaction occurred in 25 of 39 (64%) cats manifesting as icterus in 15 cats after a median of 1.9 days and haemolytic serum in 19 cats after a median of 2 days. Of the 18 cats alive at 1 week after discharge, 15 (83%) were still alive at a median of 173 days after xenotransfusion. All owners contacted remembered that their cats had received a xenotransfusion. Clinical Significance Xenotransfusion of canine packed red blood cells to cats is possible but haemolysis should be expected between 1 and 6 days after transfusion.

Urethral obstruction is a life-threatening form of feline lower urinary tract disease. Ultrasonographic risk factors for reobstruction have not been previously reported. Purposes of this retrospective cross-sectional study were to describe urinary tract ultrasound findings in cats following acute urethral obstruction and determine whether ultrasound findings were associated with reobstruction. Inclusion criteria were a physical examination and history consistent with urethral obstruction, an abdominal ultrasound including a full evaluation of the urinary system within 24 h of hospitalization, and no cystocentesis prior to ultrasound examination. Medical records for included cats were reviewed and presence of azotemia, hyperkalemia, positive urine culture, and duration of hospitalization were recorded. For medically treated cats with available outcome data, presence of reobstruction was also recorded. Ultrasound images were reviewed and urinary tract characteristics were recorded. A total of 87 cats met inclusion criteria. Common ultrasound findings for the bladder included echogenic urine sediment, bladder wall thickening, pericystic effusion, hyperechoic pericystic fat, and increased urinary echoes; and for the kidneys/ureters included pyelectasia, renomegaly, perirenal effusion, hyperechoic perirenal fat, and ureteral dilation. Six-month postdischarge outcomes were available for 61 medically treated cats and 21 of these cats had reobstruction. No findings were associated with an increased risk of reobstruction. Ultrasonographic perirenal effusion was associated with severe hyperkalemia (P = 0.009, relative risk 5.75, 95% confidence interval [1.54-21.51]). Findings supported the use of ultrasound as an adjunct for treatment planning in cats presented with urethral obstruction but not as a method for predicting risk of reobstruction.

No abstract

Although our study results failed to find a difference in the incidence of rUO and severity of lower urinary tract signs among cats receiving prazosin and those receiving placebo, these study results should be interpreted cautiously as our study was underpowered to identify such differences. Larger placebo-controlled, prospective studies are needed to determine the clinical utility of prazosin in prevention of rUO.

IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted protein that shares a high degree of homology with human IL-24. Expression of mob-5 and its putative cell surface receptors was shown to be upregulated by oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a strikingly similar genomic structure but also that the rat MOB-5 protein can bind to and signal through the human IL-24 receptors. Like human IL-24, binding of the rat MOB-5 protein to the human IL-24 receptors leads to activation of the JAK/STAT pathway, which in turn supports receptor-dependent survival and proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines with somatic knockout of either the mutant or the wild-type k-ras allele, we demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras. Taken together, these results provide strong experimental evidence that MOB-5 is indeed the rat homolog of human IL-24.

Type I collagen is a fibril-forming heterotrimer composed of two ␣1 and one ␣2 chains and plays a crucial role in cell-matrix adhesion and cell differentiation. Through a comprehensive differential display screening of oncogenic ras target genes, we have shown that the ␣1 chain of type I collagen (col1a1) is markedly down-regulated by the ras oncogene through the mitogen-activated protein kinase pathway. Although ras-transformed cells are no longer able to produce and secrete endogenous collagen, they can still adhere to exogenous collagen, suggesting that the cells express a collagen binding factor(s) on the cell surface. When the region of col1a1 encompassing the C-terminal glycine repeat and C-prodomain (amino acids 1000 -1453) was affinity-labeled with human placental alkaline phosphatase, the secreted trimeric fusion protein could bind to the surface of Ras-transformed cells. Using biochemical purification followed by matrix-assisted laser desorption/ionization mass spectrometry analysis, we identified this collagen binding factor as Endo180 (uPARAP, CD280), a member of the mannose receptor family. Ectopic expression of Endo180 in CosE5 cells followed by in situ staining and quantitative binding assays confirmed that Endo180 indeed recognizes and binds to placental alkaline phosphatase. The interaction between Endo180 and the C-terminal region of type I collagen appears to play an important role in cell-matrix adhesion.