Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B‐cell lymphoma cells harboring gain‐of‐function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL‐AF9,MLL‐AF4, and AML1‐ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

-A sensitive urinary biomarker for acute kidney injury (AKI) was investigated in beagle dogs with nephrotoxicity induced by gentamicin. Gentamicin sulphate at 25 or 50 mg/kg was injected (s.c.) for 9 days, and conventional urinalysis, ELISA assay of neutrophil gelatinase-associated lipocal (NGAL) in urine, blood chemistry, and pathological examinations were performed. The dog given gentamicin at 25 mg/kg only showed slight deposition of lysosomal granules in the proximal tubular epithelium of the kidneys without any other significant changes even though urinary NGAL was elevated on Day 10 (day of necropsy). In the dog receiving gentamicin at 50 mg/kg, increases in urinary NGAL were observed on Days 3 and 5, and absence of urination, marked increases in serum urea nitrogen and creatinine, enlargement and discoloration of the kidneys with marked necrosis, and swelling of proximal epithelium were observed. In conclusion, urinary NGAL is considered to be a candidate as a sensitive predictable biomarker of AKI in the gentamicin-induced nephrotoxicity model in dogs.Key words: NGAL, Dogs, Acute kidney injury, Urinary biomarker, Gentamicin Correspondence: Kiyonori Kai (E-mail: kai.kiyonori.xb@daiichisankyo.co.jp) LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.38, No.2, 269-277, 2013 Vol. 38 No. 2 269 addition to these biomarkers, neutrophil gelatinase-associated lipocal (NGAL), a member of the lipocalin superfamily, has been proposed as a candidate for a sensitive urinary biomarker to detect AKI Mori, 2005;Mori and Nakao, 2007). Unfortunately, in part due to the lack of commercially available assays for non-rodents, limited data comparing the performance of the exploratory and approved markers are publicly available so far.In this study, we selected gentamicin, a well-known nephrotoxic agent that induces AKI in experimental animals and humans, and injected it subcutaneously to beagle dogs for 9 days and evaluated urinary NGAL using a commercial ELISA kit as a sensitive urinary biomarker in comparison with conventional blood and urinary toxicity makers and pathological examinations. MATERIALS AND METHODS Test articleELTACIN injection, an injectable product of gentamicin sulfate was purchased from FujiPharma (Shizuoka, Japan). Animals and housing conditionsTwo male beagle dogs were purchased from Narc Corporation (Chiba, Japan) for gentamicin treatment, and 6 males and 6 females were additionally obtained from Marshall BioResources, Japan (Ibaraki, Japan) for collection background data of urinalysis. The dogs were individually housed in stainless steel cages (W93.5 cm × W80 cm × H78.5 cm) in an air-conditioned room (temperature, 18 to 28°C; relative humidity, 30 to 70%). A light/dark cycle of 12 hr and ventilation rate of 10 to 20 air changes/ hr were used in the animal rooms. Two hundred and twenty grams of basal diet (Certified Canine Diet 5007, PMI Nutrition International, Inc., St. Louis, MO, USA) was given to each dog in the morning and tap water was available ad libitum. All experimen...

RPE65 is a retinoid isomerase essential for rod function, but its contribution to cone vision is enigmatic. Using selective RPE65 inhibitors, Kiser et al. demonstrate that cone function depends only partially on continuous RPE65 activity, providing support for cone-specific regeneration mechanisms.

The neural retina metabolizes glucose through aerobic glycolysis generating large amounts of lactate. Lactate flux into and out of cells is regulated by proton‐coupled monocarboxylate transporters (MCTs), which are encoded by members of the Slc16a family. MCT1, MCT3, and MCT4 are expressed in the retina and require association with the accessory protein basigin, encoded by Bsg, for maturation and trafficking to the plasma membrane. Bsg−/− mice have severely reduced electroretinograms (ERGs) and progressive photoreceptor degeneration, which is presumed to be driven by metabolic dysfunction resulting from loss of MCTs. To understand the basis of the Bsg−/− phenotype, we generated mice with conditional deletion of Bsg in rods (RodΔBsg), cones (Cone∆Bsg), or retinal pigment epithelial cells (RPEΔBsg). RodΔBsg mice showed a progressive loss of photoreceptors, while ConeΔBsg mice did not display a degenerative phenotype. The RPEΔBsg mice developed a distinct phenotype characterized by severely reduced ERG responses as early as 4 weeks of age. The loss of lactate transporters from the RPE most closely resembled the phenotype of the Bsg−/− mouse, suggesting that the regulation of lactate levels in the RPE and the subretinal space is essential for the viability and function of photoreceptors.