Arsenic trioxide (As 2 O 3 ) is a highly effective treatment for patients with refractory/ relapsed acute promyelocytic leukemia (APL), but resistance to As 2 O 3 has recently been seen. In the present study, we report the findings that 2 of 15 patients with refractory/relapsed APL treated with IntroductionAcute promyelocytic leukemia (APL) is characterized by the reciprocal chromosomal translocation t(15;17)(q22;q21), leading to fusion of the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor-␣ gene (RARA) on chromosome 17. 1 PML-RARA fusions are detectable in Ͼ 95% of patients with APL. In 1985, all-trans retinoic acid (ATRA) was introduced for the treatment of APL as a differentiation therapy, and a dramatic improvement in the overall survival of patients with APL has been obtained. [2][3][4] However, approximately 10%-30% of patients eventually relapse after treatment with combination chemotherapies with ATRA. [5][6][7] Arsenic trioxide (As 2 O 3 ) is a critical drug for the treatment of APL and is clinically effective even in ATRA-resistant patients. 8 As 2 O 3 is a natural substance that has been used medically for over 2400 years. In the 1970s, a group in China identified As 2 O 3 as a component of an anticancer reagent. 9 Over the last 18 years, clinical trials conducted worldwide have demonstrated the efficacy of As 2 O 3 for the treatment of relapsed patients with APL. 10,11 Recently, it was also reported that As 2 O 3 improves event-free survival and overall survival of adult APL when As 2 O 3 is used as a consolidation treatment after obtaining the first remission. 12 Currently, the role of As 2 O 3 in frontline therapy is under investigation. 10,13 Rapid degradation of PML-RARA via targeting of PML has been reported as a molecular mechanism for the effectiveness of As 2 O 3 . 14 Furthermore, As 2 O 3 induces posttranslational modifications of PML-RARA with small ubiquitin-related modifier (SUMO) and ubiquitin, resulting in the transfer of PML-RARA from the soluble fraction to the insoluble nuclear matrix 14 and the degradation of both PML and PML-RARA. [14][15][16][17] In addition to the significant clinical effectiveness of As 2 O 3 for patients with APL, acquired resistance to As 2 O 3 therapy has been recognized in clinical practice. 18 Several studies have indicated that arsenicresistant NB4 cells in vitro show higher glutathione levels than in parental cells. [19][20][21] However, the detailed molecular mechanisms of resistance to As 2 O 3 remain unclear.Very recently, 2 studies reported that As 2 O 3 binds directly to cysteine residues in zinc fingers located within the RBCC motif that contains 3 cysteine-rich zinc-binding domains, a RING-finger (R), 2 B-box motifs (B1 and B2), and a coiled-coil (CC) domain, 22,23 in PML-RARA and PML. 24,25 An intriguing hypothesis is that impairment of As 2 O 3 binding to PML-RARA due to conformational changes may result from genetic mutations and/or abnormal posttranslational modifications. These events may be related to resis...

Some intracellular proteins involved in the endosomal sorting complex required for transport (ESCRT) system have microtubule interacting and transport (MIT) domains and bind to ESCRT-III protein family members named charged multivesicular body proteins (CHMPs) at their C-terminal regions containing MIT-interacting motifs (MIMs). While two types of MIMs (MIM1 and MIM2) have been reported, CHMP1B has MIM1 and IST1 has both MIM1 and MIM2. Previously, we demonstrated that CHMP1B and IST1 directly interacted with a tandem repeat of MIT domains of calpain-7 (CL7MIT) and that autolytic activity of calpain-7 was enhanced by IST1 in vitro but not by overexpression of IST1 in HEK293T cells. In this study, we detected enhancement of autolysis of mGFP-fused calpain-7 by coexpression with CHMP1B and observed further activation by additional coexpression of IST1 in HEK293T cells. We found that CL7MIT interacted with the second α-helical region of CHMP1B but not with the canonical C-terminal region containing MIM1 in vitro. Co-immunoprecipitation assays demonstrated that the interaction between CL7MIT and CHMP1B and between CL7MIT and IST1 became stronger when IST1 or CHMP1B was additionally coexpressed, suggesting formation of ternary complex of calpain-7, IST1 and CHMP1B. Moreover, subcellular fractionation analyses revealed increase of calpain-7 in membrane/organelle fractions by concomitant overexpression of these ESCRT-III family member proteins.

In this study, the entire coding sequence and the exon-intron junctions of the thiopurine S-methyltransferase (TPMT) gene from 200 Japanese individuals were screened for mutation. Three novel single nucleotide polymorphisms (SNPs) were identified-106G>A in exon 3 (Gly36Ser, *20 allele), 967A>G in 3'-untranslated region, and -87C>T in intron 8. The allele frequencies were 0.003 for 106G>A, 0.003 for 967A>G, and 0.010 for IVS8 -87C>T. In addition, the three known SNPs, 474T>C (Ile158Ile), 719A>G (Tyr240Cys, *3C allele), and IVS4 +35C>T were detected at frequencies of 0.299, 0.010, and 0.421, respectively.

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Background/Aim: To prevent infusion-related reactions (IRRs), H1-antihistamines (H 1 AT) are recommended as a premedication for monoclonal antibodies, such as Ramucirumab (RAM), even though there are H 1 AT-related side effects, such as drowsiness and dizziness. Here, we investigated the safety of H 1 AT-free RAM regimens in patients with solid cancer. Patients and Methods: We retrospectively reviewed the patients with solid cancer receiving RAM without H 1 AT at Osaka Medical College Hospital between 2015 and 2019. Results: Among the 123 registered patients, 58 were identified as eligible. The total number of RAM infusions was 291, and the median number of RAM administration was 4 cycles (range=1-23 cycles). IRRs were not observed in any patient. Conclusion: Although our data are preliminary and limited, H 1 AT-free RAM regimens may be a treatment option for cancer patients having a significant risk of developing H 1 AT-related side effects. Further studies are needed to confirm the safety of H 1 AT-free RAM regimens.Monoclonal antibodies (mAbs) have been widely used for the treatment of various malignancies (1-3). As most mAbs show lower toxicity than conventional anticancer agents, they are generally better tolerated (2-4). However, like other infused 3489 This article is freely accessible online.