Nobuyuki Kakiuchi

Oxovanadium complex-catalyzed oxidation of propargylic alcohols using molecular oxygen

Abstract Oxovanadium complexes work as useful catalysts for the oxidation of propargylic alcohols to the corresponding carbonyl compounds in the presence of 3 A molecular sieves under an atmospheric pressure of molecular oxygen.

Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: Impact on outcome of stem cell transplantation

Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.

Pathogenicity of IgG in patients with IgG4-related disease

Objective IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. Design We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). Results Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. Conclusions IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

Palladium(II)-catalyzed oxidation of terminal alkenes to methyl ketones using molecular oxygen

Palladium(II) acetate catalyzes the aerobic oxidation of terminal alkenes in toluene into the corresponding methyl ketones in the presence of a catalytic amount of pyridine using propan-2-ol as a reductant and molecular oxygen as an oxidant. Two catalytic cycles sharing a Pd(II)–OOH species are proposed. One is the formation of a Pd(II)–H species in the oxidation of propan-2-ol to acetone, followed by reaction with molecular oxygen to give a Pd(II)–OOH species, and the other is peroxypalladation of an alkene with the Pd(II)–OOH species produced to afford a methyl ketone in the presence of H2O2 produced by the former catalytic cycle.

Palladium(II)-supported hydrotalcite as acatalyst for selective oxidation of alcohols using molecular oxygen

Palladium(II)-supported hydrotalcite acts as a reusable catalyst for the oxidation of alcohols to aldehydes and ketones in the presence of pyridine under atmospheric pressure of oxygen.

Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children.

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Palladium(II)-catalysed oxidation of alcohols under an oxygen atmosphere in a fluorous biphase system (FBS)

Palladium(II) acetate catalyses the aerobic oxidation of alcohols into the corresponding aldehydes and ketones in the presence of a catalytic amount of a novel perfluoroalkylated-pyridine as a ligand using molecular oxygen in a fluorous biphase system (FBS) composed of toluene and perfluorodecalin. This catalytic system is applicable to various benzylic and aliphatic alcohols. The fluorous phase containing the active palladium species is easily separated and can be reused several times without a significant loss of catalytic activity.

TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma

The number of patients with nonalcoholic fatty liver disease (NAFLD)‐related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD‐related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD‐HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD‐HCC tumor samples from these 10 patients by whole‐exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole‐exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD‐HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole‐exome sequencing and 14 representative HCC‐associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array‐based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD‐HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD‐HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD‐related liver carcinogenesis.

Erratum to: Early diagnosis of pancreatic necrosis based on perfusion CT to predict the severity of acute pancreatitis

Yoshihisa Tsuji • Naoki Takahashi • Hiroyoshi Isoda • Koji Koizumi • Sho Koyasu • Miho Sekimoto • Yuichi Imanaka • Shujiro Yazumi • Masanori Asada • Yoshihiro Nishikawa • Hiroshi Yamamoto • Osamu Kikuchi • Tsukasa Yoshida • Tetsuro Inokuma • Shinji Katsushima • Naoki Esaka • Akihiro Okano • Chiharu Kawanami • Nobuyuki Kakiuchi • Masahiro Shiokawa • Yuzo Kodama • Ichiro Moriyama • Takafumi Kajitani • Yoshikazu Kinoshita • Tsutomu Chiba Published online: 26 April 2017 Japanese Society of Gastroenterology 2017

The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia–derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.