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Mogamulizumab (MOG), a humanized monoclonal anti-CCR4 antibody, exerts strong antibody-dependent cellular cytotoxic effects on CCR4-positive adult T-cell leukemia/lymphoma (ATLL) cells. As CCR4 is highly expressed on regulatory T cells as well as ATLL cells, pre-transplant MOG induces severe graft-versus-host disease (GvHD). However, limited data are available on post-transplant use of MOG for relapsed ATLL. Here we describe the case of a patient with ATLL who experienced post-transplant relapse with involvement of peripheral blood, skin, lungs, and lymph nodes. Neither tacrolimus dose reduction nor cytotoxic chemotherapy was effective, but a single dose of MOG (1 mg/kg) induced complete remission. After treatment with MOG, leukemic cells in the peripheral blood rapidly disappeared, and the skin, lymph node, and lung lesions gradually regressed. Most notably, the long-term remission was accompanied by recurrence of moderate acute GvHD (grade II, skin stage 2, gut stage 1, liver stage 0). Our findings indicate that MOG can augment allogeneic immune-mediated anti-tumor reactions through graft-versus-ATLL (GvATLL) even during post-transplant relapse involving the lymph nodes and lungs, along with inducing GvHD.

We examined whether there were gains in lifespan among patients who died from hematological cancers in Japan between 1990 and 2015 using the novel average lifespan shortened (ALSS) measure. We obtained mortality data from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. ALSS measure was calculated as a ratio of YLL to the expected lifespan. The ALSS results showed that the lifespan of patients who died from hematological cancers has improved over time. For instance, women who died of leukemia in 1990 lost about 34% of their lifespan; conversely, those who died in 2015 lost about 20%. Likewise, men dying from non-Hodgkin lymphoma lost about 22% of their lifespan in 1990, whereas men lost about 14% in 2015. In summary, the new ALSS measure shows prolonged lifespans among patients who died from hematological cancers in Japan over the study period.

Reduction of blood group ABO antigens on red blood cells (RBCs) is well known in patients with leukemias, and this reduction of ABO expression is strongly associated with DNA methylation of the ABO promoter. Previously, we reported a two-nucleotide deletion in RUNX1 encoding an abnormally elongated protein lacking the trans-activation domain in a patient with myelodysplastic syndrome (MDS) showing A-antigen loss on RBCs. This prompted us to investigate the underlying mechanism responsible for A-antigen reduction on RBCs in another patient with MDS.Screening of somatic mutations was carried out using a targeted sequencing panel with genomic DNA from peripheral blood mononuclear cells from the patient and eleven MDS controls without A- or B-antigen loss. DNA methylation of the ABO promoter was examined by bisulfite genomic sequencing. Transient transfection assays were performed for functional evaluation of mutations.Screening of somatic mutations showed missense mutations in RUNX1 and GATA2 in the patient, while no mutation was found in exons of those genes in the controls. There was no significant difference in ABO promoter methylation between the patient and the controls. Transient transfection experiments into COS-7 and K562 cells suggested that the amino acid substitutions encoded by those mutations reduced or lost the trans-activation potential of the ABO expression.Considering the discrepancy between the variant frequencies of these mutations and the ratios of the RBCs with A-antigens loss, the antigen reduction might be associated with these somatic mutations and hypermethylation of the ABO promoter.

Transplant acquired food allergy (TAFA) is a well-known complication following pediatric liver transplantation, but post-cord blood transplantation (post-CBT) TAFA has rarely been reported. Here, we describe a case of new-onset food anaphylaxis after CBT in an adult patient that demonstrates that post-CBT allergen-challenge is not a risk for long-term allergic sensitization even in adult recipients. The patient was a 39-year-old Japanese man with aggressive NK cell leukemia. He had no previous history of allergies. After receiving CBT, the patient had an unbalanced diet with high preference for bread, bananas, miso-soup, cow's milk, cheese, egg, sesame and buckwheat soba noodles, and experienced repeated diarrhea. Six months later, he developed symptoms such as vomiting, epigastric pain, diarrhea, high fever and hypotension. The condition was initially diagnosed as enterocolitis, but symptoms recurred after consumption of buckwheat. Anaphylaxis induced by buckwheat was confirmed with serum radioallergosorbent tests (RAST), showing allergen-specific IgE for buckwheat (greater than 100 U/mL, Class 6) and egg ovomucoid (Class 4). Nineteen months after a buckwheat and egg-free diet, serum RAST for buckwheat and egg significantly improved. As a result, the patient acquired a tolerance and was able to consume buckwheat and egg without allergic symptoms.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been accepted as a treatment option for aggressive (acute or lymphoma type) adult T cell leukemia/lymphoma (ATLL) patients with a poor prognosis, when a suitable HLA-matched donor is not available. However, haplo-HSCT carries a potential risk of treatment-related mortality including severe graft-versus-host disease (GVHD). Therefore, we conducted a prospective pilot study in order to evaluate the efficacy and safety of reduced-intensity haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with low-dose thymoglobulin (2.5 mg/kg only on day −2), fludarabine, melphalan, and total body irradiation 4 Gy for aggressive ATLL. Three consecutive acute type ATLL patients, who were ineligible for conventional myeloablative conditioning due to advanced age or comorbidities, were enrolled. One patient received pretransplant mogamulizumab therapy. All the patients were not in complete remission (CR) at the time of transplantation. Our transplantation protocol was safely carried out. CR was achieved in all the patients after transplantation. HTLV-I viral loads became undetectable after transplantation. No severe adverse events such as grade III-IV GVHD or viral/fungal diseases were observed. At a follow-up of 2 years, they were still in CR. However, T cell receptor repertoire diversities were low 1 year after transplantation in next-generation sequencing. Our results show encouraging therapeutic benefits of this pilot approach using reduced-intensity haplo-PBSCT with low-dose thymoglobulin for aggressive ATLL patients.

We investigated the antitumor effects of oleanolic acid (OA) and ursolic acid (UA) on adult T-cell leukemia cells. OA and UA dose-dependently inhibited the proliferation of adult T-cell leukemia cells. UA-treated cells showed caspase 3/7 and caspase 9 activation. PARP cleavage was detected in UA-treated MT-4 cells. Activation of mTOR and PDK-1 was inhibited by UA. Autophagosomes were detected in MT-4 cells after UA treatment using electron microscopy. Consistently, mitophagy was observed in OA- and UA-treated MT-4 cells by confocal microscopy. The mitochondrial membrane potential in MT-4 cells considerably decreased, and mitochondrial respiration and aerobic glycolysis were significantly reduced following UA treatment. Furthermore, MT-1 and MT-4 cells were sorted into two regions based on their mitochondrial membrane potential. UA-treated MT-4 cells from both regions showed high activation of caspase 3/7, which were inhibited by Z-vad. Interestingly, MT-4 cells cocultured with sorted UA-treated cells showed enhanced proliferation. Finally, UA induced cell death and ex vivo PARP cleavage in peripheral blood mononuclear cells from patients with adult T-cell leukemia. Therefore, UA-treated MT-4 cells show caspase activation following mitochondrial dysfunction and may produce survival signals to the surrounding cells.

The human ABO blood group system is of great importance in blood transfusion and organ transplantation. ABO transcription is known to be regulated by a constitutive promoter in a CpG island and regions for regulation of cell-specific expression such as the downstream + 22.6-kb site for epithelial cells and a site in intron 1 for erythroid cells. Here we investigated whether the + 22.6-kb site might play a role in transcriptional regulation of the gene encoding odorant binding protein 2B (OBP2B), which is located on the centromere side 43.4 kb from the + 22.6-kb site. In the gastric cancer cell line KATOIII, quantitative PCR analysis demonstrated significantly reduced amounts of OBP2B and ABO transcripts in mutant cells with biallelic deletions of the site created using the CRISPR/Cas9 system, relative to those in the wild-type cells, and Western blotting demonstrated a corresponding reduction of OBP2B protein in the mutant cells. Moreover, single-molecule fluorescence in situ hybridization assays indicated that the amounts of both transcripts were correlated in individual cells. These findings suggest that OBP2B could be co-regulated by the + 22.6-kb site of ABO.

The rare chromosomal translocation t(16;21) has been associated with CD56 expression and extramedullary lesions in acute myeloid leukemia (AML). We herein report the first case of the development of isolated pericardial relapse after HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). A 42-year-old male AML patient with t(16;21)(p11.2;q22) received haplo-PBSCT at partial remission, and he exhibited dyspnea due to massive pericardial effusion 11 months later. The effusion analysis revealed CD56+ leukemic cells, and G-banded karyotyping of the cells demonstrated t(16;21)(p11.2;q22). Salvage chemotherapy was administered, but only a transient improvement of the effusion was achieved. Moreover, the pleural effusion developed without bone marrow relapse.

Currently, allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative modality for patients with adult T-cell leukemia-lymphoma (ATL). When used in conjunction with posttransplantation cyclophosphamide (PTCY) for graft-versus-host disease prophylaxis, allo-HCT from an HLA haplo-identical donor yields promising outcomes for many diseases other than ATL. However, appropriate comparisons with other donor sources, especially cord blood and conventional HLA haplo-identical donors, are needed to validate the safety and efficacy of this modality. In this study, we retrospectively evaluated the outcome of allo-HCT without PTCY in patients with ATL registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database between 1985 and 2015. During that period, 46 patients received allo-HCT without PTCY and survivors were followed for a median of 2316.5 days (range: 220-3884 days). Although the estimated 1- and 5-year overall survival rates of the entire cohort were 34.5% and 17.7%, respectively, the cumulative 1- and 5-year non-ATL mortality rates of 41.3% and 55.8%, respectively, were high. The results of our study will serve as a platform for discussions of the safety and efficacy of haplo-HCT for future clinical trials in patients with ATL.

Summary Background Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3–7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Rod‐like inclusions have rarely been described in cases of monoclonal gammopathy of renal significance or multiple myeloma. The key finding in our case is the strong κ‐light chain positivity of rod‐like inclusions in plasma cells, which confirms their immunoglobulin nature. Therapeutic benefit of bortezomib was also observed.

Background Loss of blood group ABO antigens on red blood cells (RBCs) is well known in patients with leukemias, and such decreased ABO expression has been reported to be strongly associated with hypermethylation of the ABO promoter. We investigated the underlying mechanism responsible for A-antigen reduction on RBCs in a patient with myelodysplastic syndrome. Study design and methods Genetic analysis of ABO was performed by PCR and sequencing using peripheral blood. RT-PCR were carried out using cDNA prepared from total bone marrow (BM) cells. Bisulfite genomic sequencing was performed using genomic DNA from BM cells. Screening of somatic mutations was carried out using a targeted sequencing panel with genomic DNA from BM cells, followed by transient transfection assays. Results Genetic analysis of ABO did not reveal any mutation in coding regions, splice sites, or regulatory regions. RT-PCR demonstrated reduction of A-transcripts when the patient's RBCs were not agglutinated by anti-A antibody and did not indicate any significant increase of alternative splicing products in the patient relative to the control. DNA methylation of the ABO promoter was not obvious in erythroid cells. Targeted sequencing identified somatic mutations in ASXL1, EZH2, RUNX1, and WT1. Experiments involving transient transfection into K562 cells showed that the expression of ABO was decreased by expression of the mutated RUNX1. Conclusion Because the RUNX1 mutation encoded an abnormally elongated protein without a transactivation domain which could act as dominant negative inhibitor, this frame-shift mutation in RUNX1 may be a genetic candidate contributing to A-antigen loss on RBCs.

BACKGROUND The ABO system is of fundamental importance in the fields of transfusion and transplantation and has apparent associations with certain diseases, including cardiovascular disorders. ABO expression is reduced in the late phase of erythroid differentiation in vitro, whereas histone deacetylase inhibitors (HDACIs) are known to promote cell differentiation. Therefore, whether or not HDACIs could reduce the amount of ABO transcripts and A or B antigens is an intriguing issue. STUDY DESIGN AND METHODS Quantitative polymerase chain reactions were carried out for the ABO transcripts in erythroid-lineage K562 and epithelial-lineage KATOIII cells after incubation with HDACIs, such as sodium butyrate, panobinostat, vorinostat, and sodium valproate. Flow cytometric analysis was conducted to evaluate the amounts of antigen in KATOIII cells treated with panobinostat. Quantitative chromatin immunoprecipitation (ChIP) assays and luciferase assays were performed on both cell types to examine the mechanisms of ABO suppression. RESULTS HDACIs reduced the ABO transcripts in both K562 and KATOIII cells, with panobinostat exerting the most significant effect. Flow cytometric analysis demonstrated a decrease in B-antigen expression on panobinostat-treated KATOIII cells. ChIP assays indicated that panobinostat altered the modification of histones in the transcriptional regulatory regions of ABO, and luciferase assays demonstrated reduced activity of these elements. CONCLUSION ABO transcription seems to be regulated by an epigenetic mechanism. Panobinostat appears to suppress ABO transcription, reducing the amount of antigens on the surface of cultured cells.

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874.

To the editor: Human T-cell lymphotropic virus type I (HTLV-I) is a pathogenic retrovirus associated with adult T-cell leukemia/lymphoma (ATLL) and HTLV-I–associated myelopathy.[1][1],[2][2] HTLV-I infection can be transmitted by infected lymphocytes during breastfeeding, sexual contact, needle

To clarify the mechanism of localized corrosion on zirconium in chloride environments, corrosion tests of zirconium and its alloys were performed using conventional and micron-scale measurement systems with surface areas of 0.35 cm2 and less than 0.04 cm2, respectively. The pitting potential significantly dropped by more than 1 V when zirconium was alloyed with over 10 mol% of tin. Zr4Sn and Zr5Sn3 intermetallics hindered the formation of passive films on the substrate. Additionally, tin was found on the surface of a commercially pure zirconium. From the micron-scale measurement results, the inclusion with the highest concentration of tin (at least 0.44 mol%) in the tested area was selected as the preferential initiation site for pitting corrosion. Thus, tin played an important role in determining the corrosion resistance of zirconium in chloride environments.

An 85-year-old male presented with 1-year history of a right breast mass. Needle biopsy of the mass revealed diffuse proliferation of large lymphoid cells that were positive for CD20, BCL2, BCL6, and MUM1 and negative for CD5, CD10, MYC, and EBER. The patient was diagnosed as having diffuse large B-cell lymphoma, a type of primary breast lymphoma (PBL). Sex hormone imbalance, which causes conditions such as gynecomastia, is associated with PBL development in males. Estramustine is a nitrogen mustard moiety linked to estradiol. For 5 years, the patient underwent estramustine therapy for treating prostate cancer. Our case suggests an important role of estrogen in PBL development.

Display Omitted Triangular fin channel double-gate MOSFETs were fabricated on SOTB.A high threshold voltage shift was obtained in triangular fin devices.A smaller variability was confirmed in triangular fin devices by wet etching.Uniform line edges of a triangular fin were formed by wet etching.A damage-free BOX layer was obtained by the orientation dependent wet etching. Triangular fin (Tri-Fin) channel double-gate (DG) MOSFETs were successfully fabricated on (100) SOTB wafers using orientation dependent wet etching, and their electrical characteristics were systematically compared to the rectangular fin (Rec-Fin) ones by RIE. Thanks to the wide bottom area and the suppressed line edge roughness of Tri-Fins by the wet process, a higher threshold voltage (Vt) tunability and a smaller Vt variation were obtained as compared to the Rec-Fin ones. Moreover, the wet processed Tri-Fin devices provide a damage-free BOX layer, which is useful for the fabrication of multiple Vt devices with an ultrathin BOX layer.

We investigated the impact of fin length ( T fin ) on the threshold voltage ( V th ) modulation by back bias ( V b ) for independent double-gate (IDG) tunnel fin field-effect transistors (tFinFETs). It was found that V th can be tuned by V b for IDG tFinFETs regardless of T fin , which can be explained by the back-gate-effect model of IDG FinFETs. For IDG tFinFETs, the slope (back-gate-effect factor ( γ )) of V th with respect to V b increases with thinning T fin . This means that T fin thinning is effective for tuning V th by V b for IDG tFinFETs. Furthermore, it was demonstrated that this back-bias-effect is consistent with the results of device simulation using an advanced nonlocal band-to-band model.

The SMARCE1 (SWI / SNF-related, matrix-associated, and actin-dependent regulator of chromatin, subfamily e, member 1) encodes BAF57 protein. Previously, we reported that BAF57 is a predictive marker of endometrial carcinoma. In this study, we investigated BAF57 expression in ovarian cancer cell lines and their sensitivities to cisplatin, doxorubicin, paclitaxel, and 5-fluorouracil. BAF57 expression was strongly correlated with sensitivities to cisplatin, doxorubicin, and 5-fluorouracil in 10 ovarian cancer cell lines. Paclitaxel sensitivity was also correlated with BAF57 expression, but without significance. In A2780 ovarian cancer cells, knockdown of BAF57 using specific siRNA increased cell cycle arrest at G1 phase and the sensitivities to these anticancer agents. cDNA microarray analysis of A2780 cells transfected with BAF57 siRNA showed that 134 genes were positively regulated by BAF57, including ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2) encoding breast cancer resistance protein (BCRP). We confirmed that knockdown of BAF57 decreased BCRP expression in ovarian cancer cells by Western blot analysis, and that ABCG2 gene expression might be regulated transcriptionally. These results suggested that BAF57 is involved in ovarian cancer cell growth and sensitivity to anticancer agents, and that BAF57 may be a target for ovarian cancer therapy.

We studied the efficacy and safety of THP-COP(pirarubicin, cyclophosphamide, vincristine, and prednisolone)for elderly patients with diffuse large B-cell lymphoma(DLBCL).We retrospectively investigated the efficacy and adverse events of THP-COP in previously untreated patients with DLBCL who completed THP-COP as first-line chemotherapy between December 2009 and December 2014.The study included 32 previously untreated DLBCL patients aged 67- 85 years(median, 77 years). The median number of treatment courses was 6, and 30 patients completed the treatment (93.8%). The response rate(CR/CRu/PR)was 81.3%, and 21 patients(65.6%)achieved a complete response(CR). The 1- year overall survival rate for all patients was 96.3%(95%CI: 76.5-99.5%). The most common grade 3-4 adverse events were neutropenia, leukocytopenia, infection, and febrile neutropenia. Grade 1-2 adverse events included thrombocytopenia, anemia, peripheral neuropathy, and constipation. Dose reduction was required in 19 patients. The median relative dose intensities (RDI)were 80.8%, 80.2%, and 68.0% for pirarubicin, cyclophosphamide, and vincristine, respectively.Our results suggest that THP-COP is safe and effective for elderly patients with DLBCL.

Background and Objectives Previously, a weak phenotype Am or Bm was assumed to be caused by a reduction of A or B gene expression in bone marrow cells, but not in mucus-secreting cells. However, ABO expression has not been examined in erythroid progenitor cells of Am or Bm individuals. Materials and Methods We carried out in vitro erythroid differentiation of CD34+ cells from peripheral blood of a Bm individual harbouring a 3·0-kb deletion including an erythroid cell-specific regulatory element, named the +5·8-kb site, in intron 1 of the human ABO blood group gene. Results During the in vitro differentiation of CD34+ cells from this Bm individual into erythroid cells, B-antigens were not detectable on the cultured cells by flow cytometric analysis, and allele-specific RT-PCR consistently detected the transcripts from the O allele, but not from the B allele. Moreover, chromatin immunoprecipitation assay demonstrated that both RUNX1 and GATA-2 or GATA-1 were bound to the +5·8-kb site in cultured erythroid cells expressing ABO. Conclusion It is likely that the +5·8-kb site enhances transcription from the ABO promoter in erythroid cells through binding of RUNX1 and GATA-2 or GATA-1.

The scaled charge trapping (CT) type silicon on insulator (SOI) FinFET flash memories with different blocking layer materials of Al2O3 and SiO2 have successfully been fabricated, and their electrical characteristics including short-channel effect (SCE) immunity, threshold voltage (Vt) variability, and the memory characteristics have been comparatively investigated. It was experimentally found that the better SCE immunity and a larger memory window are obtained by introducing a high-k Al2O3 blocking layer instead of a SiO2 blocking layer. It was also confirmed that the variability of Vt before and after one program/erase (P/E) cycle is almost independent of the blocking layer materials.

Y. X. Liu, T. Matsukawa, K. Endo, S. O’uchi, J. Tsukada, H. Yamauchi, Y. Ishikawa, W. Mizubayashi, Y. Morita, S. Migita, H. Ota, and M. Masahara National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 2, 1-1-1 Umezono, Tsukuba-shi, Ibaraki 305-8568, Japan. Tel: +81-29-861-3417, Fax: +81-29-861-5170, E-mail: yx-liu@aist.go.jp Three-dimensional (3D) fin-channel devices provide excellent short-channel effect (SCE) immunity thanks to the strong controllability of channel potential by the multiple gates. Therefore, the scaled charge trapping (CT) type FinFET flash memories have actively been developed in the past few years (1-3). Very recently, we have also developed floating gate (FG) type SOI-FinFET flash memories with different gate structures (4, 5), and experimentally confirmed that tri-gate (TG) structure shows the better SCE immunity and a larger memory window than double-gate (DG) structure. As a further study, in this work, we fabricate CT type TG-structured SOI-FinFET flash memories with different gate materials and different blocking layer materials, and comparatively investigate their electrical characteristics. 1. Device Fabrication In the device fabrication, we used (110)-oriented SOI wafers, and the Si-fin channels were fabricated by using orientation dependent wet etching (6). To fabricate TG structure, the SiO2 fin hard-mask layer was removed by RIE. Then, a 4.3-nm-thick tunnel oxide was formed by thermal oxidation, followed by the deposition of a 10-nm-thick nitride (Si3N4) layer by LPCVD. As the blocking layer, a 10-nm-thick Al2O3 layer or a 9-nm-thick SiO2 layer was deposited on the different sample wafers. As the different gate materials, we used n+-poly-Si and PVD-TiN metal. Figure 1(a) shows the SEM image of the fabricated FinFET flash memory with a scaled gate length (Lg) of 26 nm. The cross-sectional STEM images of the fabricated n+-poly-Si gate SONOS, PVD-TiN metal gate MONOS and MANOS with a high-k Al2O3blocking layer are shown in Figs. 1(b), 1(c) and 1(d), respectively. It is clear that uniform and ultrathin Si-fin channels are successfully fabricated thanks to the orientation dependent wet etching. 2. Gate Material Dependent of Memory Property At first, we measured the initial Id-Vg characteristics of the fabricated SONOS and MONOS type FinFET flash memories, and the threshold voltage (Vt) values were evaluated at a constant drain current of Id = 1 mA. It was experimentally found that almost the same sVt is obtained in the SONOS and MONOS devices. This result indicates that Vt variation is independent of gate material. Then, we measured P/E characteristics of the fabricated SONOS and MONOS devices. It was found that a larger memory window is obtained in the MONOS devices than the SONOS ones due to the higher work function of PVD-TiN gate than the n+-poly-Si gate as shown in Fig. 2. The higher gate work function is effective to the suppression of electron back tunneling during erase operation [7]. 3. Blocking Layer Dependent of Memory Property To investigate blocking layer material dependence on the electrical characteristics of the CT type FinFET flash memories, we fabricated MONOS and MANOS type devices with different blocking layers of SiO2 and Al2O3 as mentioned before. The initial Id-Vg characteristics of the fabricated MONOS and MANOS type FinFET flash memories with different Lg values from 26 to 103 nm were measured and the SCE immunity was systematically evaluated. It was found that the smaller Vt roll-off and the better subthreshold slope (S-slope) are observed in the MANOS devices as compared to the MONOS ones due to the high-k effect of Al2O3 in MANOS devices. The P/E characteristics of the fabricated MONOS and MANOS devices were also comparatively investigated. It was found that a significant memory window increment is obtained by introducing an Al2O3 blocking layer instead of the SiO2 one as shown in Fig. 3. This result is reasonable because a high-k Al2O3blocking layer is effective to enhance the electric field across the tunnel oxide layer and to reduce the electric field across itself. Therefore, electron back tunneling from the gate to nitride layer is effectively suppressed during erase operation. As a result, a deep erase and a large memory window are obtained in the MANOS devices than the MONOS ones. It was also confirmed that the fabricated MONOS and MANOS devices can operate over 100 k cycles, and can maintain a reasonable memory window after 10 years. In summary, we have investigated the gate material and blocking layer material dependences on the electrical characteristics of the fabricated CT type FinFET flash memories. It was experimentally found that a high work function metal gate and a high-k blocking layer are very useful to the enhancement of memory window. Acknowledgment: This work was supported in part by the Nanotechnology Project of NEDO, Japan. [1] P. Xuan et al., IEDM Tech. Dig., 609 (2003). [2] M. Spechi et al., IEDM Tech. Dig., 1083 (2004). [3] S-K. Sung et al., Symp. VLSI Tech. Dig., 106 (2006). [4] Y. X. Liu et al., Ext. Abstract, SSDM, 985 (2011). [5] T. Kamei et al., IEEE EDL 33345 (2012). [6] Y. X. Liu et al., IEEE EDL 24484 (2003). [7] C. H. Lee et al., IEDM Tech. Dig., 613 (2003).

A 37-year-old woman was admitted to a hospital due to a prolonged fever and a rash on her legs. She had systemic lymphadenitis and a skin abscess on her left leg. Pathological findings of a left leg skin biopsy revealed abscess formation with granulomatous dermatitis, Mycobacterium abscessus complex was cultured from the resected left supraclavicular lymph node, and disseminated M. abscessus complex infection was diagnosed. She was treated with combination treatment with antimicrobials and percutaneous drainage, and her clinical findings improved. Four months later, she developed acute lymphocytic leukemia. Leukemia is a risk factor for disseminated M. abscessus complex infection, even before developing leukemia.

The ABO system is of fundamental importance in the fields of transfusion and transplantation and has apparent associations with certain diseases, including cardiovascular disorders. ABO expression is reduced in the late phase of erythroid differentiation in vitro, whereas histone deacetylase inhibitors (HDACIs) are known to promote cell differentiation. Therefore, whether or not HDACIs could reduce the amount of ABO transcripts and A or B antigens is an intriguing issue.Quantitative polymerase chain reactions were carried out for the ABO transcripts in erythroid-lineage K562 and epithelial-lineage KATOIII cells after incubation with HDACIs, such as sodium butyrate, panobinostat, vorinostat, and sodium valproate. Flow cytometric analysis was conducted to evaluate the amounts of antigen in KATOIII cells treated with panobinostat. Quantitative chromatin immunoprecipitation (ChIP) assays and luciferase assays were performed on both cell types to examine the mechanisms of ABO suppression.HDACIs reduced the ABO transcripts in both K562 and KATOIII cells, with panobinostat exerting the most significant effect. Flow cytometric analysis demonstrated a decrease in B-antigen expression on panobinostat-treated KATOIII cells. ChIP assays indicated that panobinostat altered the modification of histones in the transcriptional regulatory regions of ABO, and luciferase assays demonstrated reduced activity of these elements.ABO transcription seems to be regulated by an epigenetic mechanism. Panobinostat appears to suppress ABO transcription, reducing the amount of antigens on the surface of cultured cells.

FinFETs with the low temperature microwave annealing process have been successfully fabricated and the superiority of the microwave annealing process has been precisely studied. For the first time, it is revealed that the microwave annealed FinFET exhibits less Vth variability and lower gate leakage.

An increased risk of lymphoproliferative disorders (LPD) has been demonstrated in patients treated with methotrexate (MTX) for rheumatoid arthritis (RA). The role of Epstein-Barr virus (EBV) has been discussed in the pathogenesis of immunodeficiency-associated LPDs. We herein present a RA patient, who developed Burkitt lymphoma during MTX treatment. The patient was a 61-year-old Japanese female with a 10-year history of weekly MTX therapy for RA. She presented with a one-month history of submandibular lymph node swelling and fever. Remarkable increases in serum lactate dehydrogenase and blood EBV DNA were observed. Serology for HIV was negative. Biopsy specimens demonstrated diffuse proliferation of medium-sized lymphoid cells. The cells were positive for CD10, CD20 and BCL6, and negative for BCL2, MUM1, terminal deoxynucleotidyl transferase and CD34. The MIB-1 index was almost 100%. EBV in the tumor cells was identified by using EBV-encoded RNA in situ hybridization. A chromosomal translocation t(8;14) was found and further confirmed by fluorescence in situ hybridization. Her condition improved following discontinuation of MTX and initiation of prednisolone. After three cycles of a dose-reduced CHOP-like regimen, chemotherapy was discontinued due to severe complications. However, there has been no sign of recurrence for six years to date without additional intensive chemotherapy.

We report on performance enhancement of FinFETs with a 25-nm-short extension of the source/drain by using atomic layer deposition (ALD) of SiO 2 thin films for the side-wall spacer (SWS) of the gate electrode. Recently, the higher parasitic resistance ( R para ) of the source/drain region due to the narrow fin width is one of the issues to be solved for the FinFET devices. In this study, the performance of the FinFETs has been successfully improved by the reduction of the parasitic resistance using the ALD-SWS.

ON-current (Ion) variability is comprehensively investigated for fin-shaped FETs (FinFETs) by measurement-based analysis. Variation sources of Ion are successfully extracted as independent contributions of threshold voltage Vt, transconductance Gm, and parasitic resistance Rpara. As well as Vt variability, Gm variation exhibits a linear relationship in the Pelgrom plot. However, the Gm variation is not reduced with scaling the gate dielectric thickness unlike the Vt variation. Perspective for 14-nm FinFETs represents that the Gm variation will be the dominant Ion variation source. A solution to reduce the Gm variation for the FinFET is also proposed.

The ABO blood group is of great importance in blood transfusion and organ transplantation. However, the mechanisms regulating human ABO gene expression remain obscure. On the basis of DNase I–hypersensitive sites in and upstream of ABO in K562 cells, in the present study, we prepared reporter plasmid constructs including these sites. Subsequent luciferase assays indicated a novel positive regulatory element in intron 1. This element was shown to enhance ABO promoter activity in an erythroid cell–specific manner. Electrophoretic mobility–shift assays demonstrated that it bound to the tissue-restricted transcription factor GATA-1. Mutation of the GATA motifs to abrogate binding of this factor reduced the regulatory activity of the element. Therefore, GATA-1 appears to be involved in the cell-specific activity of the element. Furthermore, we found that a partial deletion in intron 1 involving the element was associated with Bm phenotypes. Therefore, it is plausible that deletion of the erythroid cell–specific regulatory element could down-regulate transcription in the Bm allele, leading to reduction of B-antigen expression in cells of erythroid lineage, but not in mucus-secreting cells. These results support the contention that the enhancer-like element in intron 1 of ABO has a significant function in erythroid cells.

A correlation between the characteristics of the 30-nm LG fin-shaped field-effect transistors and the static random-access memory performance is precisely studied. By investigating an effect of the Vth variation to the static noise margin (SNM) variation of two different memory states of the storage node, it is revealed that the Vth variations of the pull-up, pull-down, and pass-gate transistors correlate with the SNM. Moreover, the contribution and the severity of each transistor variation to σSNM are clarified.

The crystal-Si and poly-Si fin-channel flash memories with a thin n+-poly-Si floating-gate (FG) layer have successfully been fabricated, and their electrical characteristics have systematically been investigated. It was experimentally found that the better short-channel effect (SCE) immunity, the smaller threshold voltage (Vt) variations and a higher program speed are obtained in the crystal-Si fin-channel tri-gate (TG)-type flash memories than in the double-gate (DG)-type ones. It was also confirmed that split-gate crystal-Si fin-channel flash memories show highly suppressed over-erase as compared to that in stack-gate memories. Moreover, it was found that Vt variation in the poly-Si fin-channel flash memories after a program/erase (P/E) cycle became comparable to that in the crystal-Si fin-channel memories. The measured source-drain breakdown voltage (BVDS) was higher than 3.2 V even the gate length (Lg) was down to 76 nm. The developed technology is very useful for the fabrication of scaled NOR-type flash memory.