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青木真美教授定年退職記念号(Special issue in commemoration of Prof. Mami Aoki's retirement)

Background/Aim: We assessed the prognosis of patients with refractory or relapsed multiple myeloma (RRMM) by focusing on the change in absolute lymphocyte counts (ALCs) after lenalidomide and dexamethasone (Ld) initiation. Patients and Methods: In total, 72 patients with RRMM were treated with Ld. ALCs were evaluated before treatment and at 1, 2, and 3 months after Ld initiation. The median ALCs in the entire cohort before and at 1, 2, 3 months after Ld initiation were 1,131, 1,059, 1,222, and 1,162/μl, respectively. Results: ALCs before Ld initiation did not affect time to next treatment (TNT) or overall survival (OS). However, the patients with ALCs equal to or greater than the median at 3 months showed relatively better TNT than those with lower lymphocyte counts, with a significant difference. OS was also significantly longer in patients with higher ALCs. Conclusion: Immunomodulation by lenalidomide may improve prognosis in patients with RRMM.

研究(Article)

The alignment process of ultraviolet (UV) nanoimprint lithography requires a further sophisticated method to detect infinitesimal misalignments between a synthetic quartz mold and a silicon substrate. Previously, we proposed a fluorescence-alignment method based on the analysis of the additive-type moiré fringes generated by the interferences of fluorescence emission from fluorescent UV-curable liquid filling the concave bar-mark arrays on a synthetic quartz mold and a silicon substrate. The proposed method significantly reduces the cost of mold fabrication and simplifies the in-liquid process compared to the conventional method based on multiplicative-type moiré fringes prevailing in the industry. This is because the fluorescence-alignment method is free from the problem of the refractive index matching between mold and UV-curable liquid materials. However, its position accuracy remains as large as sub-10 nm scales in principle. In this study, through simulation using image drawing and analysis software, we demonstrate that a sophisticated fluorescence alignment can realize atomic-scale precision for position accuracy by attempting the following concepts: (i) the application of the principle on position determination of a fluorescent single-molecule to that of an individual bar-mark fluorescence signal; (ii) effective use of high bit-depth of recent imaging devices; and (iii) accumulations of the information on the positions of multiple bar-marks with periodicities by fitting their fluorescence intensity profiles using a periodic function.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS-directed therapy or standard therapy alone. CNS-directed therapy was associated with a significantly better 2-year CNS-free survival (100% vs. 63%

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a pandemic threat worldwide and causes severe health and economic burdens. Contaminated environments, such as personal items and room surfaces, are considered to have virus transmission potential. Ultraviolet C (UVC) light has demonstrated germicidal ability and removes environmental contamination. UVC has inactivated SARS-CoV-2; however, the underlying mechanisms are not clear. It was confirmed here that UVC 253.7 nm, with a dose of 500 μW/cm2, completely inactivated SARS-CoV-2 in a time-dependent manner and reduced virus infectivity by 10–4.9-fold within 30 s. Immunoblotting analysis for viral spike and nucleocapsid proteins showed that UVC treatment did not damage viral proteins. The viral particle morphology remained intact even when the virus completely lost infectivity after UVC irradiation, as observed by transmission electronic microscopy. In contrast, UVC irradiation-induced genome damage was identified using the newly developed long reverse-transcription quantitative-polymerase chain reaction (RT-qPCR) assay, but not conventional RT-qPCR. The six developed long RT-PCR assays that covered the full-length viral genome clearly indicated a negative correlation between virus infectivity and UVC irradiation-induced genome damage (R2 ranging from 0.75 to 0.96). Altogether, these results provide evidence that UVC inactivates SARS-CoV-2 through the induction of viral genome damage.

藤原秀夫教授古稀祝賀記念号, Honorable issue in commemoration of Prof. Hideo Fujiwara's 70 years of age

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

Individual authentication using artefact metrics has received increasing attention, as greater importance has been placed on the security of individual information. These artefact metrics must satisfy the requirements of individuality, measurement stability, durability, and clone resistance, in addition to possessing unique physical features. In this study, we proposed that nanostructures of synthetic quartz (SQ) deposited on an SQ plate may provide sophisticated artefact metrics if morphological changes could be intentionally introduced into the SQ nanostructures at certain positions. We fabricated SQ nanopillars using a mass-production method (ultraviolet nanoimprint lithography) and investigated their mechanical deformation using nanoindentation with a spheroid diamond tip through a loading and unloading cycle. The SQ nanopillars with an aspect ratio of 1 (i.e., diameters D of 100 and 200 nm with corresponding heights H of 100 and 200 nm, respectively) could be plastically deformed without collapsing within a specified pillar-array format at programmed positions. The plastically deformed SQ nanopillar arrays demonstrated multi-scale (sub-millimetre, micrometre, and nanometre) and multi-level (shape, area, diameter, and height) individuality authentication and clone resistance. Because SQ is physically and chemically stable and durable, individuality authentication can be a highly reliable tool on Earth and in space.

Ultraviolet (UV)-cured spin-coated resist films of 100 nm and thinner thicknesses made with bisphenol A-based dimethacrylate monomers on silicon substrates were hybridized by multiple-pulsed vapor infiltration of sequential trimethylaluminum (TMA) doses and a final H2O dose. Nondestructive x-ray reflectivity measurements without film shrinkage enabled characterization of the internal layer structures of the UV-cured films unmodified before hybridization and hybridized by TMA infiltration and chemical fixing. It was possible to determine the thickness, density, and interface roughness of each layer in the unmodified and hybridized UV-cured films. The TMA infiltration and chemical fixing resulted in the formation of the highest-density Al-rich layer near the film surface. The presence of the highest-density layer arising from the most abundant component, Al, was confirmed through energy-dispersive x-ray spectroscopy and time-of-flight secondary ion mass spectrometry. The increase in the cycle number of TMA dose from 100 to 150 and 200 cycles had little effect on organic–inorganic hybridization of the 100 nm-thick UV-cured films. The thickness of the outermost Al-rich layer near the film surface was approximately 30 nm, which was unchanged when the film thicknesses of 100, 75, and 50 nm were changed. The outermost skin layer suppressed the infiltration of TMA into the UV-cured films. The infiltration of TMA into the UV-cured films progressed as the film thicknesses decreased.

Background: After long-term analysis of the JALSG-APL204 study we recently reported that maintenance therapy with tamibarotene was more effective than all-trans retinoic acid (ATRA) by reducing relapse in APL patients. Here, the clinical significance of other important prognostic factors was evaluated with multivariate analyses. Patients and Methods: Newly diagnosed acute promyelocytic leukemia (APL) patients were registered with the study. Induction was composed of ATRA and chemotherapy. Patients who achieved molecular remission after consolidation were randomly assigned to maintenance with tamibarotene or ATRA. Results: Of the 344 eligible patients, 319 (93%) achieved complete remission (CR). After completing consolidation, 269 patients underwent maintenance random assignment&mdash, 135 to ATRA, and 134 to tamibarotene. By multivariate analysis, overexpression of CD56 in blast was an independent unfavorable prognostic factor for relapse-free survival (RFS) (p = 0.006) together with more than 10.0 &times, 109/L WBC counts (p = 0.001) and the ATRA arm in maintenance (p = 0.028). Of all phenotypes, CD56 was related most clearly to an unfavorable prognosis. The CR rate, mortality rate during induction and overall survival of CD56+ APL were not significantly different compared with CD56- APL. CD56 is continuously an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy.

Between April 2004 and December 2010, we conducted a prospective randomized controlled study comparing tamibarotene with all-trans retinoic acid (ATRA) in the maintenance therapy of newly diagnosed acute promyelocytic leukemia (APL), and here report the final results of this study with a median follow-up of 7.3 years. Of 344 eligible patients who had received ATRA and chemotherapy, 319 (93%) achieved complete remission (CR). After completion of three courses of consolidation chemotherapy, 269 patients in molecular remission underwent maintenance randomization, 135 to ATRA (45 mg/m2 daily), and 134 to tamibarotene (6 mg/m2 daily) for 14 days every 3 months for 2 years. The primary endpoint was relapse-free survival (RFS). The 7-year RFS was 84% in the ATRA arm and 93% in the tamibarotene arm (p = 0.027, HR = 0.44, 95% CI, 0.21 to 0.93). The difference was prominent in high-risk patients with initial leukocytes ≥ 10.0 × 109/L (62% vs. 89%; p = 0.034). Tamibarotene was significantly superior to ATRA by decreasing relapse in high-risk patients. Overall survival after randomization did not differ (96% vs. 97%; p = 0.520). Secondary hematopoietic disorders developed in nine patients, secondary malignancies in 11, and grade 3 or more late cardiac comorbidities in three. These late complications did not differ between the two arms.

高井紳二教授定年退職記念号, Special issue in commemoration of Prof. Shinji Takai's retirement

上田慧教授古稀祝賀記念号, Honorable issue in commemoration of Prof. Satoshi Ueda 70 years of age

In the field of cell imaging, it is still a practical challenge to obtain the high quality live imaging of suspension cells, mainly due to undesirable cell movement in the imaging field during observation. This study describes a porous nanosheet wrapping method to noninvasively immobilize suspension cells for their live imaging. Perforated nanopores are fabricated on a nanosheet to enable the addition of external chemicals to cells, ranging from small molecules to macromolecules. Through several case studies, such as the live imaging of membrane staining of liposomes, transferrin endocytosis of B cells, and activation of platelets, it is verified that the confined space made by the nanosheet could provide a hydrodynamically stable environment for suspension cells, even if an aqueous stimulus is added through the nanopores in a static or a flowing condition. With this method, the live imaging of the whole activation process on a specific suspension cell in the imaging field is achieved, which is not feasible with the existing cell immobilization methods. This study suggests that the method of porous nanosheet wrapping will facilitate the visualization of the dynamic functions of suspension cells.

To demonstrate area selective atomic layer deposition (ALD) using UV-nanoimprinted resin patterns as physical passivation masks, we investigated the removal of UV-cured resin films subjected to sequential mutual doses of trimethylaluminum (TMA) and H2O by using dry etching procedures. On the basis of the removal of a residual layer characteristic from imprint resin patterns by anisotropic oxygen reactive ion etching (O2 RIE), oxidatively etched UV-cured films were modified with TMA and H2O in an ALD-like cyclic manner. Atomic force microscopy and time-of-flight secondary ion mass spectrometry [time-of-flight secondary ion mass spectrometry (TOF-SIMS)] analysis suggested that the combination of physical Ar ion milling and subsequent chemical O2 RIE enabled the elimination of oxidized UV-cured resin masks modified with 5-cycle TMA doses. By contrast, Ar ion milling or O2 RIE left organic or inorganic residues on silicon surfaces, respectively. A TMA-modified hybridized resin layer was etched by physical Ar ion milling; subsequently, the organic residual resin layer was removed by chemical O2 RIE in the case of 5-cycle modification with TMA. The mapping image of Al+ visualized by TOF-SIMS suggested that line patterns of aluminum oxide were left selectively on unmasked silicon substrate surfaces by site-selective dry etching of TMA-modified imprint resin passivation masks with 500 nm linewidth.

In the present study, the effect of immunophenotyping on the prognoses of patients with multiple myeloma (MM) treated with bortezomib plus dexamethasone was investigated. The study involved 46 patients with MM, and analyzed the prognostic significance of the expression of cluster of differentiation (CD)45, CD56 and mature plasma cell (MPC)-1, and other factors including the International Staging System (ISS) stage, age, gender, the immunoglobulin subtype and the treatment line number prior to bortezomib treatment. Although CD56 and MPC-1 expression did not appear to affect the time to next treatment (TNT) or overall survival rate (OS), the univariate analysis determined that CD45 positivity was an adverse prognostic factor for TNT and OS, and that being male was significantly associated with inferior TNT and OS. Multivariate analyses determined that CD45 expression was prognostically significant for TNT and OS. In conclusion, CD45 positivity is an adverse prognostic factor in MM patients treated with bortezomib. The data from the present study demonstrate the clinical importance of classifying MM cells immunophenotypically to determine the prognoses of patients.

SARS-CoV-2 is the causative agent of COVID-19, which is a global pandemic. SARS-CoV-2 is transmitted rapidly via contaminated surfaces and aerosols, emphasizing the importance of environmental disinfection to block the spread of virus. Ultraviolet C radiation and chemical compounds are effective for SARS-CoV-2 disinfection, but can only be applied in the absence of humans due to their toxicities. Therefore, development of disinfectants that can be applied in working spaces without evacuating people is needed. Here we showed that TiO2-mediated photocatalytic reaction inactivates SARS-CoV-2 in a time-dependent manner and decreases its infectivity by 99.9% after 20 min and 120 min of treatment in aerosol and liquid, respectively. The mechanistic effects of TiO2 photocatalyst on SARS-CoV-2 virion included decreased total observed virion count, increased virion size, and reduced particle surface spike structure, as determined by transmission electron microscopy. Damage to viral proteins and genome was further confirmed by western blotting and RT-qPCR, respectively. The multi-antiviral effects of TiO2-mediated photocatalytic reaction implies universal disinfection potential for different infectious agents. Notably, TiO2 has no adverse effects on human health, and therefore, TiO2-induced photocatalytic reaction is suitable for disinfection of SARS-CoV-2 and other emerging infectious disease-causing agents in human habitation.

The fabrication of resist patterns using UV nanoimprinting is required on consideration of the reduction of the use of hydrocarbons along recent amendments for environmental sustainability. In this study, we investigated the generation of resist pattern defects through UV nanoimprinting in a readily condensable trans-1,3,3,3-tetrafluoropropene (TFP) gas with a low global warming potential for elimination of nonfill defects arising from a bubble trap and subsequent sequential infiltration synthesis (SIS) to result in a vapor phase organic-inorganic hybridization for dry etching durability. A bisphenol A-based UV-curable imprint resin enabled the nanostructure fabrication of resist patterns without any nonfill defects in TFP; however, SIS consisting of subsequent mutual doses of trimethylaluminum and water caused a resist pattern collapse of 100-nm-height patterns with linewidths of

Magnetic carriers with efficient loading, delivery, and release of drugs are required for magnetically guided drug delivery system (DDS) as the potential cancer therapy. The present article describes the fabrication of porous FePt capsules approximately 340 nm in diameter with large pores of 20 nm in an ultrathin shell of 10 nm and demonstrates their application to a magnetically guided DDS in vitro. An aqueous anti-cancer drug is easily introduced in the hollow space of the capsules without external stimuli and released to cancer cells on cue through the magnetic shell composed of an ordered-alloy FePt network structure, which exhibits superparamagnetic features at approximately body temperature. The drug-loaded magnetic capsules coated with a lipid membrane are efficiently guided to the cancer cells within 15 min using a NdFeB magnet (0.2 T), and more than 70% of the cancer cells are destroyed.

研究(Article)

生活習慣病予防を目的としてSNSの仕組みを導入したシステムによる歩行運動継続支援が試みられている．これらは，システム内のユーザ間交流により仲間意識や競争意識を高め，歩行運動を継続させることが狙いである．しかし既存のシステムではテキストを介した対話による交流がユーザの歩行運動継続を動機付けており，比較的長文のテキスト入力も苦にしない一部の対象者にしか受け入れられない．本研究ではより広い範囲のユーザを動機付けるために，より少ない入力情報を用いて歩行運動継続を動機付けるSNSシステムを設計・実装し，対話を用いない競争機構によりどの程度の動機付けが可能かを評価した．本システムの設計では動機付けのレベルを「自己記録の視覚的確認」「友人との競争」「ライバルとの競争」3段階に分類し，各々に3種類の競争機能を組み込むことで効果的な動機付け機構の実現を試みた.本システムの評価結果より，対話を用いない競争機能によって相応の動機付け効果が期待できることを確認したので報告する．