Publications by authors named "Takeshi Kobayashi"

475 Publications

An Autopsy Case of Multicentric Castleman Disease Presenting with Severe Jaundice.

Intern Med 2021 Jun 5. Epub 2021 Jun 5.

¹Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

A 70-year-old man with multicentric Castleman disease (MCD) was admitted to our hospital with jaundice and ascites. Elevations in his bilirubin and interleukin-6 levels were noted, and computed tomography revealed hepatic atrophy and portal vein and bile duct disorders. Steroid therapy was started for MCD, but he died of hepatic failure. An autopsy revealed that the MCD activity was mild, but advanced fibrosis and cholestasis were observed in the liver. Mild infiltration of IL-6-positive plasma cells was noted in the highly fibrotic area of the liver. Although rare, liver and biliary tract damage may be also considered organ disorders of MCD.
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http://dx.doi.org/10.2169/internalmedicine.6835-20DOI Listing
June 2021

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia.

Acta Haematol 2021 Jun 1:1-7. Epub 2021 Jun 1.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.
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http://dx.doi.org/10.1159/000516347DOI Listing
June 2021

Outcome of allogeneic hematopoietic stem cell transplantation for T-cell lymphoblastic leukemia/lymphoma: A single-center study.

Leuk Res 2021 May 18;108:106627. Epub 2021 May 18.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Although the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL) are similar, few studies have compared its outcomes for T-ALL/LBL and Ph-negative B-ALL. The clinical data of 28 patients with T-ALL, 16 with T-LBL, and 99 with Ph-negative B-ALL who underwent the first allo-HSCT from 2000 to 2019 were retrospectively analyzed. Complete remission (CR) rates at allo-HSCT were 79 %, 63 %, and 75 % for T-ALL, T-LBL, and B-ALL, respectively; the 3-year overall survival (OS) rates were 55.7 %, 56.2 %, and 58.6 %, respectively (p = 0.92). Univariate analysis revealed that disease subtypes were not significantly associated with OS (B-ALL vs. T-ALL: hazard ratio [HR]=0.89, p = 0.70; T-LBL vs. T-ALL: HR=0.87, p = 0.75), and CR at allo-HSCT was the only prognostic factor for OS (HR=0.25, p < 0.001). Multivariate analysis demonstrated that CR at allo-HSCT was the only predictor of OS (HR=0.24, p < 0.001). In all three disease subtypes, patients in CR at allo-HSCT tended to have a lower cumulative incidence of relapse than did those in non-CR (T-ALL: 13.6 % vs. 50.0 %, p = 0.10; T-LBL: 20.0 % vs. 50.0 %, p = 0.21; B-ALL: 10.0 % vs. 56.0 %, p < 0.01). Thus, the outcomes of allo-HSCT for T-ALL/LBL were comparable to those of Ph-negative B-ALL. Irrespective of the disease subtypes, achieving CR before allo-HSCT was associated with a favorable OS. Further advances in chemotherapy before allo-HSCT and defining the optimal timing of allo-HSCT would improve the prognosis of patients with T-ALL/LBL.
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http://dx.doi.org/10.1016/j.leukres.2021.106627DOI Listing
May 2021

Indirectly Detected DNP-Enhanced O NMR Spectroscopy: Observation of Non-Protonated Near-Surface Oxygen at Naturally Abundant Silica and Silica-Alumina.

Chemphyschem 2021 May 21. Epub 2021 May 21.

U.S. DOE Ames Laboratory, Iowa State University, Ames, Iowa 50011-3020, United States.

Recent studies have shown that dynamic nuclear polarization (DNP) can be used to detect O solid-state NMR spectra of naturally abundant samples within a reasonable experimental time. Observations using indirect DNP, which relies on H mediation in transferring electron hyperpolarization to O, are currently limited mostly to hydroxyls. Direct DNP schemes can hyperpolarize non-protonated oxygen near the radicals; however, they generally offer much lower signal enhancements. In this study, we demonstrate the detection of signals from non-protonated O in materials containing silicon. The sensitivity boost that made the experiment possible originates from three sources: indirect DNP excitation of Si via protons, indirect detection of O through Si nuclei using two-dimensional Si{ O} D-HMQC, and Carr-Purcell-Meiboom-Gill refocusing of Si magnetization during acquisition. This Si-detected scheme enabled, for the first time, 2D O- Si heteronuclear correlation spectroscopy in mesoporous silica and silica-alumina surfaces at natural abundance. In contrast to the silanols showing motion-averaged O signals, the framework oxygens exhibit unperturbed powder patterns as unambiguous fingerprints of surface sites. Along with hydroxyl oxygens, detection of these moieties will help in gaining more atomistic-scale insights into surface chemistry.
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http://dx.doi.org/10.1002/cphc.202100290DOI Listing
May 2021

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation.

Transplant Cell Ther 2021 May 12. Epub 2021 May 12.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.
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http://dx.doi.org/10.1016/j.jtct.2021.05.003DOI Listing
May 2021

Epidemiology and genetic diversity of group A rotavirus in pediatric patients with acute gastroenteritis in Thailand, 2018-2019.

Infect Genet Evol 2021 May 8:104898. Epub 2021 May 8.

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Emerging and Re-emerging Diarrheal Viruses Cluster, Chiang Mai University, Chiang Mai, Thailand; Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Group A rotaviruses (RVAs) are the major viruses that cause acute gastroenteritis in young children worldwide. The objective of this study was to investigate the prevalence and genotype diversity of RVAs circulating in children with acute gastroenteritis in Thailand in 2018-2019. A total of 1170 stool specimens were obtained from children admitted to hospitals with diarrhea and screened for RVAs by nested RT-PCR. The RVA genotypes were determined by multiplex-PCR or nucleotide sequencing and phylogenetic analysis. Out of 1170 stool specimens, 209 (17.9%) were positive for RVAs. The RVA G9P[8] genotype (24.4%) was the most dominant genotype, followed by G3P[8] (22.9%), G8P[8] (22.0%), G1P[8] (16.7%), G2P[4] (6.7%), G1P[6] (2.3%), G1P[4] (1.0%), G3P[4] (1.0%), G9P[4] (1.0%), mixed-infections of G1P[4] + G1P[8] (1.0%), and GXP[8] (0.5%). Moreover, an uncommon RVA G3P[10] genotype (0.5%), bearing bat-like VP7 and VP4 genes, was detected. This study reveals the prevalence and genetic diversity of RVA genotypes in children with acute gastroenteritis in Thailand. The knowledge obtained from this study is helpful for understanding the epidemiology of rotavirus in Thailand. The emergence of uncommon RVA strain G3P[10] provides an evidence for interspecies transmission of human and animal rotaviruses.
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http://dx.doi.org/10.1016/j.meegid.2021.104898DOI Listing
May 2021

[Clinical features of tuberculosis among allogeneic hematopoietic stem cell transplantation recipients].

Rinsho Ketsueki 2021 ;62(4):239-244

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

The incidence of tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is 10-40 times higher than that in the general population, which ranges from 0.1% to 5.5%. However, the clinical features of TB among allo-HSCT recipients in Japan remain unknown. We retrospectively analyzed the incidence of TB and the clinical features of culture-positive TB among allo-HSCT recipients at our hospital between 2002 and 2018. Of 1,047 recipients, 5 (0.4%) developed pulmonary TB (with an incidence rate of 472 per 100,000 population) at a median of 1,730 (range: 586-2,526) days after allo-HSCT. Three patients had chronic graft-versus-host disease upon the onset of TB, which was well-controlled with tacrolimus and/or steroid. Three of five patients completed TB treatment, and the disease did not flare up after therapy completion. The incidence of TB was higher in allo-HSCT recipients than in the general population (0.01%, with an incidence rate of 12.3 per 100,000 population). Therefore, TB should be considered a late complication among allo-HSCT recipients.
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http://dx.doi.org/10.11406/rinketsu.62.239DOI Listing
May 2021

Bronchiolitis obliterans after stem cell transplantation for hematologic malignancies rescued by lung transplantation: A report of two cases.

Respir Investig 2021 Apr 18. Epub 2021 Apr 18.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Bronchiolitis obliterans syndrome (BOS) occurring after hematopoietic stem cell transplantation (HSCT) for hematologic malignancies is a progressive and refractory disease, and lung transplantation (LTx) seems to be the only promising treatment. We report two cases of BOS after HSCT, which showed distinct clinical courses and were successfully treated with LTx. The respiratory symptoms and function of the two patients progressively deteriorated to a critical level during the waiting period. In one patient, recurrent and intractable pneumothoraxes consistent with thoracic air-leak syndrome (TALS) occurred, which were associated with pleuroparenchymal fibroelastosis. TALS could accelerate clinical deterioration, thus permitting a shorter waiting period for LTx.
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http://dx.doi.org/10.1016/j.resinv.2021.03.007DOI Listing
April 2021

Morin attenuates dexamethasone-mediated oxidative stress and atrophy in mouse C2C12 skeletal myotubes.

Arch Biochem Biophys 2021 Jun 10;704:108873. Epub 2021 Apr 10.

Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Tokushima, Japan. Electronic address:

Glucocorticoids are the drugs most commonly used to manage inflammatory diseases. However, they are prone to inducing muscle atrophy by increasing muscle proteolysis and decreasing protein synthesis. Various studies have demonstrated that antioxidants can mitigate glucocorticoid-induced skeletal muscle atrophy. Here, we investigated the effect of a potent antioxidative natural flavonoid, morin, on the muscle atrophy and oxidative stress induced by dexamethasone (Dex) using mouse C2C12 skeletal myotubes. Dex (10 μM) enhanced the production of reactive oxygen species (ROS) in C2C12 myotubes via glucocorticoid receptor. Moreover, Dex administration reduced the diameter and expression levels of the myosin heavy chain protein in C2C12 myotubes, together with the upregulation of muscle atrophy-associated ubiquitin ligases, such as muscle atrophy F-box protein 1/atrogin-1, muscle ring finger protein-1, and casitas B-lineage lymphoma proto-oncogene-b. Dex also significantly decreased phosphorylated Foxo3a and increased total Foxo3a expression. Interestingly, Dex-induced ROS accumulation and Foxo3a expression were inhibited by morin (10 μM) pretreatment. Morin also prevented the Dex-induced reduction of myotube thickness, together with muscle protein degradation and suppression of the upregulation of atrophy-associated ubiquitin ligases. In conclusion, our results suggest that morin effectively prevents glucocorticoid-induced muscle atrophy by reducing oxidative stress.
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http://dx.doi.org/10.1016/j.abb.2021.108873DOI Listing
June 2021

Changes in vaccination strategies contribute to the development of invasive pneumococcal disease in allogeneic hematopoietic stem cell transplantation recipients: a retrospective study for promoting vaccination.

Int J Hematol 2021 Apr 12. Epub 2021 Apr 12.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at high risk of developing invasive pneumococcal disease (IPD) with substantial morbidity and mortality. Pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) are the primary prevention strategy. The difference between the Japanese and international guidelines is limited except when to start PCV13. However, Japanese data regarding the incidence of IPD after allo-HSCT that include vaccination status are limited. Therefore, we aimed to study the clinical characteristics of patients with IPD following allo-HSCT, focusing on unvaccinated patients. We retrospectively reviewed allo-HSCT recipients between April 2005 and December 2018 at Komagome Hospital. Among 1,091 recipients, 11 (1008/100,000 recipients) developed 13 episodes of IPD. The median period from the first allo-HSCT to the first IPD episode was 686 days (10-3040 days). Ten patients developed IPD before vaccination, and seven of these unvaccinated patients with late-onset IPD were ineligible for vaccination based on domestic guidelines. Although appropriate treatments resulted in a good short-term prognosis, most episodes of IPD developed in unvaccinated allo-HSCT recipients. Our data support the promotion of better adherence to the current guidelines and the importance of pneumococcal vaccination even years after allo-HSCT to protect against late-onset IPD.
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http://dx.doi.org/10.1007/s12185-021-03146-2DOI Listing
April 2021

Structure evolution of single-site Pt in a metal-organic framework.

J Chem Phys 2021 Mar;154(9):094710

Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.

Heterogeneous single-metal-site catalyst or single-atom catalyst research has grown rapidly due to the accessibility of modern characterization techniques that can provide invaluable information at the atomic-scale. Herein, we study the structural evolution of isolated single Pt sites incorporated in a metal-organic framework containing bipyridine functional groups using in situ diffuse reflectance infrared Fourier transform spectroscopy with CO as the probe molecule. The structure and electronic properties of the isolated Pt sites are further corroborated by x-ray photoelectron spectroscopy and aberration-corrected scanning transmission electron microscopy. We find the prerequisite of high temperature He treatment for Pt activation and CO insertion and inquire into the structural transformation of Pt site process by dynamic nuclear polarization-enhanced solid-state nuclear magnetic resonance spectroscopy.
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http://dx.doi.org/10.1063/5.0041904DOI Listing
March 2021

Efficiency analysis of helium-cooled MAS DNP: case studies of surface-modified nanoparticles and homogeneous small-molecule solutions.

Phys Chem Chem Phys 2021 Mar;23(8):4919-4926

Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan and Center for Quantum Information and Quantum Biology, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Toyonaka, Osaka 560-0043, Japan.

Despite the growing number of successful applications of dynamic nuclear polarization (DNP)-enhanced magic-angle spinning (MAS) NMR in structural biology and materials science, the nuclear polarizations achieved by current MAS DNP instrumentation are still considerably lower than the theoretical maximum. The method could be significantly strengthened if experiments were performed at temperatures much lower than those currently widely used (∼100 K). Recently, the prospects of helium (He)-cooled MAS DNP have been increased with the instrumental developments in MAS technology that uses cold helium gas for sample cooling. Despite the additional gains in sensitivity that have been observed with He-cooled MAS DNP, the performance of the technique has not been evaluated in the case of surfaces and interfaces that benefit the most from DNP. Herein, we studied the efficiency of DNP at temperatures between ∼30 K and ∼100 K for organically functionalized silica material and a homogeneous solution of small organic molecules at a magnetic field B0 = 16.4 T. We recorded the changes in signal enhancement, paramagnet-induced quenching and depolarization effects, DNP build-up rate, and Boltzmann polarization. For these samples, the increases in MAS-induced depolarization and DNP build-up times at around 30 K were not as severe as anticipated. In the case of the surface species, we determined that MAS DNP at 30 K provided ∼10 times higher sensitivity than MAS DNP at 90 K, which corresponds to the acceleration of experiments by multiplicative factors of up to 100.
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http://dx.doi.org/10.1039/d0cp05658hDOI Listing
March 2021

Requirement of the Ca channel β subunit for sympathetic PKA phosphorylation.

J Pharmacol Sci 2021 Mar 2;145(3):253-261. Epub 2021 Jan 2.

Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan.

Facilitation of cardiac function in response to signals from the sympathetic nervous system is initiated by the phosphorylation of L-type voltage-dependent Ca channels (VDCCs) by protein kinase A (PKA), which in turn is activated by β-adrenoceptors. Among the five subunits (α, β, α/δ, and γ) of VDCCs, the α subunit and the family of β subunits are substrates for PKA-catalyzed phosphorylation; however, the subunit responsible for β-adrenergic augmentation of Ca channel function has yet to be specifically identified. Here we show that the VDCC β subunit is required for PKA phosphorylation upon sympathetic acceleration. In mice with β subunit-null mutations, cardiac muscle contraction in response to isoproterenol was reduced and there was no significant increase in Ca channel currents upon PKA-dependent phosphorylation. These findings indicate that within the sympathetic nervous system the β subunit of VDCCs is required for physiological PKA-dependent channel phosphorylation.
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http://dx.doi.org/10.1016/j.jphs.2020.12.011DOI Listing
March 2021

Gravity sensing in plant and animal cells.

NPJ Microgravity 2021 Feb 8;7(1). Epub 2021 Feb 8.

Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Gravity determines shape of body tissue and affects the functions of life, both in plants and animals. The cellular response to gravity is an active process of mechanotransduction. Although plants and animals share some common mechanisms of gravity sensing in spite of their distant phylogenetic origin, each species has its own mechanism to sense and respond to gravity. In this review, we discuss current understanding regarding the mechanisms of cellular gravity sensing in plants and animals. Understanding gravisensing also contributes to life on Earth, e.g., understanding osteoporosis and muscle atrophy. Furthermore, in the current age of Mars exploration, understanding cellular responses to gravity will form the foundation of living in space.
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http://dx.doi.org/10.1038/s41526-020-00130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870899PMC
February 2021

[Two Cases of Alpha-Fetoprotein Producing Gastric Cancer].

Gan To Kagaku Ryoho 2020 Dec;47(13):2018-2020

Dept. of Surgery, Miyoshi Central Hospital.

Case 1: A 51-year-old man underwent total gastrectomy for esophagogastric junction cancer. Pathological diagnosis was alpha-fetoprotein(AFP)producing cancer. One month after the surgery, lung metastasis was found on CT. Despite systemic chemotherapy, he died 4 months after the surgery. Case 2: A 79-year-old man underwent open distal gastrectomy for gastric cancer. Pathological diagnosis was AFP producing cancer. Six months after the surgery, multiple lymph node metastases were found on CT. He received chemotherapy and radiation therapy. He is currently alive 9 years 8 months after the surgery.
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December 2020

Oxidation-induced thermopower inversion in nanocrystalline SnSe thin film.

Sci Rep 2021 Jan 15;11(1):1637. Epub 2021 Jan 15.

Materials Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Yokosuka, Kanagawa, 240-0196, Japan.

Given the growing demand for environmentally friendly energy sources, thermoelectric energy conversion has attracted increased interest as a promising CO-free technology. SnSe single crystals have attracted attention as a next generation thermoelectric material due to outstanding thermoelectric properties arising from ultralow thermal conductivity. For practical applications, on the other hand, polycrystalline SnSe should be also focused because the production cost and the flexibility for applications are important factors, which requires the systematic investigation of the stability of thermoelectric performance under a pseudo operating environment. Here, we report that the physical properties of SnSe crystals with nano to submicron scale are drastically modified by atmospheric annealing. We measured the Seebeck effect while changing the annealing time and found that the large positive thermopower, + 757 μV K, was completely suppressed by annealing for only a few minutes and was eventually inverted to be the large negative value, - 427 μV K. This result would further accelerate intensive studies on SnSe nanostructures, especially focusing on the realistic device structures and sealing technologies for energy harvesting applications.
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http://dx.doi.org/10.1038/s41598-021-81195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810839PMC
January 2021

Phase-sensitive γ-encoded recoupling of heteronuclear dipolar interactions and H chemical shift anisotropy.

Solid State Nucl Magn Reson 2021 Feb 6;111:101712. Epub 2021 Jan 6.

US DOE, Ames Laboratory, Ames, IA, 50011, USA.

γ-encoded recoupling sequences are known to produce strong amplitude modulations that lead to sharp doublets when Fourier transformed. These doublets depend very little on the recoupled tensor asymmetry and thus enable for the straightforward determination of dynamic order parameters. It can, however, be difficult to measure small anisotropies, or small order parameters, using such sequences; the resonances from the doublet may overlap with each other, or with the zero-frequency glitch. This limitation has prevented the widespread use of H chemical shift anisotropy (CSA) for the measurement of dynamics, particularly for CH protons which typically have CSAs of only a few ppm when immobile. Here, we introduce a simple modification to the traditional H CSA and proton-detected local field pulse sequences that enables the acquisition of a hypercomplex dataset and the removal of the uncorrelated magnetization that results in the zero-frequency glitch. These new sequences then yield a frequency shift in the indirect dimension, rather than a splitting, which is easily identifiable even in cases of weak interactions.
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http://dx.doi.org/10.1016/j.ssnmr.2020.101712DOI Listing
February 2021

Falciform ligament hernia with specific abdominal symptom.

Clin J Gastroenterol 2021 Apr 15;14(2):566-569. Epub 2021 Jan 15.

Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Falciform ligament hernia is a very rare internal hernia and is difficult to diagnose before surgery. We report a case of falciform ligament hernia with a specific symptom and image findings, which led to an accurate diagnosis and subsequent laparoscopic surgery. A 15-year-old adolescent boy with no previous medical history showed epigastric pain and was referred to our hospital. The abdominal pain was strong in the supine position and was alleviated in the knee-chest position. Contrast-enhanced computed tomography showed that the round ligament was recognized as a cord-like structure, and the mesentery of the small intestine was located at the cranioventral side of the ligament. He was diagnosed as having falciform ligament hernia, and emergency laparoscopic surgery was performed. The small intestine passed through the falciform ligament; however, it showed no sign of ischemia, and bowel resection was not required. The malposed intestine was repositioned, and the falciform ligament was cut to prevent hernia recurrence. The specific abdominal symptom and computed tomography image finding were useful to make the correct diagnosis in this case.
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http://dx.doi.org/10.1007/s12328-020-01323-0DOI Listing
April 2021

Rotavirus reverse genetics systems: Development and application.

Virus Res 2021 Apr 10;295:198296. Epub 2021 Jan 10.

Department of Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. Electronic address:

Rotaviruses (RVs) cause acute gastroenteritis in infants and young children. Since 2006, live-attenuated vaccines have reduced the number of RV-associated deaths; however, RV is still responsible for an estimated 228,047 annual deaths worldwide. RV, a member of the family Reoviridae, has an 11-segmented double-stranded RNA genome contained within a non-enveloped, triple layered virus particle. In 2017, a long-awaited helper virus-free reverse genetics system for RV was established. Since then, numerous studies have reported the generation of recombinant RVs; these studies verify the robustness of reverse genetics systems. This review provides technical insight into current reverse genetics systems for RVs, as well as discussing basic and applied studies that have used these systems.
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http://dx.doi.org/10.1016/j.virusres.2021.198296DOI Listing
April 2021

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin.

Ann Hematol 2021 Mar 11;100(3):743-752. Epub 2021 Jan 11.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan.

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 10/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 10/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 10/L and platelets ≥ 50 × 10/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 10/L and platelets ≥ 50 × 10/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.
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http://dx.doi.org/10.1007/s00277-020-04365-zDOI Listing
March 2021

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation.

Sci Rep 2020 12 17;10(1):22218. Epub 2020 Dec 17.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8/CMV pp65 tetramer cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson's index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2-4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.
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http://dx.doi.org/10.1038/s41598-020-79363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747720PMC
December 2020

[Vacuolar myelopathy after allogeneic bone marrow transplantation in a patient with acute lymphoblastic leukemia].

Rinsho Ketsueki 2020 ;61(11):1625-1627

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

Vacuolar myelopathy (VM) is known to be a neurological complication in patients with acquired immunodeficiency syndrome (AIDS). In autopsy-based studies, VM was reported in approximately 20-50% of patients with AIDS. It manifests in various says, mainly presenting as a painless spastic paraparesis with a sensory ataxia. We present a rare case of VM after bone marrow transplantation (BMT) in a patient without AIDS. A 50-year-old man developed weakness in the lower legs, leg muscle atrophy, and difficulty in walking 86 days after BMT. The patient died from septic shock on day 309. The autopsy revealed intralamellar vacuolation in the spinal white matter, which was compatible with VM.
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http://dx.doi.org/10.11406/rinketsu.61.1625DOI Listing
February 2021

Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol.

BMJ Open 2020 12 4;10(12):e040467. Epub 2020 Dec 4.

Department of Hematology/Oncology, The Institute of Medical Science The University of Tokyo, Tokyo, Japan.

Introduction: A better long-term quality of life after umbilical cord blood transplantation (CBT) is observed compared with transplants from other alternative donors, whereas graft failure and relapses after CBT are still major issues. To minimise graft failure and relapse after CBT, intensification of conditioning by the addition of high-dose cytosine arabinoside (CA) and concomitant continuous use of granulocyte-colony stimulating factor (G-CSF) are reported to convey a significantly better survival after CBT in some retrospective studies. To confirm the effect of G-CSF plus CA combination, in addition to the standard conditioning regimen, cyclophosphamide (CY)/total body irradiation (TBI), we design a randomised controlled study comparing CA/CY/TBI with versus without G-CSF priming (G-CSF combined conditioned cord blood transplantation [G-CONCORD] study).

Methods And Analysis: This is a multicentre, open-label, randomised phase III study that aimed to compare G-CSF+CA/CY/TBI as a conditioning regimen for CBT with CA/CY/TBI. Patients with acute myeloid leukaemia or myelodysplastic syndrome, aged 16-55 years, are eligible. The target sample size is 160 and the registration period is 4 years. The primary endpoint is the 2-year disease-free survival rate after CBT. The secondary endpoints are overall survival, relapse, non-relapse mortality, acute and chronic graft-versus-host disease, engraftment rate, time to neutrophil recovery, short-term adverse events, incidence of infections and causes of death.This study employs a single one-to-one web-based randomisation between the with-G-CSF versus without-G-CSF groups after patient registration. Combination of high-dose CA and CY/TBI in both groups is used for conditioning.

Ethics And Dissemination: The study protocol was approved by the central review board, Nagoya University Certified Review Board, after the enforcement of the Clinical Trials Act in Japan. The manuscripts presenting data from this study will be submitted for publication in quality peer-reviewed medical journals. Study findings will be disseminated via presentations at national/international conferences and peer-reviewed journals.

Trial Registration Numbers: UMIN000029947 and jRCTs041180059.
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http://dx.doi.org/10.1136/bmjopen-2020-040467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722372PMC
December 2020

Generation of recombinant rotaviruses encoding a split NanoLuc peptide tag.

Biochem Biophys Res Commun 2021 01 26;534:740-746. Epub 2020 Nov 26.

Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. Electronic address:

Recombinant viruses expressing fluorescent or luminescent reporter proteins are used to quantitate and visualize viral replication and transmission. Here, we used a split NanoLuc luciferase (NLuc) system comprising large LgBiT and small HiBiT peptide fragments to generate stable reporter rotaviruses (RVs). Reporter RVs expressing NSP1-HiBiT fusion protein were generated by placing an 11 amino acid HiBiT peptide tag at the C-terminus of the intact simian RV NSP1 open reading frame or truncated human RV NSP1 open reading frame. Virus-infected cell lysates exhibited NLuc activity that paralleled virus replication. The antiviral activity of neutralizing antibodies and antiviral reagents against the recombinant HiBiT reporter viruses were monitored by measuring reductions in NLuc expression. These findings demonstrate that the HiBiT reporter RV systems are powerful tools for studying the viral life cycle and pathogenesis, and a robust platform for developing novel antiviral drugs.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.007DOI Listing
January 2021

Prognosis after acute exacerbation in patients with interstitial lung disease other than idiopathic pulmonary fibrosis.

Clin Respir J 2021 Mar 10;15(3):336-344. Epub 2020 Dec 10.

Department of Pulmonary Medicine, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.

Background: Acute exacerbation (AE) is recognized as a life-threatening condition with acute respiratory worsening in idiopathic pulmonary fibrosis (IPF). AE also occurs in fibrotic interstitial lung disease (ILD) other than IPF, including other types of idiopathic interstitial pneumonias (IIPs), ILD associated with collagen vascular disease (CVD-ILD), and chronic hypersensitivity pneumonia (CHP). However, the clinical impact after AE in those patients is still unclear.

Methods: A retrospective review of 174 consecutive first-episodes with AE of ILD in our institution from 2002 to 2016 was performed. AE was defined according to the revised definition and diagnostic criteria proposed by an international working group in 2016. Clinical characteristics, 90-day survival, and the requirement of long-term oxygen therapy (LTOT) after AE were evaluated in each underlying ILD.

Results: There were 102 patients with AE of IPF (AE-IPF) and 72 with AE of ILD other than IPF, including non-IPF IIPs (n = 29) and secondary ILD (n = 43) [CVD-ILD (n = 39), CHP (n = 4)]. In CVD-ILD, rheumatoid arthritis (n = 17) was most common. The 90-day mortality after AE was 57% in IPF, 29% in non-IPF IIPs, and 33% in secondary ILD. After AE, ILD other than IPF had a significantly better survival rate than IPF (P < 0.001). Among survivors, the rates of patients requiring LTOT after AE were 63% in IPF, 35% in non-IPF IIPs, and 46% in secondary ILD, respectively.

Conclusions: AE of ILD other than IPF might have a better prognosis than AE-IPF, but both are fatal conditions that cause chronic respiratory failure.
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http://dx.doi.org/10.1111/crj.13304DOI Listing
March 2021

[Lung Metastasis from Alpha-Fetoprotein Resulting in Esophagogastric Junction Cancer-A Case Report].

Gan To Kagaku Ryoho 2020 Sep;47(9):1367-1369

Dept. of Surgery, Miyoshi Central Hospital.

A 51-year-old male underwent total gastrectomy for esophagogastric junction cancer(T3N0M0, Stage ⅡA). He was diagnosed with an alpha-fetoprotein(AFP) producing tumor and hepatoid adenocarcinoma. One month after radical surgery, computed tomography(CT) showed lung metastasis, and the patient's serum AFP level was high. He underwent chemotherapy( S-1 and wPTX/RAM)and eventually died 4 months after surgery.
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September 2020

Reverse Genetics Approach for Developing Rotavirus Vaccine Candidates Carrying VP4 and VP7 Genes Cloned from Clinical Isolates of Human Rotavirus.

J Virol 2020 12 22;95(2). Epub 2020 Dec 22.

Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Species A rotaviruses (RVs) are a leading cause of severe acute gastroenteritis in infants and children younger than 5 years. Currently available RV vaccines were adapted from wild-type RV strains by serial passage of cultured cells or by reassortment between human and animal RV strains. These traditional methods require large-scale screening and genotyping to obtain vaccine candidates. Reverse genetics is a tractable, rapid, and reproducible approach to generating recombinant RV vaccine candidates carrying any VP4 and VP7 genes that provide selected antigenicity. Here, we developed a vaccine platform by generating recombinant RVs carrying VP4 (P[4] and P[8]), VP7 (G1, G2, G3, G8, and G9), and/or VP6 genes cloned from human RV clinical samples using the simian RV SA11 strain (G3P[2]) as a backbone. Neutralization assays using monoclonal antibodies and murine antisera revealed that recombinant VP4 and VP7 monoreassortant viruses exhibited altered antigenicity. However, replication of VP4 monoreassortant viruses was severely impaired. Generation of recombinant RVs harboring a chimeric VP4 protein for SA11 and human RV gene components revealed that the VP8* fragment was responsible for efficient infectivity of recombinant RVs. Although this system must be improved because the yield of vaccine viruses directly affects vaccine manufacturing costs, reverse genetics requires less time than traditional methods and enables rapid production of safe and effective vaccine candidates. Although vaccines have reduced global RV-associated hospitalization and mortality over the past decade, the multisegmented genome of RVs allows reassortment of VP4 and VP7 genes from different RV species and strains. The evolutionary dynamics of novel RV genotypes and their constellations have led to great genomic and antigenic diversity. The reverse genetics system is a powerful tool for manipulating RV genes, thereby controlling viral antigenicity, growth capacity, and pathogenicity. Here, we generated recombinant simian RVs (strain SA11) carrying heterologous VP4 and VP7 genes cloned from clinical isolates and showed that VP4- or VP7-substituted chimeric viruses can be used for antigenic characterization of RV outer capsid proteins and as improved seed viruses for vaccine production.
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http://dx.doi.org/10.1128/JVI.01374-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944460PMC
December 2020

Diffusivity and Structure of Room Temperature Ionic Liquid in Various Organic Solvents.

J Phys Chem B 2020 Nov 21;124(44):9931-9937. Epub 2020 Oct 21.

U.S. DOE Ames Laboratory, Ames, Iowa 50011, United States.

Room-temperature ionic liquids (RTILs) hold promise for applications in electric double layer capacitors (EDLCs), owing to a much wider potential window, lower vapor pressure, and better thermal and chemical stabilities compared to conventional aqueous and organic electrolytes. However, because the low diffusivity of ions in neat RTILs negates the EDLCs' advantage of high power density, the ionic liquids are often used in mixture with organic solvents. In this study, we measured the diffusivity of cations and anions in RTIL, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) ([BMIM][TFSI]), mixed with 10 organic solvents, by using the pulsed-field gradient NMR method. The ion diffusivity was found to follow that of neat solvents and in most studied solvents showed an excellent agreement with the predicted values reported in the recent molecular dynamics (MD) study [Thompson, M. W.; 2019, 123, 1340-1347]. In two solvents consisting of long-chain molecules, however, the MD simulations predictions slightly underestimated the ionic diffusivities. The degree of ion dissociation was also estimated for each solvent by comparing the ionic conductivity with the molar conductivity derived from the diffusion measurements. The degree of ion dissociation and the hydrodynamic radius of ions suggest that the ions are coordinated by ∼1 solvent molecule. The scarcity of solvent-ion interactions explains the fact that the diffusivity of ions in the mixture significantly depends on the viscosity of the solvent.
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http://dx.doi.org/10.1021/acs.jpcb.0c07582DOI Listing
November 2020

Construction and characterization of an infectious clone generated from Chikungunya virus SL11131 strain.

Virology 2021 Jan 6;552:52-62. Epub 2020 Oct 6.

Department of Microbiology and Infection Control, Osaka Medical College, Takatsuki, Japan.

Chikungunya virus (CHIKV) is a mosquito-borne RNA virus that causes Chikungunya fever in humans. In this study, we generated two DNA-based CHIKV infectious clones derived from an Indian Ocean Lineage SL11131 strain and a prototype Ross strain. When the replication capabilities of the infectious CHIKV in various cell lines were evaluated, the SL11131 strain was found to replicate more efficiently than the Ross strain in Aedes albopictus C6/36 cells, whereas SL11131 underwent limited replication in a BHK-21-derivative cell line named BHK-DRV. Infection experiments using chimeric CHIKV between SL11131 and Ross revealed that these different replication activities of SL11131 in C6/36 and BHK-DRV cells were determined by structural and nonstructural genes, respectively. Therefore, the infectious clones created in this study will be a useful tool for investigating the virological features of a recent epidemic strain of CHIKV and benefit the development of effective prevention and treatment of CHIKV infection.
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http://dx.doi.org/10.1016/j.virol.2020.09.006DOI Listing
January 2021