Clonal origin of Epstein-Barr virus-infected T/NK-cell subpopulations in chronic active Epstein-Barr virus infection

Clonal expansion of Epstein-Barr virus (EBV) infected B-cells occasionally occurs in immunocompromized subjects. EBV-infected T/natural killer (NK)-cells proliferate in patients with chronic active EBV infection (CAEBV) that is a rare mononucleosis syndrome. It is classified into either T-cell type or NK-cell type according to the primary target of infection, while the pathogenesis remains unclear. To search the clonal origin of EBV-infected T/NK-cells, virus distribution and clonotype were assessed by using highly purified cell fractions obtained from 6 patients. Patient 1 had a monoclonal proliferation of EBV-infected T-cell receptor Vδ2/Vγ9-expressing cells, and carried lower copy number of EBV in αβT-cells. Patients 2 and 3 had a clonal expansion of EBV-infected CD4+T-cells, and lower EBV load in CD56+cells. Patients 4, 5 and 6 had an expansion of CD56+cells with higher EBV load than CD3+cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in major subsets of 4 patients. However, EBV was not detected in bone marrow-derived lineage negative CD34+cells of patients. These results suggested that EBV could infect T/NK-cells at differentiation stage, but spared bone marrow CD34+hematopoietic stem cells in CAEBV patients

Design and synthesis of dinuclear bismuth(III) complexes with potent ribonuclease-like activity

Several metal complexes with ribonuclease-like activity have been developed as chemical biology tools for RNA regulation. However, their RNA-cleavage activity is insufficient under physiological conditions. Here, we have identified novel dinuclear bismuth(III) complexes that contain dipyridine/dipicolinate-based ligands as artificial ribonucleases to induce efficient RNA cleavage. Our optimization studies of the ligand structure indicated that the dipyridine/dipicolinate scaffold of the ligands plays a key role in maintaining the dinuclear arrangement of the bismuth(III) centers and tuning the Lewis acidity of the bismuth(III) ions to achieve potent RNA-cleavage activity. The mechanistic analysis of the RNA-cleavage reaction suggested that cooperative activation of a phosphate group in RNAs and water molecules coordinated by two bismuth(III) centers results in a rapid nucleophilic attack of the 2′-hydroxy group of a ribose to the phosphate and facilitates the removal of a 5′-alkoxide by protonation to generate a 2′,3′-cyclic phosphate and a 5′-hydroxy product. Thus, the developed dinuclear bismuth(III) complexes represent promising tools for chemical biology studies

Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

Yosuke Ota, Yukihiro Itoh, Takashi Kurohara, Ritesh Singh, Elghareeb E. Elboray, Chenliang Hu, Farzad Zamani, Anirban Mukherjee, Yuri Takada, Yasunobu Yamashita, Mie Morita, Mano Horinaka, Yoshihiro Sowa, Mitsuharu Masuda, Toshiyuki Sakai, and Takayoshi Suzuki. ACS Medicinal Chemistry Letters 2022 13 (10), 1568-1573. DOI: 10.1021/acsmedchemlett.2c00126. Copyright © 2022 American Chemical Society.Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1, 9, and 32, conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs

Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1, 9, and 32, conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.Yosuke Ota, Yukihiro Itoh, Takashi Kurohara, Ritesh Singh, Elghareeb E. Elboray, Chenliang Hu, Farzad Zamani, Anirban Mukherjee, Yuri Takada, Yasunobu Yamashita, Mie Morita, Mano Horinaka, Yoshihiro Sowa, Mitsuharu Masuda, Toshiyuki Sakai, and Takayoshi Suzuki. ACS Medicinal Chemistry Letters 2022 13 (10), 1568-1573. DOI: 10.1021/acsmedchemlett.2c00126. Copyright © 2022 American Chemical Society

Response of a Micro Pixel Chamber to heavy ions with the energy of several hundreds of MeV/n

Beam tests were performed for a Micro Pixel Chamber (m-PIC) with a detection volume of 10 x 10 x 10 cm3 to investigate the response to heavy ions. The three dimensional tracks of carbon, silicon, and iron beams were successfully observed and their track lengths were measured. Additionally, Linear Energy Transfer (LET) distributions of each ion were obtained, and the mean LET values were consistent with the theoretical calculation of mass stopping power within an error of ~10%. This detector is a candidate for an ideal dosimeter in space