Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway.

Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway.

Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation.

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis.

Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producing cells facilitates de novo infection.

Background: Viruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, release extracellular vesicles such as exosomes containing proteins and miRNAs, and use these vesicles to mediate intercellular communication. However, the roles of exosomes in viral infection remain unclear.

[Complete remission after standard induction therapy in a patient with acute myeloid leukemia associated with double-minute chromosomes].

Acute myeloid leukemia (AML) associated with double-minute chromosomes (dmin) is a rare condition and has a poor prognosis. A 68-year-old man with leukocytosis and thrombocytopenia was admitted to our hospital. Bone marrow aspiration showed that 79.

Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.

BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.

Intrapatient variability in concentration/dose ratio of tacrolimus predicts transplant-associated thrombotic microangiopathy.

Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous.

Clinical usefulness of diagnostic criteria for transplant-associated thrombotic microangiopathy.

One major cause of treatment-related death is transplant-associated thrombotic microangiopathy (TA-TMA). Because of difficulties with diagnosis, many criteria for TA-TMA have been defined. Some patients clinically suspected as TA-TMA have been treated as TA-TMA regardless of TA-TMA criteria fulfillment (clinical-TMA).

Permanent Impairment-Free, Relapse-Free Survival: A Novel Composite Endpoint to Evaluate Long-Term Success in Allogeneic Transplantation.

Permanent impairment (PI) of vital organs is one of the transplantation-related health problems affecting the quality of life and morbidity even in patients who do not develop graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT), but no data are available on PI of multiple organs. This retrospective study aimed to estimate a novel composite endpoint of PI-free, relapse-free survival (PIRFS) in 164 allo-HCT recipients. We defined PI as >26% to 30% impairment of the whole person in 6 vital organs using the whole person impairment rating.

Two-photon microscopic observation of cell-production dynamics in the developing mammalian neocortex in utero.

Morphogenesis and organ development should be understood based on a thorough description of cellular dynamics. Recent studies have explored the dynamic behaviors of mammalian neural progenitor cells (NPCs) using slice cultures in which three-dimensional systems conserve in vivo-like environments to a considerable degree. However, live observation of NPCs existing truly in vivo, as has long been performed for zebrafish NPCs, has yet to be established in mammals.

Impact of a Nutritional Risk Index on Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Nutritional status is an important component of cancer care, and malnutrition itself can cause death in 10% to 20% of cancer patients. A nutritional risk index (NRI) is a useful tool for nutritional assessment of cancer patients. This study aimed to evaluate the impact of pretransplant NRI values on outcomes of allogeneic hematopoietic cell transplantation (allo-HSCT).

Patterns of onset and outcome of cryptogenic organizing pneumonia after allogeneic hematopoietic stem cell transplantation.

Cryptogenic organizing pneumonia (COP) after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by frequent recurrence. Few studies have examined onset and recurrence patterns of COP after HSCT. We investigated the clinical features of COP after HSCT in a single-center retrospective study including 165 consecutive patients who underwent allogeneic HSCT.

Optimal dosage of methotrexate for GVHD prophylaxis in umbilical cord blood transplantation.

The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. In the present study, we investigated the impact of MTX dosage on clinical outcomes following UCBT in a single-center retrospective study.

Decline of forced expiratory volume in 1 s after allogeneic hematopoietic cell transplantation is a good indicator for pulmonary damage and is associated with busulfan use.

Reduced pulmonary function is commonly observed after allogeneic hematopoietic stem cell transplantation (HSCT); however, its relationship with the development of noninfectious pulmonary complications (NIPCs) is unclear, and the impact of changes in pulmonary function test (PFT) values on HSCT outcome remains controversial. We conducted a retrospective study including 150 patients to investigate changes in PFTs and impact on clinical outcome. PFT data at around 1 year after HSCT were available in 84 patients, and showed a significant time-dependent decline in percentage predicted forced expiratory volume in 1 s and other parameters.

Promising Outcome of Umbilical Cord Blood Transplantation in Patients with Multiple Comorbidities.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group).

Acute Megakaryoblastic Leukemia Developing as Donor Cell Leukemia after Umbilical Cord Blood Transplantation.

A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts.

Neurogenin2-d4Venus and Gadd45g-d4Venus transgenic mice: visualizing mitotic and migratory behaviors of cells committed to the neuronal lineage in the developing mammalian brain.

To achieve highly sensitive and comprehensive assessment of the morphology and dynamics of cells committed to the neuronal lineage in mammalian brain primordia, we generated two transgenic mouse lines expressing a destabilized (d4) Venus controlled by regulatory elements of the Neurogenin2 (Neurog2) or Gadd45g gene. In mid-embryonic neocortical walls, expression of Neurog2-d4Venus mostly overlapped with that of Neurog2 protein, with a slightly (1 h) delayed onset. Although Neurog2-d4Venus and Gadd45g-d4Venus mice exhibited very similar labeling patterns in the ventricular zone (VZ), in Gadd45g-d4Venus mice cells could be visualized in more basal areas containing fully differentiated neurons, where Neurog2-d4Venus fluorescence was absent.

TAG-1-assisted progenitor elongation streamlines nuclear migration to optimize subapical crowding.

Neural progenitors exhibit cell cycle-dependent interkinetic nuclear migration (INM) along the apicobasal axis. Despite recent advances in understanding its underlying molecular mechanisms, the processes to which INM contributes mechanically and the regulation of INM by the apicobasally elongated morphology of progenitors remain unclear. We found that knockdown of the cell-surface molecule TAG-1 resulted in retraction of neocortical progenitors' basal processes.

Improved orange and red Ca²± indicators and photophysical considerations for optogenetic applications.

We have used protein engineering to expand the palette of genetically encoded calcium ion (Ca(2+)) indicators to include orange and improved red fluorescent variants, and validated the latter for combined use with optogenetic activation by channelrhodopsin-2 (ChR2). These indicators feature intensiometric signal changes that are 1.7- to 9.

Herpes simplex virus 1 VP22 regulates translocation of multiple viral and cellular proteins and promotes neurovirulence.

Herpes simplex virus 1 (HSV-1) protein VP22, encoded by the UL49 gene, is a major virion tegument protein. In the present study, we showed that VP22 was required for efficient redistribution of viral proteins VP16, VP26, ICP0, ICP4, and ICP27 and of cellular protein Hsc-70 to the cytoplasm of infected cells. We found that two dileucine motifs in VP22, at amino acids 235 and 236 and amino acids 251 and 252, were necessary for VP22 regulation of the proper cytoplasmic localization of these viral and cellular proteins.

Nucleolin is required for efficient nuclear egress of herpes simplex virus type 1 nucleocapsids.

Herpesvirus nucleocapsids assemble in the nucleus and must cross the nuclear membrane for final assembly and maturation to form infectious progeny virions in the cytoplasm. It has been proposed that nucleocapsids enter the perinuclear space by budding through the inner nuclear membrane, and these enveloped nucleocapsids then fuse with the outer nuclear membrane to enter the cytoplasm. Little is known about the mechanism(s) for nuclear egress of herpesvirus nucleocapsids and, in particular, which, if any, cellular proteins are involved in the nuclear egress pathway.

Effects of phosphorylation of herpes simplex virus 1 envelope glycoprotein B by Us3 kinase in vivo and in vitro.

We recently reported that the herpes simplex virus 1 (HSV-1) Us3 protein kinase phosphorylates threonine at position 887 (Thr-887) in the cytoplasmic tail of envelope glycoprotein B (gB) (A. Kato, J. Arii, I.

Regulation of the catalytic activity of herpes simplex virus 1 protein kinase Us3 by autophosphorylation and its role in pathogenesis.

Us3 is a serine/threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). We recently identified serine at Us3 position 147 (Ser-147) as a physiological phosphorylation site of Us3 (A. Kato, M.