Rituximab-combination chemotherapy achieves a 10th cycle of remission for Burkitt's lymphoma.

A 14-year-old girl with multiple intra-abdominal tumors was diagnosed with stage III Burkitt's lymphoma. She achieved complete remission after multi-drug chemotherapy, but she relapsed after six courses. Autologous peripheral blood stem cells (PBSC) or allogeneic PBSC harvested from an HLA-identical sibling were insufficient, and her family did not agree to bone marrow collection from the sibling. Although the patient relapsed nine times (the relapses involved intra-abdominal organs or bone) during the following 4 years 7 months, treatment with rituximab monotherapy or in combination with ifosphamide, carboplastin, and etoposide, or local irradiation (33.8-40.0 Gy) to treat the bone metastases, proved effective, resulting in complete or partial remission. At the time of writing, the patient was in a 10th cycle of remission lasting 1 year 6 months and had not required transplantation. Thus, a chemotherapy regimen including rituximab might be effective for Burkitt's lymphoma in patients experiencing multiple relapse

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

3\u27-Phosphoadenosine 5\u27-Phosphosulfate Transporter (PAPST) Enhanced Sulfation of Keratan Sulfate Proteoglycan to Reduce Radiation-Induced Apoptosis in a Human Burkitt Lymphoma Cell Line

[Objectives] Sulfation of various molecules plays an essential role in biological and pathological processes.Two members of 3\u27-Phosphoadenosine 5\u27-phosphosulfate transporters (PAPSTs), PAPST1 and PAPAT2, arecurrently identified in humans. However, the influence of sulfate transporter on radiosensitvity of malignanttumors remains unknown. This study aimed at clarifying the role of sulfate transporter in radiation-inducedapoptosis of lymphoma cells.[Methods] A human Burkitt\u27 s lymphoma cell line, Namalwa, was transfected with an expression vector ofhuman PAPST1 or PAPST2, or siRNA targeted against each PAPST. Apoptosis was evaluated by Hoechst 33258staining 24 h after irradiation with X-rays or C-ion.[Results] The level of PAPST1 transcripts was approximately 5-fold higher than that of PAPST2 in Namalwacells. Overexpression of each PAPST reduced radiation-induced apoptosis, whereas the repression of PAPSTexpression enhanced apoptosis. In contrast, keratan sulafate proteoglycan (KSPG) was expressed on the cellsurface of Namalwa cells, and depletion of KS with keratanase significantly increased radiation-inducedapoptosis. Three (CHST2, 6, and 7) of five sulfotransferases involved in KS synthesis were expressed inNamalwa cells and the sulfation catalyzed by all three sulfotransferases promoted anti-apoptotic effects ofKSPG. PAPST1 enhanced phosphorylation of p38 MAPK and Akt in Namalwa cells, whereas inhibition of p38MAPK or PI-3K increased radiation-induced apoptosis.[Conclussions] PAPST inhibited radiation-induced apoptosis through sulfation of KSPG. These findingssuggest that KSPG plays an important role in anti-apoptotic signaling in human Burkitt\u27 s lymphoma, and PAPSTis useful to increase the efficacy of radiotherapy and decrease side effects through the regulation of KSPG.The 2nd Japan-China Symposium on Cancer Researc

Development of Training Games of Physical Posture for People with Developmental Disorders

Abstract—This paper describes two prototypes of training games of physical posture adaptive for people with developmental disorders. Two types of games are developed and their prototypes are produced. One is a game for exercise user’s body posture control. The other is a simulator of holding some object horizontally. Though it is said that ASD people generally have resistance against new, inexperienced items, all of the ASD subjects are interested in the games without refusal. This fact is considered to be an effective utilization of attraction and diffusing potential that games have.

Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in human Burkitt\u27s lymphoma cell lines

This study focuses on clarifying the contribution of sulfation to radiation-induced apoptosis in human Burkitt\u27s lymphoma cell lines, using 3\u27-phosphoadenosine 5\u27-phosphosulfate transporters (PAPSTs). Overexpression of PAPST1 or PAPST2 reduced radiation-induced apoptosis in Namalwa cells, whereas the repression of PAPST1 expression enhanced apoptosis. Inhibition of PAPST slightly decreased keratan sulfate (KS) expression, so that depletion of KS significantly increased radiation-induced apoptosis. In addition, the repression of all three N-acetylglucosamine-6-O-sulfotransferases (CHST2, CHST6, and CHST7) increased apoptosis. In contrast, PAPST1 expression promoted the phosphorylation of p38 MAPK and Akt in irradiated Namalwa cells. These findings suggest that 6-O-sulfation of GlcNAc residues in KS reduces radiation-induced apoptosis of human Burkitt\u27s lymphoma cells

Sla1, a Schizosaccharomyces pombe Homolog of the Human La Protein, Induces Ectopic Meiosis when Its C Terminus Is Truncated

Sla1 is a Schizosaccharomyces pombe homolog of the human La protein. La proteins are known to be RNA-binding proteins that bear conserved RNA recognition motifs (La and RRMs), but their biological functions still have not been fully resolved. In this study, we show that the S. pombe La homolog (Sla1) is involved in regulating sexual development. Sla1 truncated in the C terminus (Sla1ΔC) induced ectopic sporulation in the ras1Δ strain and several other sporulation-deficient mutants. The C terminus contains a nuclear localization signal. While full-length Sla1 localizes in the nucleus, Sla1ΔC is found throughout the cell, suggesting the cytoplasmic localization of Sla1ΔC is involved in its sporulation-inducing activity. Further deletion analysis of Sla1 indicated that a small region (35 amino acids) that includes a portion of RRM2 is sufficient to induce sporulation. The La motif (RRM1) is not involved in this activity. Strikingly, Sla1ΔC induced haploid meiosis in a heterothallic strain, similar to the pat1-114 or mei2-SATA mutation. Sla1ΔC induced sporulation in a mei3 disruptant but not in a mei2 disruptant, indicating that Sla1ΔC requires Mei2 to induce haploid meiosis. Deletion of the chromosomal sla1 gene lowered the temperature sensitivity of the pat1-114 mutant. Two-hybrid analysis indicated that Pat1 interacts with Sla1ΔC but not full-length Sla1. Thus, Sla1ΔC may block Pat1 activity. This block would remove the inhibition on Mei2, which would then drive the cell into haploid meiosis. Finally, Sla1 was degraded prior to the start of meiosis when we monitored Sla1 in cells in which meiosis was synchronously induced. The ability of truncated Sla1 to induce ectopic meiosis represents a very novel function that has hitherto not been suspected for the La family of proteins

Crystallographic Analysis of Phase Dissociation Related to Anomalous Solubility of Irsogladine Maleate

We report the anomalous solubility of the pharmaceutical salt irsogladine maleate, which is associated with phase dissociation. The anomalous solubility was demonstrated by the similarity of solubility and miscibility between the salt and its base in ethanol solvent. The phase dissociation was revealed and confirmed by distinguishing irsogladine maleate and its free base using single-crystal X-ray analysis. Herein, the crystal structures of irsogladine maleate and its base were reported for the first time, and the plausible mechanism for phase dissociation was established based on the structural correlations between those phases