4T1乳がんに起因して起こる宿主肝臓の炎症には血清アミロイドαは不要である

京都大学新制・課程博士博士(医学)甲第24800号医博第4992号新制||医||1067(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 伊藤 貴浩, 教授 波多野 悦朗, 教授 妹尾 浩学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Development of computational methods for immune repertoire analysis : from sequence to specificity

The immune system plays a key role in maintaining human health. Accurately characterizing the immune receptors with immune repertoire sequencing (IRseq) provides an essential way for understanding the adaptive immune system. Towards this goal, we developed a bioinformatics tool, Molecular Identifier Clustering-based IR-Seq (MIDICRS), to quantitatively measure immune repertoire. We have demonstrated MIDCIRS’ accuracy, high coverage and wide dynamic range, which allow us to analyze various types of immune repertoires. Immune repertoire is continuously shaped by encountered antigens; thus, its components reflect an individual’s historical disease status. We applied MIDCIRS to measure the antibody repertoire from malaria-experienced individuals and found unexpected mutable capability of infants adaptive immune system. We also used MIDCIRS to measure Follicular helper T cells (Tfhs) directly obtained from untreated HIV patients’ lymph nodes and found (1) evidence for intact antigen-driven clonal expansion of Tfh cells and (2) selective utilization of specific complementarity-determining region 3 (CDR3) motifs during chronic HIV infection. Both studies demonstrated MIDCIRS functionality and versatility for studying antigen driven immune response. Bridging the gap between immune receptor sequences and their biological function (i.e. antigen specificity) is attractive and useful for directly measuring immune repertoire changes with respect to pathogen infection. Using experimentally validated CD8+ TCR sequences with their antigen specificity, we developed a computational tool, Linear programming based Motif Pick and Enrichment analysis for Tcrs (LiMPETs), to find significant motifs within the TCR CDR3 region for determining antigen specificity. We demonstrated LiMPETs’ advantages by comparing with existing tools on both public and in-house dataBiomedical Engineerin

Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells

がん治療薬による乳がん細胞の老化とpH調整の解明 --新規細胞老化のメカニズム解明に貢献--. 京都大学プレスリリース. 2023-11-27.Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy

Serum amyloid alpha 1-2 are not required for liver inflammation in the 4T1 murine breast cancer model

がんに起因して起こる宿主の肝臓の急性期応答と炎症 --血清アミロイドαは乳がんモデルにおける肝臓の炎症の原因ではない--. 京都大学プレスリリース. 2023-02-06.Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly in vivo. Here, we investigate the in vivo significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require Saa1-2. This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model

Comparing levonorgestrel intrauterine system versus hysteroscopic resection in patients with postmenstrual spotting related to a niche in the caesarean scar (MIHYS NICHE trial) : Protocol of a randomised controlled trial

Funding This work was supported by National Key Research and Development Programme (2018YFC1002102), Research Project of Shanghai Health and Fitness Commission (201940012,20184Y0344)),Shanghai Municipal Key Clinical Specialty (shslczdzk01802), Medical Engineering Cross Funds from Shanghai Jiao Tong University (YG2017QN38, ZH2018QNA36, YG2021ZD31), Medical innovation research project of the 2020 'Science and Technology Innovation Action Plan' of Shanghai Science and Technology Commission (20Y11907700), and Clinical Science and Technology Innovation Project of Shanghai Hospital Development Center(SHDC22020216).Peer reviewedPublisher PD

Murine breast cancers disorganize the liver transcriptome in a zonated manner

がんが宿主の臓器に及ぼす悪影響を捉えた --がんをもつ個体における「肝機能の空間的制御」の破綻--. 京都大学プレスリリース. 2023-02-01.The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver

Surface orientation of hydrophilic groups in sulfonated poly(ether ether ketone) membranes

Sulfonated poly(ether ether ketone) copolymers (SPEEK) with a range of sulfonate contents (SC 77\u201351%) were synthesized via nucleophilic substitution polycondensation from hydroquinone and sulfonated hydroquinone. Membranes obtained by solvent casting from dimethylacetamide onto glass surfaces were analyzed for surface behavior. The surfaces of a membrane were hydrophobic in air, but hydrophilic in water. This surface behavior was corroborated by water contact angle vs. time, using sessile drop measurements. Hydrophilic sulfonic group aggregates on SPEEK chain and various media contacting with the top or bottom surfaces of the membrane during the fabrication process caused differences in surface behavior. Angle-dependent XPS showed that there was a higher atomic S/C ratio of the bottom surface than on the corresponding top surface. The hydrophilic sulfonic groups were in higher concentration within the membrane, with the concentration gradually decreasing towards the surface for SPEEK-HQ-80 and SPEEK-HQ-70 membranes. Acidification with strong acid and higher temperature induced a more hydrophilic surface on a membrane than a milder acidification process. The depth profile at the membrane surface was examined by a combination of contact angle, XPS and ATR-FTIR.Peer reviewed: YesNRC publication: Ye

Completely mitochondrial genome of Neolissochilus heterostomus

In this study, we determined the complete mitochondrial genome of Neolissochilus heterostomus. The genome is 16,585 bp in length, including 2 ribosomal RNA genes, 13 proteins-coding genes, 22 transfer RNA genes, and two non-coding control regions. Sequence analysis showed that the overall base composition of N. heterostomus is T 24.8%, C 27.7%, A 31.7%, and G 15.8%. The sequence is a slight A + T bias of 56.5%, which is similar to other fishes. We describe a phylogenetic analysis of 16 species of Cypriniformes based on the complete mitochondrial genome, and the result showed that N. stracheyi is most closely related to N. heterostomus. This mitogenome sequence data would play an important role in the investigation of phylogenetic relationship of the Cyprinidae