Extracellular vesicles synchronize cellular phenotypes of differentiating cells

細胞外小胞が細胞の分化を同調させる現象の発見. 京都大学プレスリリース. 2021-10-01.Cells act in unison when next to each other. 京都大学プレスリリース. 2021-10-01.During embryonic development, cells differentiate in a coordinated manner, aligning their fate decisions and differentiation stages with those of surrounding cells. However, little is known about the mechanisms that regulate this synchrony. Here we show that cells in close proximity synchronize their differentiation stages and cellular phenotypes with each other via extracellular vesicle (EV)-mediated cellular communication. We previously established a mouse embryonic stem cell (ESC) line harbouring an inducible constitutively active protein kinase A (CA-PKA) gene and found that the ESCs rapidly differentiated into mesoderm after PKA activation. In the present study, we performed a co-culture of Control-ESCs and PKA-ESCs, finding that both ESC types rapidly differentiated in synchrony even when PKA was activated only in PKA-ESCs, a phenomenon we named ‘Phenotypic Synchrony of Cells (PSyC)’. We further demonstrated PSyC was mediated by EVs containing miR-132. PKA-ESC-derived EVs and miR-132-containing artificial nano-vesicles similarly enhanced mesoderm and cardiomyocyte differentiation in ESCs and ex vivo embryos, respectively. PSyC is a new form of cell-cell communication mediated by the EV regulation of neighbouring cells and could be broadly involved in tissue development and homeostasis

Diminished Gastric Resection Preserves Better Quality of Life in Patients with Early Gastric Cancer

Using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, we compared the surgical outcomes and the quality of life (QOL) between patients undergoing limited gastrectomies and those undergoing conventional gastrectomies. In Oomoto Hospital between January 2004 and December 2013, a total of 124 patients who met the eligibility criteria were enrolled. Using the main outcome measures of PGSAS-45, we compared 4 types of limited gastrectomy procedures (1/2 distal gastrectomy [1/2DG] in 21 patients; pylorus-preserving gastrectomy [PPG] in 15 patients; segmental gastrectomy [SG] in 26 patients; and local resection [LR] in 13 patients) with conventional gastrectomy (total gastrectomy [TG] in 24 patients and 2/3 or more distal gastrectomy [WDG] in 25 patients). The TG group showed the worst QOL in almost all items of the main outcome measures. The 1/2DG, PPG, and SG groups showed better QOL than the WDG group in many of the main outcome measures, including the body weight ratio, total symptom score, ingested amount of food per meal, and the dissatisfaction for daily life subscale. The LR group showed a better intake of food than the 1/2DG, PPG, and SG groups. The body weight ratio of the LR group was better than that of the SG group. Diminished gastric resection preserved better QOL in patients with early gastric cancer

胃癌におけるクローディン4標的化によるシスプラチン化学療法感受性の向上

Claudins are major tight-junction proteins that mediate cellular polarity and differentiation. The present study investigated whether the 4D3 antibody to the human CLDN4 extracellular domain (that we previously established) is capable of modulating chemotherapeutic sensitivity in gastric cancer (GC). The results of the present study showed that CLDN4 was overexpressed in 137 of the 192 analyzed GC cases, and that CLDN4 expression was retained in tumors of a lower histological grade (more differentiated), and/or those that were caudal-type homeobox protein 2 (CDX2)-positive, but was reduced in more highly undifferentiated, and CDX2-negative GC cases. The study also compared the synergic effects of combining 4D3 with CDDP treatment and knocking down CLDN4 expression in MKN74 and TMK-1 human GC cells. Co-treatment with 4D3 increased anti-tumor effects of CDDP, whereas CLDN4 knockdown did not. In the TMK-1 cells, non-tight junction CLDN4 associated with integrin β1, increasing stem cell-associated proteins via FAK-c-SRC signals. The anti-tumoral effect of CDDP and 4D3 was examined in a nude mouse subcutaneous tumor model. In the two GC cell lines, concurrent treatment with 4D3 and CDDP synergistically inhibited cell proliferation and increased tumor necrosis and apoptosis to a greater degree than CDDP treatment alone. These findings suggest that 4D3 might increase chemotherapeutic sensitivity by evoking structural disintegration of tight-junction CLDN4 expressed in gastric cancer.博士（医学）・甲第713号・令和元年6月26日Copyright: Nishiguchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor

Targeted therapies for malignant melanoma have improved patients’ prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma

Effect of Environmental Change while Climbing Mt. Daisen on Forced Vital Capacity and Forced Expiratory Volume % in Young Women

The aim of the present study was to clarify the effects of environmental change while climbing Mt. Daisen on forced vital capacity and forced expiratory volume % in young women in summer. Seven healthy Japanese women (age: 22.6 ± 4.2 years) volunteered to climb Mt. Daisen (1,709m), located in Tottori prefecture, in August. Participants\u27 expiratory forced vital capacity (FVC), forced expiratory volume % (FEV_%) and arterial oxygen saturation (SpO_2) were measured at 4 points (Ground: 10m, Rest point: 780m, Summit: 1,709m, Goal point: 780m). The measurements were conducted soon after the subjects\u27 arrival at each point. The degree of dyspnea sensation was measured at Ground, Rest point, Goal point and at each station. There were no significant changes in FVC. FEV_% at the summit was significantly lower than at the Ground and Rest point. No significant differences were found in SpO_2 at each measuring point. The degree of dyspnea sensation at each station soon after the subjects\u27 arrival was significantly higher than those at the Rest point. The results of this study indicated mild airway contraction induced by stresses on the respiratory system from increasing exercise intensity during an ascent of Mt. Daisen

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPDX (capecitabine +OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p <0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p <0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing

ADAR1 is a promising risk stratification biomarker of remnant liver recurrence after hepatic metastasectomy for colorectal cancer

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy