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記述言語：英語   出版者・発行元：Surgery Today  

Purpose: Lynch syndrome (LS), the most common hereditary colorectal cancer (CRC), is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite instability-high (MSI-H) tumors. Lynch-like syndrome (LL) exhibits MSI-H and MMR deficiency, but lacks identifiable germline MMR mutations. Although LS/LL CRCs share clinical and molecular features, they are distinct from sporadic MSI-H (SM) CRCs, emphasizing the need for refined molecular classification. This study investigated the somatic alterations that distinguish LS/LL CRC from SM CRC. Methods: Whole-exome sequencing (WES) was performed on 49 LS/LL CRC and 96 SM CRC samples. Tumor-normal paired data were analyzed using GATK and MuTect2 to detect somatic variants. Mutation frequencies were compared using Fisher’s exact test (p < 0.005). Logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate the discriminatory performance. Results: We identified 11 gene regions that were significantly enriched in LS/LL CRC, including KRAS, ITGB3BP, CLEC16A, ARHGEF28, PIK3CA, and RBM26. A variant panel based on these alterations showed an area under the curve (AUC) of 0.85 and an Akaike information criterion of 129.81. Conclusions: These findings support the utility of LS/LL-specific somatic variants in stratifying MSI-H CRCs and identifying hereditary cases for personalized management.

DOI： 10.1007/s00595-025-03212-w

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記述言語：英語  

DOI： 10.1245/s10434-025-17955-w

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記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Programmed cell death ligand 1 (PD-L1) expression within the tumor microenvironment (TME) is a key predictor of immune checkpoint inhibitor (ICI) efficacy in esophageal squamous cell carcinoma (ESCC). Chemotherapy-induced modulation of the TME, particularly through some immune cells including tumor-associated macrophages, may influence PD-L1 expression and impact treatment outcomes. Patients and Methods: A retrospective analysis was conducted on 241 patients with ESCC, with or without preoperative chemotherapy, who underwent curative esophagectomy at our single institute, Kyushu University. Propensity score matching accounted for clinical factors. Immunohistochemistry evaluated PD-L1, PD-L2, HLA class I, CD8, and CD68 expression. RNA sequencing data from 92 patients with ESCC from the cancer genome atlas underwent TME deconvolution analysis. In vitro experiments utilized ESCC cell lines, THP-1-derived macrophages, and chemotherapeutics (5-fluorouracil, cisplatin, and docetaxel) to explore their effects on PD-L1 expression. Results: Chemotherapy-treated patients showed significantly elevated PD-L1 expression in tumor and interstitial cells. These patients also had increased peritumoral CD68-positive macrophage accumulation, correlating positively with tumor PD-L1 expression. In silico analysis pinpointed polarized macrophages as the primary immune cells linked to PD-L1 upregulation in the TME. In vitro, PD-L1 expression in tumor cells rose post-chemotherapy and further increased when co-cultured with activated macrophages, indicating a synergistic effect. Conclusions: Cytotoxic drugs and tumor-associated macrophages surge PD-L1 expression in ESCC, likely through cytokine-mediated pathways. This interaction suggests that integrating cytotoxic chemotherapy with macrophage activation may boost immune checkpoint inhibitor (ICI) efficacy, offering a viable strategy to optimize immunotherapy in ESCC.

DOI： 10.1245/s10434-025-17710-1

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記述言語：英語   出版者・発行元：Journal of Gastroenterology  

Background: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, which is often driven by chromosomal amplifications at 1q. Vacuolar sorting protein 45 (VPS45), a gene located on chromosome 1q, is involved in the endocytic recycling pathway; however, its role in HCC remains unclear. In this study, we aimed to investigate the functional significance of VPS45 in the progression of HCC. Methods: VPS45 expression was analyzed using public databases, clinical HCC samples, and cell lines. Functional assays, including VPS45 knockout and rescue experiments, were conducted to assess the effect on tumor progression in vitro and in vivo. The molecular mechanisms underlying VPS45 function, particularly its role in β1 integrin recycling and FAK-AKT signaling activation, were also explored. Results: VPS45 expression was significantly elevated in HCC owing to DNA copy number amplification and correlated with poor prognosis. Moreover, VPS45 knockout suppressed cell proliferation, migration, and invasion, while promoting apoptosis. VPS45 interacted with syntaxin16 and rabenosyn-5 to facilitate the recycling of β1 integrin to the cell membrane, thereby activating FAK-AKT signaling, which promotes oncogenic phenotypes. In xenograft models, VPS45 knockout significantly suppressed tumor growth, further supporting its role in HCC progression. Conclusions: VPS45 is a key oncogene in HCC that promotes tumor progression by enhancing β1 integrin recycling and activating FAK-AKT signaling. Given its strong association with poor prognosis and tumor malignancy, VPS45 may serve as a promising prognostic biomarker and a potential therapeutic target for HCC.

DOI： 10.1007/s00535-025-02278-0

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記述言語：英語   出版者・発行元：Cancer Science  

Polarity genes form intracellular protein complexes that establish epithelial cell polarity and homeostasis for various normal cellular functions. Partitioning Defective 6B (PARD6B), a polarity gene, functions as a scaffold node for the Par protein complex. However, its contribution to colon cancer is not well understood. In this study, we showed that PARD6B regulates tumor progression in colorectal cancer (CRC). PARD6B is located on chromosome 20, which is frequently amplified in CRC, and its expression in CRC correlates with DNA copy number amplification, including enhancer regions. Immunohistochemistry and single-cell analyses also showed that PARD6B expression was significantly higher in cancer cells. Furthermore, unlike other polarity gene groups comprising the Par complex, PARD6B mRNA expression was the only independent poor prognostic factor. In vitro and in vivo experiments revealed that PARD6B positively regulates cell proliferation and cell cycle progression. In silico analysis also showed that PARD6B expression positively regulated MYC expression, a pathway believed to be associated. Additional in silico and in vitro analyses supported the hypothesis that PARD6B regulates miR-34c, which directly targets and represses MYC expression. Pan-cancer analysis indicated that PARD6B is highly expressed in gastrointestinal tumors, including CRC, and that high PARD6B mRNA expression is a poor prognostic factor in other cancer types. In summary, highly expressed PARD6B can promote CRC growth by upregulating MYC expression while suppressing miR-34c expression, making PARD6B a potential prognostic biomarker and therapeutic target for CRC.

DOI： 10.1111/cas.70119

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記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide. The progression of HCC involves complex molecular mechanisms, including chromosomal amplification and alterations in pre-mRNA splicing. In this study, we investigated sodium channel modifier 1 (SCNM1), a component of the minor spliceosome, as a potential oncogenic driver of HCC. Methods: We analyzed SCNM1 expression and its relationship with clinical outcomes using The Cancer Genome Atlas and GSE14520 datasets and patient samples. Functional assays, including realtime-quantitative polymerase chain reaction, Western blotting, colony formation, and apoptosis analyses, were performed to elucidate the role of SCNM1 in HCC progression. We also evaluated the correlations between SCNM1 and its downstream targets DERL2 and BAG6. Results: Because of DNA copy number gain and arm-level amplification of chromosome 1q, SCNM1 expression was significantly elevated in HCC tissues. High SCNM1 expression correlated with poor prognosis and was identified as an independent prognostic factor. Via its splicing activity, SCNM1 promotes tumor growth, suppresses apoptosis, and regulates the expressions of DERL2 and BAG6, which contribute to cancer cell survival by facilitating protein degradation and suppressing apoptosis. Overexpression of SCNM1 is observed in multiple cancer types, suggesting a broad oncogenic role. Conclusions: Sodium channel modifier 1 plays a critical role in HCC progression by regulating the key pathways involved in tumor proliferation and survival. Its restricted expression in specific cancer types and influence on the minor spliceosome highlights its potential as a cancer-specific therapeutic target. Further research on SCNM1-targeted therapies may provide innovative strategies for treating HCC and other cancers.

DOI： 10.1245/s10434-025-17108-z

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出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-025-17242-8

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記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-025-17179-y

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記述言語：英語   出版者・発行元：Journal of Gastroenterology  

Background: Intracellular calcium (Ca²⁺) signaling regulates key cancer processes. Research findings suggest that the SEC61 complex, involved in protein translocation, contributes to calcium leakage from the endoplasmic reticulum. However, the mechanism by which SEC61 Translocon Subunit Gamma (SEC61G), a component of this complex, influences colorectal cancer (CRC) progression remains unclear. Methods: Bioinformatics analysis was performed using The Cancer Genome Atlas data sets to identify candidate genes on chromosome 7p, examine their association with DNA copy number amplification. In addition, SEC61G expression in CRC cells and tissues was validated using reverse-transcription quantitative polymerase chain reaction and immunohistochemistry. Moreover, in vitro and in vivo experiments were performed to investigate the effects of SEC61G overexpression and knockdown on CRC cell proliferation. Furthermore, publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) data were used to validate the role of SEC61G in CRC. Results: SEC61G was significantly upregulated in CRC tissues and was correlated with poor prognosis in patients with CRC. SEC61G overexpression enhanced cell proliferation and activated the EGFR pathway, promoting cell cycle progression from the G1 to S phase. In addition, SEC61G overexpression increased cytosolic Ca²⁺ levels, which activated EGFR signaling via calmodulin. Moreover, analyses of scRNA-seq and ST-seq data confirmed that SEC61G expression was higher in tumor epithelial cells and that it was co-expressed with EGFR pathway-related genes. Conclusions: SEC61G promotes CRC progression by regulating cytosolic Ca²⁺ concentration, EGFR activation, and cell cycle progression, highlighting its potential as a prognostic biomarker and therapeutic target in CRC.

DOI： 10.1007/s00535-025-02259-3

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記述言語：英語   出版者・発行元：Breast Cancer  

Background: The single-nucleotide polymorphism rs6507583 at the promoter of SET-binding protein 1 (SETBP1) was implicated in estrogen receptor (ER)-positive breast carcinogenesis. Here, we evaluated the clinical and biological relevance of SETBP1 expression in ER-positive breast cancer (BC). Methods: The associations between SETBP1 expression and clinical outcomes in BC patients were analyzed in independent cohorts. The localizations of SETBP1 expression in BC tissues were observed by immunohistochemical staining. Pathway analyses were conducted using TCGA dataset. In vitro proliferation assay, protein phosphatase 2A (PP2A) activity assay, and gene expression analysis were performed in SETBP1-knockdown ER-positive BC cells. We investigated the factors influencing SETBP1 mRNA expression using TCGA dataset. rs6507583 presence and SETBP1 mRNA expression in 11 mammary cell lines and 56 BC tissue samples were examined by target sequencing and RT-qPCR, respectively. Results: SETBP1 was downregulated in BC cells compared with normal ductal epithelial cells. Low SETBP1 mRNA expression was an independent prognostic factor for poor recurrence-free survival. Pathway analyses revealed an inverse relationship between decreased SETBP1 expression and the expression of E2F, MYC, and G2M checkpoint target genes in BC tissues. SETBP1 knockdown promoted proliferation, inhibition of PP2A activity, and phosphorylation of MAPK in ER-positive BC. Low SETBP1 expression was influenced by high SETBP1 promoter methylation and DNA copy number SETBP1 deletion. SETBP1 expression with rs6507583 was lower than without rs6507583 in BC. Conclusions: We demonstrated that low SETBP1 expression could be a poor prognostic biomarker that promotes ER-positive BC proliferation, possibly via phosphorylation of MAPK.

DOI： 10.1007/s12282-025-01667-w

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor survival rates. Effective molecular-targeted therapies are urgently needed. This study aimed to identify novel candidate tumor-associated genes in ESCC by analyzing chromosomal amplification regions. Materials and Methods: DNA copy number variation (CNV) and mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE). Single-cell RNA sequencing data from Gene Expression Omnibus (GEO) were analyzed using Scanpy. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded (FFPE) ESCC tissues. PDCD10 was identified as a potential tumor-associated gene, and its association with clinicopathological factors and prognostic impact was evaluated using Kaplan-Meier survival and Cox regression analyses. Pathway analysis was performed to investigate the biological processes, and drug sensitivity profiling was conducted to identify compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines. Results: PDCD10, a signaling protein involved in cell proliferation and vascular development, showed significant amplification and over-expression in ESCC cases. High PDCD10 expression was associated with poor prognosis. Single-cell RNA sequencing confirmed its tumor-specific expression. GSEA revealed enrichment of mTORC1 signaling, E2F, and Myc target pathways in high PDCD10-expressing tumors. Drug sensitivity analysis identified Azelaic acid and Rebamipide as compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines. Conclusion: PDCD10 could be a novel tumor-associated gene associated with tumor progression and poor prognosis in ESCC. Azelaic acid and Rebamipide are candidate therapeutic agents targeting PDCD10.

DOI： 10.21873/anticanres.17527

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DOI： 10.1007/s13691-025-00748-z

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

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記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: MicroRNAs (miRNAs) have been highlighted as non-invasive clinical biomarkers in liquid biopsy. This study aimed to investigate the clinical significance of circulating tumor suppressors, precursor-miR-488 (pre-miR-488) and miR-488-5p, in the blood of patients with gastric cancer (GC). Materials and Methods: The expression levels of pre-miR-488 and miR-488-5p in tumor tissues and blood were measured using RT-qPCR, and the clinicopathological and prognostic significance of their expression was assessed in patients with GC. Next, pathway analysis of miR-488-5p expression in GC tissues was performed by gene set enrichment analysis (GSEA) using the TCGA dataset. Finally, pre-miR-488 in exosomes from the plasma of GC patients was analyzed using RT-qPCR. Results: Both pre-miR-488 and miR-488-5p were down-regulated in tumor tissues, whereas their expression in the blood was significantly higher in patients with GC than in healthy controls. Low expression of pre-miR-488 or miR-488-5p in the blood was associated with poor prognosis in patients with GC. Furthermore, low pre-miR-488 expression in the blood was an independent poor prognostic factor for overall survival. miR-488-5p expression tended to be negatively correlated with the expression of gene sets involved in epithelial-mesenchymal transition and hypoxia. pre-miR-488 was detected in exosomes isolated from the plasma of patients with GC. Conclusion: Circulating pre-miR-488 and miR-488-5p expression in the blood may serve as novel prognostic biomarkers for patients with GC, predicting clinical outcomes and guiding therapeutic strategies.

DOI： 10.21873/anticanres.17399

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.40.9

CiNii Research

記述言語：英語   出版者・発行元：Surgery Today  

Background: Feasible therapeutic targets need to be identified to overcome tumor heterogeneity and ameliorate therapeutic resistance. We explored the identification of oncogenes on Ch.7q, which is amplified ubiquitously in colorectal cancer (CRC). In this study, we focused on SLC12A9, which encodes a channel protein that regulates ion concentration inside and outside of the cell. Materials and methods: Expression and survival analyses of SLC12A9 were performed using reverse transcription quantitative polymerase chain reaction, The Cancer Genome Atlas dataset, and immunohistochemistry. A gene set enrichment analysis (GSEA) was performed to elucidate the correlation between SLC12A9 and gene sets associated with tumor progression. Subsequently, an in vitro proliferation assay was performed using SLC12A9-knockdown CRC cells. Results: SLC12A9 was highly expressed in tumor cells, and its high expression was associated with a poor prognosis. The GSEA revealed an association with mTORC1 signaling. In the colony formation assay, SLC12A9 knockdown by siRNA suppressed the proliferative capacity of CRC cells. Public single-cell RNA sequencing data have revealed that SLC12A9 is derived from malignant epithelial cells in CRC tissues. Conclusion: Our results suggest that abundant SLC12A9 expression is associated with a poor prognosis due to the devastating growth of CRC cells, in part via the mTORC1 signaling pathway.

DOI： 10.1007/s00595-025-03214-8

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記述言語：英語   出版者・発行元：一般社団法人 日本外科学会  

<p><b>INTRODUCTION:</b> Glycogen storage disease type IX (GSD type IX) is caused by a deficiency in phosphorylase b kinase (PHK) and is classified into hepatic (IXa–c) and muscular (IXd) subtypes. GSD type IXd leads to exercise intolerance, rhabdomyolysis, and myoglobinuria owing to impaired glycogen breakdown. It is a rare and mild metabolic disorder, with only 19 reported cases of <i>PHKA1</i> mutations. To the best of our knowledge, this is the 1st report on the perioperative management of a patient with GSD type IXd.</p><p><b>CASE PRESENTATION:</b> A 61-year-old male presented with a right inguinal hernia requiring surgical repair. He had experienced muscle weakness since the age of 53, which progressed to severe neck muscle atrophy by the age of 58. Genetic testing confirmed a <i>PHKA1</i> mutation, leading to the diagnosis of GSD type IXd. He had previously undergone multiple surgeries without any complications. Given his underlying muscle weakness, totally extraperitoneal (TEP) inguinal hernia repair was performed to minimize postoperative pain and muscle damage. Postoperative monitoring revealed no rhabdomyolysis or myoglobinuria, and the patient was discharged without complications on POD 7.</p><p><b>CONCLUSIONS:</b> We successfully managed a patient with GSD type IXd perioperatively, without complications. Although this disease can cause rhabdomyolysis, the symptoms are often mild and may remain undiagnosed. Therefore, in patients with muscle weakness or elevated creatine kinase levels, careful surgical planning and perioperative monitoring are essential.</p>

DOI： 10.70352/scrj.cr.25-0239

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出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.

DOI： 10.1073/pnas.2408649121

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記述言語：英語   出版者・発行元：Heliyon  

Hot springs have long been used for medical purposes throughout the world. Recently, the positive effects of hot spa-bathing on circulatory diseases have been reported, while there are few reports on the mental effects of hot spa-bathing. Therefore, the purpose of this study was to clarify the relationship between hot spa-bathing habits and mental health throughout Japan. We conducted a nationwide online survey, including questions on bathing behavior, subjective satisfaction, lifestyle, and illness. The results showed a significant positive correlation between hot spa-bathing habits and multiple subjective satisfaction levels regarding mental health effects. The factor analysis results indicated that hot spa-bathing habits tended to be associated with good mental health, high health consciousness, and disease. Our study revealed that subjective satisfaction was higher among individuals with hot spa-bathing habits, suggesting that the hot spring spa-bathing habit may have a positive influence on mental health.

DOI： 10.1016/j.heliyon.2023.e19631

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記述言語：日本語   出版者・発行元：(公社)日本医学放射線学会  

記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Aim: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C-1 and C-2), grade 2 (C-3 and O-1), and grade 3 (O-2 and O-3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results: miR-196b-3p was significantly upregulated, and miR-92a-2-5p was downregulated (P <.05 and q < 0.2). TCGA data showed a high expression of miR-196b-3p in gastric cancer cases (P <.001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR-196b-3p, miR-92a-2-5p, and miR-6791-3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. Conclusion: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer.

DOI： 10.1002/ags3.12610

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

本研究の目的は、血中マイクロRNA(miRNA)をバイオマーカーとして検出することで、胃癌リスクの高い症例を同定することである。スクリーニングを行った1206名のうち、血清抗体検査でヘリコバクター・ピロリ(H.pylori)陽性で、内視鏡検査を受けた144名を本研究の対象とした。粘膜炎症の肉眼的評価には、正常粘膜をグレード0、萎縮をグレード1(C-1、C-2)、グレード2(C-3、O-1)、グレード3(O-2、O-3)に分類する木村・竹本分類を適用した。血清サンプルは2相に分け、miRNAマイクロアレイプロファイリングに使用した。グレード3の粘膜とその他のグレードの粘膜におけるmiRNAの発現を比較した。胃癌における発現は、TCGAのデータで確認した。miR-196b-3pは有意に増加し、miR-92a-2-5pは減少していた(P<0.05、q<0.2)。TCGAのデータでは、胃癌症例においてmiR-196b-3pの発現が高いことが示された(P<0.001)。グレード3とそれ以外を比較すると、検出されたmiRNAを用いた受信者動作特性曲線下面積は0.7であった。さらに、miRNAを組み合わせることで、より高い精度が得られた。miRNAを組み合わせる場合、3種類のmiRNA(miR-196b-3p、miR-92a-2-5p、miR-6791-3p)の組み合わせが高い感度と特異性を示し、曲線下面積は0.8を超えていた。ここに示されたmiRNAの組み合わせは、胃癌の前癌病変のバイオマーカーとして有望である可能性がある。

記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC. Patients and methods: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40–60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1–based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety. Results: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia. Conclusion: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

DOI： 10.1016/j.ejca.2022.02.028

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DOI： 10.1200/JCO.2022.40.4_suppl.256

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記述言語：英語   出版者・発行元：Cancer Science  

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2-associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail-anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR-Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6-mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC.

DOI： 10.1111/cas.15174

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

BCL2関連athanogene 6(BAG6)複合体の構成要素であるguided entry of tail-anchored proteins factor 4(GET4)が、大腸癌においてBAG6の細胞内局在を制御していることを明らかにした。癌ゲノムデータベースのデータセットを解析したところ、大腸癌でGET4遺伝子はしばしば増幅しており、ドライバー遺伝子の候補となることが突き止められた。GET4遺伝子は腫瘍細胞でDNAコピー数が増加しているために過剰発現していることが判明し、GET4高発現は予後不良の独立因子となっていた。BAG6には遺伝子変化が認められ、主に腫瘍細胞の細胞質内で過剰発現していた。大腸癌細胞を用いたノックアウト実験によってGET4の生物学的重要性について検討した。その結果、in vitro、in vivoのいずれでもGET4は腫瘍の増殖を促進することが示された。BAG6が媒介するp53のアセチル化が細胞質内で豊富に生じ、次いでp21発現が減少するために細胞周期の進行が促進されていると思われた。以上から、GET4はBAG6の細胞質移行を誘導して大腸癌の進行を促進する新規ドライバー遺伝子であり、予後バイオマーカーにもなることが明らかになった。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00595-019-01789-7.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.13084.

開催年月日： 2018年9月

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開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

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開催地：大阪   国名：日本国  

開催年月日： 2018年6月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大分   国名：日本国  

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