The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alteration...The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.展开更多
Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified n...Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.展开更多
AIM:To clarify the similarities and differences in gastric cancer epidemiology between Japan and China.METHODS:A comprehensive literature search of the PubMed database was performed.The relevant literature published i...AIM:To clarify the similarities and differences in gastric cancer epidemiology between Japan and China.METHODS:A comprehensive literature search of the PubMed database was performed.The relevant literature published in China was also been cited.Data on incidence and mortality rates in 2008 were obtained from the Cancer Mondial database,published by International Agency for Research on Cancer at http://www-dep.iarc.fr/.RESULTS:Gastric cancer remains a significant publichealth burden in both Japan and China.The prevalence of Helicobacter pylori(H.pylori)colonization is high in the adult populations of both countries.Accumulating evidence from intervention studies in both countries has shown the effectiveness of H.pylori eradication in reduc-ing gastric cancer incidence.There are differences,however,in many aspects of gastric cancer,including patterns of incidence and mortality,trends in the prevalence of H.pylori infection,H.pylori strains,the magnitude of risk of gastric cancer related to H.pylori infection,and associations with dietary habits.Compared with China,Japan has seen a more rapid decline in H.pylori infection among adolescents.While Japanese cohort studies have dominated the literature concerning the associations between gastric cancer and dietary habits,numerous case-control studies in China suggest a positive association between a high intake of preserved fish and vegetables and gastric cancer risk.There is a need for a multidisciplinary research approach to understand the interactions between various strains of H.pylori,host factors,and other lifestyle and environmental factors in gastric carcinogenesis in both countries.CONCLUSION:The shared high incidence of gastric cancer and high prevalence of H.pylori,as well as differences in many aspects of gastric cancer,provide an excellent opportunity to establish Sino-Japanese collaborations.展开更多
Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic opti...Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The "liquid biopsy" addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA(ct DNA) could provide diagnostic information. In this review, we provide an overview of the current status of bloodbased tests for diagnosis of pancreatic cancer and the potential utility of ct DNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ct DNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.展开更多
Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expre...Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expression can identify the diffuse-type and intestinal-type gastric cancers. Although the diffuse-type gastric cancer has been resistant to treatment, the precise mechanism and phenotypic involvement has not been revealed. It may be possible that stem cells transform into gastric cancer cells, possibly through the involvement of a molecule alteration and signaling mechanism. In this review article, we focus on the role of catenin beta 1 (CTNNB1 or β-catenin) and describe the regulation of CTNNB1 signaling in gastric cancer and stem cells.展开更多
Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations ...Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.展开更多
To clarify the trend in colorectal cancer mortality in Asian countries.We analyzed the colorectal cancer mortality in four Asian countries using the World Health Organization mortality database and the Korea National ...To clarify the trend in colorectal cancer mortality in Asian countries.We analyzed the colorectal cancer mortality in four Asian countries using the World Health Organization mortality database and the Korea National Statistics Office database.The annual age-standardized rates and truncated rated for the three age groups(30-49,50-69 and ≥ 70 years) for Hong Kong of China(1969-2009),Japan(1955-2009),South Korea(1985-2006),and Singapore(1966-2009) were estimated.A joinpoint regression model was used to detect significant trends in mortality rates.Colorectal cancer mortality in men started to decrease in 1992 in Japan followed by Singapore and Hong Kong of China in 1995.The mortality rates in women stared to decrease in 1980 in Singapore,followed by Hong Kong of China and Japan in 1996.In all countries and both genders,except for women in Singapore,the decrease in mortality began in the younger age groups.The colorectal cancer mortality in the four studied Asian countries has started to decrease,and the decrease occurred first in the younger age groups.展开更多
Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients(60%-70%) does not respond well to neoadjuvant treat...Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients(60%-70%) does not respond well to neoadjuvant treatments and develop severe adverse effects. Therefore, predictive markers for individualization of multimodality treatments are urgently needed in esophageal cancer. Recently, molecular biomarkers that predict the response to neoadjuvant therapy have been explored in multimodal approaches in esophageal cancer and successful examples of biomarker identification have been reported. In this review, promising candidates for predictive molecular biomarkers developed by using multiple molecular approaches are reviewed. Moreover, treatment strategies based on the status of predicted biomarkers are discussed, while considering the international differences in the clinical background. However, in the absence of adequate treatment options related to the results of the biomarker test, the usefulness of these diagnostic tools is limited and new effective therapies for biomarker-identified nonresponders to cancer treatment should be concurrent with the progress of predictive technologies. Further improvement in the prognosis of esophageal cancer patients can be achieved through the introduction of novel therapeutic approaches in clinical practice.展开更多
AIM: To investigate the genes regulated in mesenchymal stem cells(MSCs) and diffuse-type gastric cancer(GC),gene expression was analyzed. METHODS: Gene expression of MSCs and diffuse-type GC cells were analyzed by mic...AIM: To investigate the genes regulated in mesenchymal stem cells(MSCs) and diffuse-type gastric cancer(GC),gene expression was analyzed. METHODS: Gene expression of MSCs and diffuse-type GC cells were analyzed by microarray. Genes related to stem cells, cancer and the epithelial-mesenchymal transition(EMT) were extracted from human gene lists using Gene Ontology and reference information. Gene panels were generated, and messenger RNA gene expression in MSCs and diffuse-type GC cells was analyzed. Cluster analysis was performed using the NCSS software.RESULTS: The gene expression of regulator of G-protein signaling 1(RGS1) was up-regulated in diffuse-type GC cells compared with MSCs. A panel of stem-cell related genes and genes involved in cancer or the EMT were examined. Stem-cell related genes, such as growth arrest-specific 6, musashi RNA-binding protein 2 and hairy and enhancer of split 1(Drosophila), NOTCH family genes and Notch ligands, such as delta-like 1(Drosophila) and Jagged 2, were regulated.CONCLUSION: Expression of RGS1 is up-regulated, and genes related to stem cells and NOTCH signaling are altered in diffuse-type GC compared with MSCs.展开更多
Familial pancreatic cancer(FPC)is broadly defined as two first-degree-relatives with pancreatic cancer(PC)and accounts for 4%-10%of PC.Several genetic syndromes,including Peutz-Jeghers syndrome,hereditary pancreatitis...Familial pancreatic cancer(FPC)is broadly defined as two first-degree-relatives with pancreatic cancer(PC)and accounts for 4%-10%of PC.Several genetic syndromes,including Peutz-Jeghers syndrome,hereditary pancreatitis,hereditary breast-ovarian cancer syndrome(HBOC),Lynch syndrome,and familial adenomatous polyposis(FAP),also have increased risks of PC,but the narrowest definition of FPC excludes these known syndromes.When compared with other familial tumors,proven genetic alterations are limited to a small proportion(<20%)and the familial aggregation is usually modest.However,an ethnic deviation(Ashkenazi Jewish>Caucasian)and a younger onset are common also in FPC.In European countries,"anticipation"is reported in FPC families,as with other hereditary syndromes;a trend toward younger age and worse prognosis is recognized in the late years.The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia(Pan IN)foci,with various K-ras mutations,similar to colorectal polyposis seen in the FAP patients.As with HBOC patients,a patient who is a BRCA mutation carrier with unresectable pancreatic cancer(accounting for 0%-19%of FPC patients)demonstrated better outcome following platinum and Poly(ADP-ribose)polymerase inhibitor treatment.Western countries have established FPC registries since the 1990 s and several surveillance projects for highrisk individuals are now ongoing to detect early PCs.Improvement in lifestyle habits,including non-smoking,is recommended for individuals at risk.In Japan,the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.展开更多
Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An e...Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An excessive accumulation of visceral adipose tissue causes insulin resistance, dyslipidemia and adipocytokine imbalance, and these factors are suggested to be involved in cancer promotion. To prevent obesityassociated cancers, researcher attention is increasing on the so-called "functional foods". In addition, new approaches to cancer control are in high demand, and using "functional foods" as supplemental or adjuvant agents in chemotherapy is thought to be a promising approach. One of these functional ingredients is xanthophylls, which are natural fat-soluble pigments found in fruits, vegetables, algae and other plants. Xanthophylls belong to the carotenoid class and have struc-tures containing oxygen. Some studies have revealed that xanthophylls improve the inflammation status, serum triglyceride levels, blood pressure levels and liver function test values. Furthermore, recent studies show that xanthophylls possess high anti-cancer, antidiabetic, anti-obesity and anti-oxidant properties. In this review, we highlight the recent findings for five xanthophylls, namely astaxanthin, β-cryptoxanthin, fucoxanthin, neoxanthin and zeaxanthin/lutein, and their relevance to cancer prevention.展开更多
AIM To investigate genotype variation among induced pluripotent stem cell(iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS Human iPSC lines wer...AIM To investigate genotype variation among induced pluripotent stem cell(iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer(OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using nextgeneration sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants(SNVs)(missense, nonsense,and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbS NP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer. RESULTS In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1 B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer(stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the noncancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer(stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.CONCLUSION The genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.展开更多
Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations ...Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations andepigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells(CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A(ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2 AX to levels representative of growth arrest in normal cells.展开更多
AIM To investigate β-catenin(CTNNB1) signaling in cancer and stem cells, the gene expression and pathway were analyzed using bioinformatics.METHODS The expression of the catenin β 1(CTNNB1) gene, which codes for β-...AIM To investigate β-catenin(CTNNB1) signaling in cancer and stem cells, the gene expression and pathway were analyzed using bioinformatics.METHODS The expression of the catenin β 1(CTNNB1) gene, which codes for β-catenin, was analyzed in mesenchymal stem cells(MSCs) and gastric cancer(GC) cells. Beta-catenin signaling and the mutation of related proteins were also analyzed using the cB ioP ortal for Cancer Genomics and HOMology modeling of Complex Structure(HOMCOS) databases.RESULTS The expression of the CTNNB1 gene was up-regulated in GC cells compared to MSCs. The expression of EPH receptor A8(EPHA8), synovial sarcoma translocation chromosome 18(SS18), interactor of little elongation complex ELL subunit 1(ICE1), patched 1(PTCH1), mutS homolog 3(MSH3) and caspase recruitment domain family member 11(CARD11) were also shown to be altered in GC cells in the cB ioP ortal for Cancer Genomics analysis. 3D complex structures were reported for E-cadherin 1(CDH1), lymphoid enhancer binding factor 1(LEF1), transcription factor 7 like 2(TCF7L2) and adenomatous polyposis coli protein(APC) with β-catenin. CONCLUSION The results indicate that the epithelial-mesenchymal transition(EMT)-related gene CTNNB1 plays an important role in the regulation of stem cell pluripotency and cancer signaling.展开更多
Cancer statistics in Japan Cancer is the most common cause of death in Japan based on Statistics 2021~1.Since statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have be...Cancer statistics in Japan Cancer is the most common cause of death in Japan based on Statistics 2021~1.Since statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have been the main causes of death in Japan.Cancer surpassed cerebrovascular disease as the main cause of death in 1981,and the number of cancer deaths has increased.Approximately 38,000 people died of cancer in 2021.The National Cancer Center(NCC)reported that the 5-year survival rate for patients with cancer was improving(62%for males and 66.9%for females)in a population-based cancer registry.展开更多
Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent approach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI varies in individual cases even...Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent approach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI varies in individual cases even among tumors carrying the same?EGFR?mutation, suggesting the involvement of modifying factors. To characterize possible modifiers, we examined mutation state of the?EGFR?and the?KRAS?genes in Japanese NSCLC and compared them with the methylation state of lung tumor suppressors, the?CADM1 and?4.1B,?whose products have potentials to modify the functions of EGFR or KRAS. Materials and methods: A total of 103 Japanese NSCLC and 11 NSCLC cell lines were examined. Genomic DNA of exons 18–21 of the?EGFR?and exons 1 and 2 of the?KRAS?were amplified by polymerase chain reaction (PCR), followed by single-strand conformation polymorphism analysis and direct sequencing. Methylation status of gene promoters in NSCLC cells were examined by methylation-specific PCR. Results: Mutations of the?EGFR?and?KRAS?were detected mutually exclusively in 27 and 11 out of 103 NSCLC cases, respectively.?EGFR?mutations were observed exclusively in adenocarcinoma (27 of 69, 41%) and preferentially in tumors from female and non-smokers (p < 0.00001). Eight (30%) and 12 (44%) of 27 tumors carrying mutated?EGFR?and 4 (36%) and 8 (73%) of 11 tumors carrying mutated?KRAS?showed methylation of the?CADM1 and 4.1B, respectively.?EGFR-mutated tumors with methylation of either?CADM1 or 4.1B?showed more malignant features than those with unmethylated?CADM1 and 4.1B?(p < 0.05). Conclusion: Methylation state of the?CADM1 and?4.1B?are independent of the mutation status of the?EGFR?or?KRAS?but play roles in the malignant progression of NSCLC. Integration of epigenetic information would be useful for identifying possible modifiers to predict the response or recurrence of lung adenocarcinoma to the EGFR-TKI therapy.展开更多
Background:Neoadjuvant/preoperative therapy(NAT)involves the administration of chemotherapy,with or without radiation,prior to surgical resection.This approach is commonly used for locally advanced tumors to reduce tu...Background:Neoadjuvant/preoperative therapy(NAT)involves the administration of chemotherapy,with or without radiation,prior to surgical resection.This approach is commonly used for locally advanced tumors to reduce tumor volume,improve resectability,and minimize the need for extensive surgical procedures.While NAT has been shown to be effective in inducing local anti-tumor immunity in potentially resectable solid tumors,the underlying molecular mechanisms remain poorly understood.Methods:Cohort samples from pancreatic cancer patients who underwent NAT(n=26)and those who did not(n=20)were analyzed.Changes in the immune microenvironment induced by NAT were assessed using stratified bioinformatic approaches,including heatmap analysis of immunerelated genes selected via Gene Ontology,Gene Set Enrichment Analysis(GSEA)with the immunologic signature database,and Ingenuity Pathway Analysis(IPA).Findings were further validated through immunohistochemical analysis.Results:A comprehensive,stratified evaluation integrating pathological and bioinformatic approaches revealed that NAT induced the upregulation of 212 genes,including DC-SIGN(CD209),and activated 13 immuneassociated pathways,such as T-cell receptor(TCR)signaling.Additionally,NAT promoted an increased shift toward CD8(+)T-cell populations through the upregulation of MAL(T-cell differentiation protein).Immunohistochemical analysis further confirmed a significant accumulation of DC-SIGN(+)dendritic cells and MAL(+)lymphocytes in NAT-treated patients.Conclusions:NAT enhances anti-tumor immunity by promoting CD8(+)T-cell generation through the activation of DC-SIGN(+)dendritic cells and MAL(+)lymphocytes.This study is the first to report an increase in MAL(+)lymphocytes following NAT.Given its potential significance,further investigation in other solid tumors treated with NAT is warranted.展开更多
AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by im...AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P<0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P<0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.展开更多
The control of the circadian rhythm is important for health because it regulates physiological functions and is associated with health hazards.We aimed to identify a circadian biomarker of health status in human saliv...The control of the circadian rhythm is important for health because it regulates physiological functions and is associated with health hazards.We aimed to identify a circadian biomarker of health status in human saliva,since collecting saliva is non-invasive,straightforward,and cost-effective.Among 500 genes potentially controlled by the salivary clock identified using chromatin immunoprecipitation(ChIP)assays,22 of them showed reasonable transcriptional responses according to a DNA array in a salivary model system.Among these 22 genes,ARRB1,which is expressed in human salivary glands,was also expressed in model HSG cells at the transcriptional and translational levels.The profile of ARRB1 expression in human saliva was circadian,suggesting that ARRB1 could serve as a candidate circadian biomarker in saliva.We compared ARRB1 with other biomarkers in salivary samples from jetlagged individuals.The circadian profile of ARRB1 reflected the time lag more than the profile of melatonin,whereas the profiles of cortisol andα-amylase did not reflect the time lag.Overall,these findings suggest that salivary ARRB1 could serve as a candidate biomarker that could be used to monitor the internal body clock.展开更多
Embryonic stem(ES) cells are isolated from theinner cell mass of a blastocyst, and are used for the generation of gene-modified animals. In mice, the transplantation of gene-modified ES cells into recipient blastocyst...Embryonic stem(ES) cells are isolated from theinner cell mass of a blastocyst, and are used for the generation of gene-modified animals. In mice, the transplantation of gene-modified ES cells into recipient blastocysts leads to the creation of gene-targeted mice such as knock-in and knock-out mice; these gene-targeted mice contribute greatly to scientific development. Although the rat is considered a useful laboratory animal alongside the mouse, fewer genemodified rats have been produced due to the lack of robust establishment methods for rat ES cells. A new method for establishing rat ES cells using signaling inhibitors was reported in 2008. By considering the characteristics of rat ES cells, recent research has made progress in improving conditions for the stable culture of rat ES cells in order to generate gene-modified rats efficiently. In this review, we summarize several advanced methods to maintain rat ES cells and generate gene-targeted rats.展开更多
文摘The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.
基金supported by grants from the Ministry of Science and Technology,Taiwan(MOST108-2314-B-182-006,MOST109-2314-B-182-071:Lee-Yung Shih)the Ministry of Health and Welfare,Taiwan(MOHW110-TDU-B-212-134011:Lee-Yung Shih)+3 种基金Chang Gung Memorial Hospital(CMRPG3D1524,OMRPG3E0031:Lee-Yung Shih)the Grant-in-Aid for the Japan Society for the Promotion of Science(JSPS)KAKENHI(JP19H05656:Seishi Ogawa,22K16320:Yotaro Ochi)the Japan Agency for Medical Research and Development(AMED)(JP19cm0106501h0004,JP19ck0106250h0003:Seishi Ogawa)the Ministry of Education,Culture,Sports,Science and Technology of Japan(MEXT)(hp200138,hp210167:Seishi Ogawa)。
文摘Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.
基金Supported by Grant-in-Aid from the Third Term Comprehensive Control Research for Cancer,the Ministry of Health,La-bour and Welfare,Japan
文摘AIM:To clarify the similarities and differences in gastric cancer epidemiology between Japan and China.METHODS:A comprehensive literature search of the PubMed database was performed.The relevant literature published in China was also been cited.Data on incidence and mortality rates in 2008 were obtained from the Cancer Mondial database,published by International Agency for Research on Cancer at http://www-dep.iarc.fr/.RESULTS:Gastric cancer remains a significant publichealth burden in both Japan and China.The prevalence of Helicobacter pylori(H.pylori)colonization is high in the adult populations of both countries.Accumulating evidence from intervention studies in both countries has shown the effectiveness of H.pylori eradication in reduc-ing gastric cancer incidence.There are differences,however,in many aspects of gastric cancer,including patterns of incidence and mortality,trends in the prevalence of H.pylori infection,H.pylori strains,the magnitude of risk of gastric cancer related to H.pylori infection,and associations with dietary habits.Compared with China,Japan has seen a more rapid decline in H.pylori infection among adolescents.While Japanese cohort studies have dominated the literature concerning the associations between gastric cancer and dietary habits,numerous case-control studies in China suggest a positive association between a high intake of preserved fish and vegetables and gastric cancer risk.There is a need for a multidisciplinary research approach to understand the interactions between various strains of H.pylori,host factors,and other lifestyle and environmental factors in gastric carcinogenesis in both countries.CONCLUSION:The shared high incidence of gastric cancer and high prevalence of H.pylori,as well as differences in many aspects of gastric cancer,provide an excellent opportunity to establish Sino-Japanese collaborations.
文摘Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The "liquid biopsy" addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA(ct DNA) could provide diagnostic information. In this review, we provide an overview of the current status of bloodbased tests for diagnosis of pancreatic cancer and the potential utility of ct DNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ct DNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.
文摘Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expression can identify the diffuse-type and intestinal-type gastric cancers. Although the diffuse-type gastric cancer has been resistant to treatment, the precise mechanism and phenotypic involvement has not been revealed. It may be possible that stem cells transform into gastric cancer cells, possibly through the involvement of a molecule alteration and signaling mechanism. In this review article, we focus on the role of catenin beta 1 (CTNNB1 or β-catenin) and describe the regulation of CTNNB1 signaling in gastric cancer and stem cells.
基金Grants-in Aid for Scientific Research from the Ministry of Education,Science and Culture of Japan,No.26870874 to Takai E and No.25134719 to Yachida Sthe National Cancer Center Research and Development Fund(25-A-3 to Takai E and Yachida S)+5 种基金the Takeda Science Foundation(Yachida S)the Uehara Memorial Foundation(Yachida S)the Mochida Memorial Foundation for Medical and Pharmaceutical Research(Yachida S)the Medical Research Encouragement Prize of the Japan Medical Association(Yachida S)the Pancreas Research Foundation of Japan(Yachida S)Princess Takamatsu Cancer Research Fund(Yachida S)
文摘Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.
基金Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministryof Education,Science and Technology,No. 2010-0010276A Research Grant from the National Cancer Center of Korea,No.1010160
文摘To clarify the trend in colorectal cancer mortality in Asian countries.We analyzed the colorectal cancer mortality in four Asian countries using the World Health Organization mortality database and the Korea National Statistics Office database.The annual age-standardized rates and truncated rated for the three age groups(30-49,50-69 and ≥ 70 years) for Hong Kong of China(1969-2009),Japan(1955-2009),South Korea(1985-2006),and Singapore(1966-2009) were estimated.A joinpoint regression model was used to detect significant trends in mortality rates.Colorectal cancer mortality in men started to decrease in 1992 in Japan followed by Singapore and Hong Kong of China in 1995.The mortality rates in women stared to decrease in 1980 in Singapore,followed by Hong Kong of China and Japan in 1996.In all countries and both genders,except for women in Singapore,the decrease in mortality began in the younger age groups.The colorectal cancer mortality in the four studied Asian countries has started to decrease,and the decrease occurred first in the younger age groups.
文摘Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients(60%-70%) does not respond well to neoadjuvant treatments and develop severe adverse effects. Therefore, predictive markers for individualization of multimodality treatments are urgently needed in esophageal cancer. Recently, molecular biomarkers that predict the response to neoadjuvant therapy have been explored in multimodal approaches in esophageal cancer and successful examples of biomarker identification have been reported. In this review, promising candidates for predictive molecular biomarkers developed by using multiple molecular approaches are reviewed. Moreover, treatment strategies based on the status of predicted biomarkers are discussed, while considering the international differences in the clinical background. However, in the absence of adequate treatment options related to the results of the biomarker test, the usefulness of these diagnostic tools is limited and new effective therapies for biomarker-identified nonresponders to cancer treatment should be concurrent with the progress of predictive technologies. Further improvement in the prognosis of esophageal cancer patients can be achieved through the introduction of novel therapeutic approaches in clinical practice.
基金Cancer Research from the Ministry of Health,Labour and Welfare
文摘AIM: To investigate the genes regulated in mesenchymal stem cells(MSCs) and diffuse-type gastric cancer(GC),gene expression was analyzed. METHODS: Gene expression of MSCs and diffuse-type GC cells were analyzed by microarray. Genes related to stem cells, cancer and the epithelial-mesenchymal transition(EMT) were extracted from human gene lists using Gene Ontology and reference information. Gene panels were generated, and messenger RNA gene expression in MSCs and diffuse-type GC cells was analyzed. Cluster analysis was performed using the NCSS software.RESULTS: The gene expression of regulator of G-protein signaling 1(RGS1) was up-regulated in diffuse-type GC cells compared with MSCs. A panel of stem-cell related genes and genes involved in cancer or the EMT were examined. Stem-cell related genes, such as growth arrest-specific 6, musashi RNA-binding protein 2 and hairy and enhancer of split 1(Drosophila), NOTCH family genes and Notch ligands, such as delta-like 1(Drosophila) and Jagged 2, were regulated.CONCLUSION: Expression of RGS1 is up-regulated, and genes related to stem cells and NOTCH signaling are altered in diffuse-type GC compared with MSCs.
文摘Familial pancreatic cancer(FPC)is broadly defined as two first-degree-relatives with pancreatic cancer(PC)and accounts for 4%-10%of PC.Several genetic syndromes,including Peutz-Jeghers syndrome,hereditary pancreatitis,hereditary breast-ovarian cancer syndrome(HBOC),Lynch syndrome,and familial adenomatous polyposis(FAP),also have increased risks of PC,but the narrowest definition of FPC excludes these known syndromes.When compared with other familial tumors,proven genetic alterations are limited to a small proportion(<20%)and the familial aggregation is usually modest.However,an ethnic deviation(Ashkenazi Jewish>Caucasian)and a younger onset are common also in FPC.In European countries,"anticipation"is reported in FPC families,as with other hereditary syndromes;a trend toward younger age and worse prognosis is recognized in the late years.The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia(Pan IN)foci,with various K-ras mutations,similar to colorectal polyposis seen in the FAP patients.As with HBOC patients,a patient who is a BRCA mutation carrier with unresectable pancreatic cancer(accounting for 0%-19%of FPC patients)demonstrated better outcome following platinum and Poly(ADP-ribose)polymerase inhibitor treatment.Western countries have established FPC registries since the 1990 s and several surveillance projects for highrisk individuals are now ongoing to detect early PCs.Improvement in lifestyle habits,including non-smoking,is recommended for individuals at risk.In Japan,the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.
基金Supported by National Cancer Center Research and Development Fund No.25-A-15The Research Grant of the Princess Takamatsu Cancer Research Fund
文摘Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An excessive accumulation of visceral adipose tissue causes insulin resistance, dyslipidemia and adipocytokine imbalance, and these factors are suggested to be involved in cancer promotion. To prevent obesityassociated cancers, researcher attention is increasing on the so-called "functional foods". In addition, new approaches to cancer control are in high demand, and using "functional foods" as supplemental or adjuvant agents in chemotherapy is thought to be a promising approach. One of these functional ingredients is xanthophylls, which are natural fat-soluble pigments found in fruits, vegetables, algae and other plants. Xanthophylls belong to the carotenoid class and have struc-tures containing oxygen. Some studies have revealed that xanthophylls improve the inflammation status, serum triglyceride levels, blood pressure levels and liver function test values. Furthermore, recent studies show that xanthophylls possess high anti-cancer, antidiabetic, anti-obesity and anti-oxidant properties. In this review, we highlight the recent findings for five xanthophylls, namely astaxanthin, β-cryptoxanthin, fucoxanthin, neoxanthin and zeaxanthin/lutein, and their relevance to cancer prevention.
文摘AIM To investigate genotype variation among induced pluripotent stem cell(iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer(OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using nextgeneration sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants(SNVs)(missense, nonsense,and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbS NP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer. RESULTS In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1 B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer(stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the noncancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer(stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.CONCLUSION The genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.
基金Supported by Funding from the National Cancer Center Research and Development Fund Grant,No.23-C-10Grants-in-Aid for Scientific Research MEXT KAKENHI,No.20770136Grants-in-Aid for JSPS Fellows
文摘Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations andepigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells(CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A(ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2 AX to levels representative of growth arrest in normal cells.
文摘AIM To investigate β-catenin(CTNNB1) signaling in cancer and stem cells, the gene expression and pathway were analyzed using bioinformatics.METHODS The expression of the catenin β 1(CTNNB1) gene, which codes for β-catenin, was analyzed in mesenchymal stem cells(MSCs) and gastric cancer(GC) cells. Beta-catenin signaling and the mutation of related proteins were also analyzed using the cB ioP ortal for Cancer Genomics and HOMology modeling of Complex Structure(HOMCOS) databases.RESULTS The expression of the CTNNB1 gene was up-regulated in GC cells compared to MSCs. The expression of EPH receptor A8(EPHA8), synovial sarcoma translocation chromosome 18(SS18), interactor of little elongation complex ELL subunit 1(ICE1), patched 1(PTCH1), mutS homolog 3(MSH3) and caspase recruitment domain family member 11(CARD11) were also shown to be altered in GC cells in the cB ioP ortal for Cancer Genomics analysis. 3D complex structures were reported for E-cadherin 1(CDH1), lymphoid enhancer binding factor 1(LEF1), transcription factor 7 like 2(TCF7L2) and adenomatous polyposis coli protein(APC) with β-catenin. CONCLUSION The results indicate that the epithelial-mesenchymal transition(EMT)-related gene CTNNB1 plays an important role in the regulation of stem cell pluripotency and cancer signaling.
文摘Cancer statistics in Japan Cancer is the most common cause of death in Japan based on Statistics 2021~1.Since statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have been the main causes of death in Japan.Cancer surpassed cerebrovascular disease as the main cause of death in 1981,and the number of cancer deaths has increased.Approximately 38,000 people died of cancer in 2021.The National Cancer Center(NCC)reported that the 5-year survival rate for patients with cancer was improving(62%for males and 66.9%for females)in a population-based cancer registry.
文摘Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent approach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI varies in individual cases even among tumors carrying the same?EGFR?mutation, suggesting the involvement of modifying factors. To characterize possible modifiers, we examined mutation state of the?EGFR?and the?KRAS?genes in Japanese NSCLC and compared them with the methylation state of lung tumor suppressors, the?CADM1 and?4.1B,?whose products have potentials to modify the functions of EGFR or KRAS. Materials and methods: A total of 103 Japanese NSCLC and 11 NSCLC cell lines were examined. Genomic DNA of exons 18–21 of the?EGFR?and exons 1 and 2 of the?KRAS?were amplified by polymerase chain reaction (PCR), followed by single-strand conformation polymorphism analysis and direct sequencing. Methylation status of gene promoters in NSCLC cells were examined by methylation-specific PCR. Results: Mutations of the?EGFR?and?KRAS?were detected mutually exclusively in 27 and 11 out of 103 NSCLC cases, respectively.?EGFR?mutations were observed exclusively in adenocarcinoma (27 of 69, 41%) and preferentially in tumors from female and non-smokers (p < 0.00001). Eight (30%) and 12 (44%) of 27 tumors carrying mutated?EGFR?and 4 (36%) and 8 (73%) of 11 tumors carrying mutated?KRAS?showed methylation of the?CADM1 and 4.1B, respectively.?EGFR-mutated tumors with methylation of either?CADM1 or 4.1B?showed more malignant features than those with unmethylated?CADM1 and 4.1B?(p < 0.05). Conclusion: Methylation state of the?CADM1 and?4.1B?are independent of the mutation status of the?EGFR?or?KRAS?but play roles in the malignant progression of NSCLC. Integration of epigenetic information would be useful for identifying possible modifiers to predict the response or recurrence of lung adenocarcinoma to the EGFR-TKI therapy.
基金supported by JSPS KAKENHI,grant number 18K16377(KN).
文摘Background:Neoadjuvant/preoperative therapy(NAT)involves the administration of chemotherapy,with or without radiation,prior to surgical resection.This approach is commonly used for locally advanced tumors to reduce tumor volume,improve resectability,and minimize the need for extensive surgical procedures.While NAT has been shown to be effective in inducing local anti-tumor immunity in potentially resectable solid tumors,the underlying molecular mechanisms remain poorly understood.Methods:Cohort samples from pancreatic cancer patients who underwent NAT(n=26)and those who did not(n=20)were analyzed.Changes in the immune microenvironment induced by NAT were assessed using stratified bioinformatic approaches,including heatmap analysis of immunerelated genes selected via Gene Ontology,Gene Set Enrichment Analysis(GSEA)with the immunologic signature database,and Ingenuity Pathway Analysis(IPA).Findings were further validated through immunohistochemical analysis.Results:A comprehensive,stratified evaluation integrating pathological and bioinformatic approaches revealed that NAT induced the upregulation of 212 genes,including DC-SIGN(CD209),and activated 13 immuneassociated pathways,such as T-cell receptor(TCR)signaling.Additionally,NAT promoted an increased shift toward CD8(+)T-cell populations through the upregulation of MAL(T-cell differentiation protein).Immunohistochemical analysis further confirmed a significant accumulation of DC-SIGN(+)dendritic cells and MAL(+)lymphocytes in NAT-treated patients.Conclusions:NAT enhances anti-tumor immunity by promoting CD8(+)T-cell generation through the activation of DC-SIGN(+)dendritic cells and MAL(+)lymphocytes.This study is the first to report an increase in MAL(+)lymphocytes following NAT.Given its potential significance,further investigation in other solid tumors treated with NAT is warranted.
文摘AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P<0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P<0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.
基金supported by a grant from KAKENHI(Number:23592756)operational subsidies from Advanced Industrial Science and Technology
文摘The control of the circadian rhythm is important for health because it regulates physiological functions and is associated with health hazards.We aimed to identify a circadian biomarker of health status in human saliva,since collecting saliva is non-invasive,straightforward,and cost-effective.Among 500 genes potentially controlled by the salivary clock identified using chromatin immunoprecipitation(ChIP)assays,22 of them showed reasonable transcriptional responses according to a DNA array in a salivary model system.Among these 22 genes,ARRB1,which is expressed in human salivary glands,was also expressed in model HSG cells at the transcriptional and translational levels.The profile of ARRB1 expression in human saliva was circadian,suggesting that ARRB1 could serve as a candidate circadian biomarker in saliva.We compared ARRB1 with other biomarkers in salivary samples from jetlagged individuals.The circadian profile of ARRB1 reflected the time lag more than the profile of melatonin,whereas the profiles of cortisol andα-amylase did not reflect the time lag.Overall,these findings suggest that salivary ARRB1 could serve as a candidate biomarker that could be used to monitor the internal body clock.
文摘Embryonic stem(ES) cells are isolated from theinner cell mass of a blastocyst, and are used for the generation of gene-modified animals. In mice, the transplantation of gene-modified ES cells into recipient blastocysts leads to the creation of gene-targeted mice such as knock-in and knock-out mice; these gene-targeted mice contribute greatly to scientific development. Although the rat is considered a useful laboratory animal alongside the mouse, fewer genemodified rats have been produced due to the lack of robust establishment methods for rat ES cells. A new method for establishing rat ES cells using signaling inhibitors was reported in 2008. By considering the characteristics of rat ES cells, recent research has made progress in improving conditions for the stable culture of rat ES cells in order to generate gene-modified rats efficiently. In this review, we summarize several advanced methods to maintain rat ES cells and generate gene-targeted rats.
