Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. METHODS: A total of 47 patients with Stage I-III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. RESULTS: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). CONCLUSIONS: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

DOI： 10.1007/s12282-023-01449-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Background and Aims

Decompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer‐membrane vesicles (OMVs) of Escherichia coli, which is the representative pathogenic gut‐derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis.

Methods

We investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from E. coli in mice using mouse liver‐derived cells and a mouse cirrhosis model.

Results

In vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C‐type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child‐Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis.

Conclusions

In conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.

DOI： 10.1111/liv.15539

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/liv.15539

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

With the discovery of bacterial symbiosis in the tissues of various cancers, the study of the tumor microbiome is attracting a great deal of attention. Anatomically, since the gastrointestinal tract, liver, and pancreas form a continuous ductal structure, the microbiomes in the digestive juices of these organs may influence each other. Here, we report a series of microbiome data in tumor-associated tissues such as tumor, non-tumor, and lymph nodes, and body fluids such as saliva, gastric juice, pancreatic juice, bile, and feces of patients with pancreatic or biliary tract cancers. The results show that the microbiome of tumor-associated tissues has a very similar bacterial composition, but that in body fluids has different bacterial composition which varies by location, where some bacteria localize to specific body fluids. Surprisingly, Akkermansia was only detected in the bile of patients with biliary tract cancer and its presence was significantly associated with the performance of external biliary drainage (P = 0.041). Furthermore, we found that tumor-associated tissues and body fluids in deep inner body are mostly inhabited by unidentified and uncharacterized bacteria, suggesting that such bacteria may be potential targets for precision therapy in the future.

DOI： 10.1038/s41598-022-12658-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUND: T-cell receptor-engineered T-cell therapies have achieved promising response rates against synovial sarcoma in clinical trials, but their applicability is limited owing to the HLA matching requirement. Chimeric antigen receptor (CAR) can redirect primary T cells to tumor-associated antigens without requiring HLA matching. However, various obstacles, including the paucity of targetable antigens, must be addressed for synovial sarcoma. Ligands for natural killer (NK) cell-activating receptors are highly expressed by tumor cells. METHODS: The surface expression of ligands for NK cell-activating receptors in synovial sarcoma cell lines was analyzed. We analyzed RNA sequencing data deposited in a public database to evaluate NKp44-ligand expression. Primary T cells retrovirally transduced with CAR targeting NKp44 ligands were evaluated for their functions in synovial sarcoma cells. Alterations induced by various stimuli, including a histone deacetylase inhibitor, a hypomethylating agent, inflammatory cytokines, and ionizing radiation, in the expression levels of NKp44 ligands were investigated. RESULTS: Ligands for NKp44 and NKp30 were expressed in all cell lines. NKG2D ligands were barely expressed in a single cell line. None of the cell lines expressed NKp46 ligand. Primary synovial sarcoma cells expressed the mRNA of the truncated isoform of MLL5, a known cellular ligand for NKp44. NKp44-based CAR T cells specifically recognize synovial sarcoma cells, secrete interferon-γ, and exert suppressive effects on tumor cell growth. No stimulus altered the expression of NKp44 ligands. CONCLUSION: NKp44-based CAR T cells can redirect primary human T cells to synovial sarcoma cells. CAR-based cell therapies may be an option for treating synovial sarcomas.

DOI： 10.1016/j.tranon.2022.101521

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Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/ol.2022.13562

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Polyamines are aliphatic hydrocarbons with terminal amino groups and are essential for biological activities. It has been reported that polyamines have health-promoting effects in animals, such as the extension of lifespan by polyamine intake. The identification of a high polyamine-producing bacterium from foods could lead to the development of a novel probiotic candidate. We aimed to identify high polyamine-producing bacteria from food, and isolated and collected bacteria from vegetables and fermented foods produced in Japan. We successfully acquired Latilactobacillus curvatus KP 3-4 isolated from Kabura-zushi as a putrescine producing lactic acid bacteria. Comparing the polyamine synthesis capability of L. curvatus KP 3-4 with that of typical probiotic lactic acid bacteria and L. curvatus strains available from the Japan Collection of Microorganisms, it was found that only L. curvatus KP 3-4 was capable of exporting high levels of putrescine into the culture supernatant. The enhancement of putrescine production by the addition of ornithine, and whole-genome analysis of L. curvatus KP 3-4, suggest that putrescine is synthesized via ornithine decarboxylase. The administration of L. curvatus KP 3-4 to germ-free mice increased the concentration of putrescine in the feces.

DOI： 10.3390/microorganisms10040697

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Development of effective in vitro human lip models, specific to the vermilion epithelium, has not progressed as much as that of skin and oral mucosa/gingiva models in vitro. Our histologic examination demonstrated that a Japanese macaque (male, 7 years and 9 months old) had vermilion in the lip distinct from adjacent skin and oral mucosa, resembling histological characteristics of the human lip. Therefore, in this study, we examined the gene expression profile of the three distinct epithelia (skin/vermilion/oral mucosa) within the lip of a Japanese macaque to explore a single potential marker of human vermilion epithelium. Six pairwise comparisons in the skin/vermilion/oral mucosa epithelium in vitro and in vivo revealed 69 differentially up-regulated genes in vermilion epithelium in vivo, in which a few unique genes were highly expressed when compared with both skin and oral mucosa epithelium in vivo using clustering analysis. However, we could not detect a single marker specific to vermilion epithelium supported by the gene expression profile of a Japanese macaque. Instead, the pair of keratin 10 and small proline-rich protein 3 resulted in a potential marker of vermilion epithelium in the human lip (female, 53-year-old) via a double-immunostaining technique. Nonetheless, our result may provide further clues leading to other potential markers of the vermilion epithelium.

DOI： 10.3390/anatomia1010002

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A germ line copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP, was identified in families with myeloproliferative neoplasm (MPN). Here, we show that mice lacking both Atg2b and Gskip, but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP, the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double-knockout fetal livers was significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.

DOI： 10.1128/MCB.00024-21

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Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

DOI： 10.3390/ijms222413367

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.csbj.2021.05.049

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OBJECTIVE: To explore potential mechanisms and effects of gallincin on a mouse model of colitis induced by dextran sulfate sodium (DSS). METHODS: Network pharmacology analysis was used to predict the molecular mechanism of action of gallincin for treatment of colitis. Gallincin was administered orally to mice with DSS-induced colitis. Expression of tumor necrosis factor α (TNF-α), D-lactate, and interleukin-1β (IL-1β) and myeloperoxidase activity were assessed with real-time quantitative PCR and an enzyme-linked immunoassay, respectively. Expression of occludin, zonula occludens 1 (ZO-1), and phosphorylated extracellular signal-regulated protein kinase1/2 (p-ERK1/2) was analyzed with immunohistochemical staining and/or western blot assays. RESULTS: Using a network pharmacology approach, 12 mapping targets between gallincin and colitis were obtained, including ERK/mitogen-activated protein kinase. Further investigations in an experimental colitis mouse model showed that gallincin significantly ameliorated experimental colitis, reduced D-lactate levels, and remarkably increased occludin and ZO-1 expression, possibly in part by decreasing IL-1β, TNF-α, and p-ERK1/2 levels and inhibiting leukocyte penetration. CONCLUSIONS: Gallincin regulated colonic barrier function and reduced colitis-associated inflammation, suggesting it is a promising drug for the treatment of ulcerative colitis.

DOI： 10.1177/0300060520951023

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer is one of the most common and clinically important diseases worldwide. The traditional Laeuren classification divides gastric cancer into two histopathological subtypes: diffuse and intestinal. Recent cancer genomics research has led to the development of a new classification based on molecular characteristics. The newly defined genomically stable (GS) subtype shares many cases with the histopathologically diffuse type. In this study, we performed genetic profiling of recurrently and significantly mutated genes in diffuse type and GS subtype tumors. We observed significantly different genetic characteristics, although the two subtypes overlapped in many cases. In addition, based on the profiles of the significantly mutated genes, we identified molecular functions and mutational signatures characteristic of each subtype. These results will advance the clinical application of the diffuse type and GS subtype gastric cancer in precision medicine for treating gastric cancer.

DOI： 10.1016/j.csbj.2020.10.021

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Microbiome studies estimate the functions of bacterial flora in situ on the basis of species composition and gene function; however, estimation of interspecies interaction networks is challenging. This study aimed to develop a method to predict the interaction networks among bacterial species from human gut metagenome data using bioinformatics methods. Our proposed method revealed that adjacent gene pairs involved in bacterial interspecies interactions are localized at boundary regions and encode membrane proteins mediating interactions between the intracellular and extracellular environments, e.g., transporters and channel proteins, and those mediating interactions between metabolic pathways. Actual human gut metagenome data displayed numerous such highly reliable interspecies interaction gene pairs in comparison with random simulated metagenome data sets, suggesting that the species composition of the actual microbiome facilitated more robust interspecific interactions. The present results indicate that molecular interaction networks in human gut flora are organized by a combination of interaction networks common to all individuals and group-specific interaction networks.

DOI： 10.1016/j.csbj.2019.07.011

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AIMS: SMAD4 acts as a tumour suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC) patients. Although next-generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC. METHODS AND RESULTS: We retrospectively investigated 201 patients with stage I-IV CRC, by using a 415-gene panel. To analyse the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive-front pathological markers: tumour budding, poorly differentiated cluster, and Crohn-like lymphoid reaction. Fifty-six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive-front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn-like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I-III disease, SMAD4 alteration was significantly associated with poor prognosis for relapse-free and overall survival (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival. CONCLUSION: SMAD4 alteration is associated with invasive-front pathological markers and poor prognosis in stage I-III CRC patients.

DOI： 10.1111/his.13805

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Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic alterations in a single assay. We aimed to identify molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC) using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary tumor resection were analyzed. We retrospectively investigated genetic alterations using CGS of a 415-gene panel. Clinicopathological variables and genetic alterations were analyzed to identify independent prognostic factors of overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11 patients underwent conversion surgery. Univariate and multivariate analyses identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC mutation as independent prognostic factors for OS (P = 0.041, P = 0.013, P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were mutually exclusive, and SRC mutation was significantly associated with left-sided tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and P = 0.025, respectively). Eleven of the 74 initially unresectable patients underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or SRC mutations. BRAF V600E and SRC mutations are important molecular markers which can predict prognosis and conversion surgery in Stage IV CRC.

DOI： 10.1038/s41598-019-39328-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.

DOI： 10.1038/s41598-017-18560-y

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Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.

DOI： 10.1111/cas.13870

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Gut microbiota of breast-fed infants are generally rich in bifidobacteria. Recent studies show that infant gut-associated bifidobacteria can assimilate human milk oligosaccharides (HMOs) specifically among the gut microbes. Nonetheless, little is known about how bifidobacterial-rich communities are shaped in the gut. Interestingly, HMOs assimilation ability is not related to the dominance of each species. Bifidobacterium longum susbp. longum and Bifidobacterium breve are commonly found as the dominant species in infant stools; however, they show limited HMOs assimilation ability in vitro. In contrast, avid in vitro HMOs consumers, Bifidobacterium bifidum and Bifidobacterium longum subsp. infantis, are less abundant in infant stools. In this study, we observed altruistic behaviour by B. bifidum when incubated in HMOs-containing faecal cultures. Four B. bifidum strains, all of which contained complete sets of HMO-degrading genes, commonly left HMOs degradants unconsumed during in vitro growth. These strains stimulated the growth of other Bifidobacterium species when added to faecal cultures supplemented with HMOs, thereby increasing the prevalence of bifidobacteria in faecal communities. Enhanced HMOs consumption by B. bifidum-supplemented cultures was also observed. We also determined the complete genome sequences of B. bifidum strains JCM7004 and TMC3115. Our results suggest B. bifidum-mediated cross-feeding of HMOs degradants within bifidobacterial communities.

DOI： 10.1038/s41598-018-32080-3

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Purpose: It has been suggested that the biological characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to show a higher incidence in Japan than in the US. However, most genomic studies of these tumors are from Western countries and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gather data primarily from non-Asian patients. Materials and Methods: We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes on Japanese TNBC patients (N=53) and compared the results to independent data obtained from TCGA (N=123). Results: Driver alterations were identified in 51 out of 53 Japanese patients (96%). Although the overall alteration spectrum of Japanese patients was similar to that of the TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutation burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35/53) of Japanese patients, as well as 66.7% (82/123) of the TCGA cohort, had alterations in at least one actionable gene targetable by an FDA-approved drug. Conclusion: Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

DOI： 10.1200/po.17.00211

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Asia  

Persisters are multidrug-tolerant cells that are present within antibiotic-sensitive populations. Persister formation is not induced by genetic mutations, but rather by changes in the degree of expression of some genes. High redundancy has been observed among the pathways that have been hypothesized to respond to specific stresses. In this study, we conducted RNA sequencing of Escherichia coli persisters under various stress conditions to identify common mechanisms. We induced stresses such as glucose or amino acid exhaustion, acid stress and anaerobic conditions, all of which are encountered during bacterial pathogenesis. We found that most genes are differentially expressed depending on the specific stress condition
however, some genes were commonly expressed in persisters in most stress conditions. Commonly expressed genes are expected to be promising therapeutic targets for combating persistent infections. We found that knockdown of aldehyde dehydrogenase (aldB), which was expressed in every condition except for acid stress, decreased persisters in the non-stressed condition. However, the same strain unexpectedly showed an increased number of persisters in the amino acid-limited condition. Because the increase in persister number is glycolytic metabolite-dependent, metabolic flow may play a crucial role in aldB-mediated persister formation. These data suggest that environmental stresses alter persister mechanisms. Identification of environmental influences on persister formation during pathogenesis is therefore necessary to enabling persister eradication.

DOI： 10.1111/1348-0421.12587

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Language：Japanese   Publisher：(株)篠原出版新社  

Stage IV大腸癌109例を対象とし、次世代シークエンサーを用いた癌遺伝子変異解析パネル(415遺伝子)で遺伝子変異を解析した。RAS変異群26例(23.9%)、RAS変異+PTEN欠失群16例(14.7%)、PTEN欠失+ERBB2増幅群16例(14.7%)、PTEN欠失+SRC増幅/欠失群8例(7.3%)、A11野生型群27例(24.8%)、BRAF変異+RNF43変異群9例(7.3%)、その他8例(7.3%)にカテゴリー分類された。実際に抗EGFR抗体薬を使用した40例の検討では、A11野生型群は、RASKETで判定できるKRAS/NRAS遺伝子以外の遺伝子に変異のある群に比べて、無増悪生存率(PFS)が有意に良好であった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing.
Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type".
Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004).
Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

DOI： 10.18632/oncotarget.20510

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.& para;& para;Methods: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tum or tissues were obtained from surgical or biopsy specimens and were subjected, to DMA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired, with US Food and Drug Administration-approved targeted therapies, and the evaluation o f Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.& para;& para;Results: Comprehensive genomic sequencing detected at least one alteration o f 435 cancer-related genes in 194 GCs (93.7%) and o f 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomicaliy stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated. phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six dusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM duster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC. with a remarkable response to anti-HER2 therapy in the ERBB2 duster.& para;& para;Conclusions: This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

DOI： 10.1186/s13073-017-0484-3

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Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as KV3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

DOI： 10.3389/fnins.2017.00307

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).
Methods: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.
Results: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.
Conclusions: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

DOI： 10.1186/s13073-016-0387-8

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Recently, targeted drugs have been developed for the treatment of colorectal cancer (CRC). Among targets, it is well known that KRAS mutations are associated with resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies. However, response rates using anti-EGFR monotherapy for CRC were less than 20-30% in previous clinical studies. Thus, because the RAS/MAP2K/MAPK and PI3K/AKT pathways are associated with CRC resistance to chemotherapy, we analyzed gene mutations in Stage IV CRC patients using a genomic test (CancerPlex®). Medical records were reviewed for 112 patients who received treatment for CRC between 2007 and 2015 in Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital. There were 66 male and 46 female patients, and their median age was 62.5 (range, 30-86) years. Cluster analyses were performed in 110 non-hypermutated Japanese CRC patients using Euclidean distance and Ward's clustering method, and 6 typical groups were identified. Among these, patients with all wild-type actionable genes benefited from anti-EGFR therapies. The expense of targeted drugs warrants consideration of cost-effectiveness during treatment decision-making for advanced CRC patients. To this end, based on the genetic information on CRC, it is possible to develop precision medicine using CancerPlex®.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: The stigma of schizophrenia constitutes a major barrier to early detection and treatment of this illness. Anti-stigma education has been welcomed to reduce stigma among the general public. This study examined the factors associated with the effectiveness of a web-based educational program designed to reduce the stigma associated with schizophrenia.
Methods: Using Link's Devaluation-Discrimination Scale to measure stigma, the effect of the program was measured by the difference in pre-and post-program tests. In the present study, we focused on program participants whose stigma towards schizophrenia had considerably improved (a reduction of three points or more between pre-and post-program tests) or considerably worsened (an increase of three points or more). The study participants were 1,058 parents of middle or high school students across Japan, including 508 whose stigma had significantly decreased after the program and 550 whose stigma had significantly increased. We used multiple logistic regression analysis to predict a considerable reduction in stigma (by three or more points) using independent variables measured before exposure to the program. In these models, we assessed the effects of demographic characteristics of the participants and four measures of knowledge and views on schizophrenia (basic knowledge, Link's Devaluation-Discrimination Scale, ability to distinguish schizophrenia from other conditions, and social distance).
Results: Participants' employment status, occupation, basic knowledge of schizophrenia, pre-program Link's Devaluation-Discrimination Scale score, and social distance were significant factors associated with a considerable decrease in the stigma attached to schizophrenia following the educational program. Specifically, full-time and part-time employees were more likely to experience reduced stigma than parents who were self-employed, unemployed, or had other employment status. Considerable decreases in stigma were more likely among parents working in transportation and communication or as homemakers than among other occupational groups. In addition, parents with higher pre-program levels of stigma, lower basic knowledge, or lower social distance were more likely to have reduced levels of stigma.
Conclusions: Based on the regression analysis results presented here, several possible methods of reducing stigma were suggested, including increasing personal contact with people with schizophrenia and the improvement of law and insurance systems in primary and secondary industries.

DOI： 10.1186/1471-2458-14-258

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Language：Japanese  

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Other Link： http://hdl.handle.net/10191/36218

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DOI： 10.3892/mco.2013.142

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Language：English   Publisher：Scientific Research Publishing  

DOI： 10.4236/health.2012.47061

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Objective: The cost-effectiveness of renal replacement therapy (RRT) is affected by the composition of treatment. This study aimed to estimate the costs and outcomes associated with changing the composition of RRT modality over time. Methods: By using clinical and cost data from a systematic review, a Markov model was developed to assess the costs and benefits of the four main treatments available for RRT in Japan. The model included direct health service costs and quality-adjusted life years (QALY). Sensitivity analyses were performed to assess the robustness of the results. Results: Over the 15-year period of the model, the current composition of RRT (i.e., the base composition of RRT) was $84,008/QALY. The most cost-effective treatment was when the likelihood of a living donor transplant was increased by 2.4-times ($70,581/QALY). Compared with the base composition of RRT, dominant treatments with respect to cost-effectiveness were when the likelihood of a deceased donor transplant was increased by 22-times and when the likelihood of a pre-emptive living donor transplant was increased by 2.4-times. Little difference was found between these two treatments. One-way sensitivity analysis did not change the cost effectiveness except for costs of chronic hemodialysis and a living donor transplant in subsequent years. Limitations: It is difficult to increase the rate of transplant overall in the shorter term nationally and internationally. Conclusions: Appropriate distribution of all transplant options and hemodialysis is necessary to achieve the most cost-effective solution. © 2012 Informa UK Ltd All rights reserved.

DOI： 10.3111/13696998.2011.653512

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOHOKU UNIV MEDICAL PRESS  

The incidence of esophageal squamous cell carcinoma (ESCC), which is the eighth most common malignancy worldwide, is highest in China. The purpose of this study was to investigate the association between nitrogen compounds in drinking water with the incidence of ESCC by geographical spatial analysis. The incidence of ESCC is high in Shexian county, China, and environmental factors, particularly nitrogen-contaminated drinking water, are the main suspected risk factors. This study focuses on three nitrogen compounds in drinking water, namely, nitrates, nitrites, and ammonia, all of which are derived mainly from domestic garbage and agricultural fertilizer. The study surveyed 48 villages in the Shexian area with a total population of 54,716 (661 adults with ESCC and 54,055 non-cancer subjects). Hot-spot analysis was used to identify spatial clusters with a high incidence of ESCC and a high concentration of nitrogen compounds. Logistic regression analysis was used to detect risk factors for ESCC incidence. Most areas with high concentrations of nitrate nitrogen in drinking water had a high incidence of ESCC. Correlation analysis revealed a significant positive relationship between nitrate concentration and ESCC (P = 0.01). Logistic regression analysis also confirmed that nitrate nitrogen has a significantly higher odds ratio. The results indicate that nitrate nitrogen is associated with ESCC incidence in Shexian county. In conclusion, high concentrations of nitrate nitrogen in drinking water may be a significant risk factor for the incidence of ESCC.

DOI： 10.1620/tjem.226.11

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Other Link： http://hdl.handle.net/10191/29605

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOHOKU UNIV MEDICAL PRESS  

The incidence of esophageal adenocarcinoma has been rising in many countries, while esophageal squamous cell carcinoma has remained stable or even declined in the same populations over the identical periods. These differences in trends indicate that these cancer subtypes may have a different etiology, which may be caused by lifestyle factors such as alcohol consumption and cigarette smoking. Therefore, a matched case-control study to clarify the risk factors of alcohol and tobacco intake on the development of esophageal adenocarcinoma was collected in Hebei Province of China. The life expectancy of the study area was around 70 years old. In the present study, 98 patients younger than 65 years who were diagnosed with esophageal adenocarcinoma and had initial surgeries (cases) were matched with 294 healthy adults (controls) at a ratio of 1:3 according to sex and age. We found the proportions of drinkers and smokers among cases were 48.0% and 60.2%, respectively, versus 21.2% and 43.5% among controls. Univariate conditional logistic regression analyses revealed that the odds ratios (ORs) showed a nearly monotonic increase for the duration of alcohol consumption and duration of tobacco smoking. Multivariate conditional logistic regression analysis indicated that only alcohol consumption was a significant risk factor for esophageal adenocarcinoma. Additional analysis of the combination of amount and duration of alcohol consumption indicated that heavy drinkers (&gt; 30 ml/day) had significantly higher ORs, irrespective of the duration of alcohol consumption. In conclusion, heavy alcohol consumption increases the risk for esophageal adenocarcinoma independent of the duration of such consumption.

DOI： 10.1620/tjem.224.21

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Language：Japanese   Publisher：日本乳酸菌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2018.36.15_suppl.e13111

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.e15592

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Language：Japanese  

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(株)癌と化学療法社  

近年、進行再発大腸癌に対する分子標的薬治療が急速に発展している。KRAS遺伝子変異が抗EGFR抗体薬の抵抗性に関与することはすでによく知られている。しかし、KRAS遺伝子野生型であっても、実臨床では抗EGFR抗体薬の効果は20〜30%までの上乗せにとどまる。この理由として、RAS/MAP2K/MAPK経路やPI3K/AKT経路の関連が考えられている。本研究では、遺伝子変異解析パネルであるCancerPlexを用いてStage IV大腸癌に対する遺伝子変異を解析した。2007〜2015年に新潟大学医歯学総合病院、新潟県立がんセンター新潟病院を受診したStage IV大腸癌112例を対象とした。内訳は男性66例、女性46例。年齢中央値は62.5歳であった。2例はhypermutated症例であった。残りの110例を対象としてクラスタリング解析を行った。分子標的薬のターゲット候補である26遺伝子をクラスタリングに使用した。各患者がもつ共起プロファイル間のユークリッド距離を値にもつ行列からWard法によるクラスタリングを行うと、六つのサブタイプに分類された。これにより、抗EGFR抗体薬が奏効する患者群を分類できると考える。分子標的薬は高額であるため、費用対効果を考慮した大腸癌治療戦略が重要である。CancerPlexを用いることで遺伝子情報に基づいた&quot;Precision Medicine&quot;が可能になると考える。(著者抄録)

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