Biomedical subjects

Yutaka Suzuki

Publications and source records attributed to Yutaka Suzuki.

At least 19 recordsLinked to original sources

PubMed2026

YAP1 induces hepatocellular carcinoma via DNA demethylation rather than by canonical driver gene mutations.

Large-scale genome sequencing analyses have identified driver gene mutations (DGMs) in most cancers as well as their associated tumorigenic mechanisms. However, a small fraction of cancers are not positive for these canonical DGMs, leaving the mechanisms underpinning their formation a mystery. We hypothesized that canonical DGM-negative cancers might be driven by activation of the transcriptional coactivator YAP1 that led to the induction of epigenetic changes. To test this theory, we established a mouse mosaic model of hepatocellular carcinoma (HCC) in which we induced YAP1-TEAD activation in a few hepatocytes. Whole-exome sequencing did not identify canonical DGMs in HCCs, but bisulfite sequencing revealed widespread DNA demethylation leading to the transcriptional activation of multiple oncogenes. Knockdown of the DNA demethylation-promoting gene, Tet1, attenuated HCC formation in these mice. Single-cell spatial transcriptomics identified a Tet1-high subpopulation of HCC cells that interacted with other hepatic cell types. Our mechanistic mouse data align with the observation that YAP1-TEAD-TET1-associated signatures were also elevated in hepatocytes from patients with Fontan-associated liver disease (FALD), a condition associated with the development of HCCs with lower frequencies of canonical DGMs. Our study suggests that the YAP1-TEAD-TET1 axis promotes canonical DGM-negative HCC development, and provides new insights into the molecular processes involved.

Animals↗

PubMed2026

Hox/Meis-dependent gene-regulatory transition underlies cardiopharyngeal neural crest diversification.

Neural crest cells (NCCs) are multipotent migratory cells essential for cardiac development, yet the lineage trajectories and gene regulatory networks underlying their differentiation in the cardiopharyngeal region remain unclear. Here, we integrate single-cell RNA-seq, spatial transcriptomics, and multiomic analyses to construct a comprehensive map of NCC lineages in developing mouse cardiopharyngeal tissues. We identify a transition from Hox-positive pharyngeal NCCs to Hox-negative intracardiac populations associated with the outflow tract cushion, accompanied by a shift in Meis transcription factor binding and gene-regulatory network architecture. By contrast, NCCs forming the aorticopulmonary septum and great vessel smooth muscle retain distinct Hox-codes. A Meis2-Sox9-Scx gene-regulatory network defines a skeletogenic progenitor-like intermediate state that gives rise to coronary artery smooth muscle and semilunar valves. Our findings suggest that the loss of Hox-dependent regional identity enables pharyngeal NCCs to acquire new fates upon entering the cardiac cushion, providing insight into the developmental origins of coronary and valvular calcification.

Journal Article↗

PubMed2026

Spatial transcriptomics of Ciona adult brains reveals functional zonalization and insights into neural gland function.

The ascidian Ciona is a pivotal chordate model for illuminating the evolutionary origins of the vertebrate brain. Here, spatial transcriptomics of the adult Ciona neural complex, combined with image-based computational super-resolution mapping, resolved distinct tissue domains including the cerebral ganglion, neural gland, ciliated funnel, neural gland duct/dorsal strand, and body wall muscle. Within the cerebral ganglion, high-resolution mapping revealed clear molecular zonalization separating the cortex and medulla, alongside regional specialization within the cortex itself. The neural gland exhibited localized enrichment of genes associated with extracellular matrix and cell-cell interactions. These spatial features suggest that the neural gland functions as a homeostatic and signaling interface, reminiscent of primitive vertebrate meninges or choroid plexus. Overall, this spatially defined gene expression map provides a foundational framework for understanding functional regionalization in the tunicate brain and its evolutionary relationship to vertebrate nervous systems.

Ciona↗

PubMed2026

Circulating tumor-associated autoantibody signatures for diagnosis and prognosis in small-cell lung cancer and lung adenocarcinoma.

BACKGROUND: Tumour-associated autoantibodies (TAAbs) are promising biomarkers for cancer detection, but their induction and clinical relevance in lung cancer remain unclear. METHODS: Serum samples from 695 individuals were analysed for TAAb profiling by protein-array screening and two-stage ELISA validation. Diagnostic models were constructed with identified TAAbs and compared with conventional tumour markers. Potential mechanisms, clinical and prognostic features of TAAb seropositivity were analysed and its presence in prediagnostic sera was evaluated to assess the potential for early detection. RESULTS: Six TAAbs for small cell lung cancer (SCLC) and four for lung adenocarcinoma (LUAD) were identified, demonstrating excellent diagnostic performance (AUC > 0.8) and outperforming ProGRP and CEA. TAAb induction correlated with antigen overexpression, somatic mutations and HLA class II amino acid polymorphisms. TAAb panel seropositivity was associated with older age and advanced stage in both subtypes, and predicted poor survival in SCLC but a favourable outcome in advanced LUAD. In prediagnostic sera, the TAAb concentration increased progressively, with detectability up to 2 years before clinical diagnosis. CONCLUSIONS: Distinct TAAb panels were identified for SCLC and LUAD, serving as accurate diagnostic markers that enable early detection and as indicators of prognosis in different clinical contexts.

Humans↗

PubMed2026

Giants within: a new class of microbial mobile elements.

Prokaryotes harbor a diverse spectrum of extrachromosomal elements (ECEs), which are intracellular replicons maintained independently of the primary chromosome. Historically, the ECE research field has focused on relatively small ECEs, such as plasmids. However, the advent of long-read sequencing has revealed that prokaryotes also harbor various types of giant ECEs, spanning hundreds of kilobases to over 1 Mb, that were not hitherto recognized. In this review, we describe how long-read sequencing has enabled the discovery of giant ECEs and compare the genetic architectures and functional repertoires of several recently characterized examples. The functions of most genes in these ECEs remain uncharacterized, and current computational tools frequently misclassify or overlook them. We further discuss how the discovery of these giant ECEs challenges existing classification frameworks that attempt to distinguish megaplasmids, chromids, and chromosomes. Together, these findings highlight giant ECEs as a largely unexplored layer of microbial genetics, whose characterization will have broad implications for our understanding of microbial adaptation and horizontal gene transfer.

Extrachromosomal DNA↗

PubMed2025

2,3-Pyridinedicarboxylate Is Associated with Shorter Recurrence-Free Survival in Patients with Hypopharyngeal Squamous Cell Carcinoma.

UNLABELLED: Introduction: Metabolites are associated with the biology of cancer; however, no metabolites related to prognosis have been identified in head and neck cancer. This study aimed to identify metabolites associated with prognosis in patients with hypopharyngeal squamous cell carcinoma (HPSCC). METHODS: Fifty-two patients who underwent surgery for HPSCC were included and randomly divided into test and validation cohorts of 26 patients each for further metabolome analysis using capillary electrophoresis/mass spectrometry on tumor and non-tumor tissues of the hypopharynx. Twenty-two patients who received adjuvant therapy after surgery were included. The receiver operating characteristic (ROC) and univariate and multivariate analyses were used to explore the relationship between recurrence-free survival (RFS), clinicopathological factors, and differentiated metabolites. RESULTS: ROC analysis revealed six metabolites significantly associated with RFS in both cohorts, and multivariate analysis indicated that 2,3-pyridinedicarboxylate was a significantly independent poorer prognostic factor in the cohorts including patients with HPSCC without any adjuvant therapies (p = 0.017). CONCLUSION: 2,3-Pyridinedicarboxylate, involved in NAD+ metabolism and genomic stability, suggests the possibility of developing molecular-targeted drugs for the production of metabolites related to prognosis. This study identifies novel prognostic metabolites and their associated metabolic pathways in HPSCC, highlighting potential therapeutic targets for treatment. .

Humans↗

PubMed2025

STEMIN transcription factor drives selective chromatin remodeling for gene activation within a relaxed chromatin during reprogramming in the moss Physcomitrium patens.

Land plants exhibit remarkable cellular plasticity, readily reprogramming differentiated cells into stem cells in response to internal and external stimuli. While chromatin remodeling is crucial for cellular reprogramming, its interplay with gene expression during reprogramming into stem cells remains elusive. In the moss Physcomitrium patens, wounding induces reprogramming of leaf cells facing wounded cells to change into chloronema apical stem cells through the activation of the AP2/ERF transcription factor STEMIN. In this study, we employed multimodal single-nuclei RNA and ATAC sequencing to explore the interplay between gene expression and chromatin dynamics during STEMIN-mediated reprogramming. Profiling 20 883 single-nuclei from gametophores, protonemata, and cut leaves, we identified 11 distinct cell types including reprogramming leaf cells. Our analysis revealed that reprogramming leaf cells exhibit a partly relaxed chromatin landscape and STEMIN transcription factors selectively enhance accessibility at specific genomic loci essential for stem cell formation. Thus, our results indicate that wounding initiates a broad chromatin relaxation, creating a permissive environment and specific transcription factors act to refine this permissive state by specifically relaxing chromatin regions critical for reprogramming.

Bryopsida↗

PubMed2024

Targeted Dynamic Phospho-Proteogenomic Analysis of Gastric Cancer Cells Suggests Host Immunity Provides Survival Benefit.

Despite of massive emergence of molecular targeting drugs, the mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using a reverse-phase protein array-based proteogenomic analysis of a panel of 8 GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs, including 5-fluorouracil (5FU), cisplatin, and etoposide. Resistance to cisplatin and etoposide, but not 5FU, was negatively associated with global copy number loss, vimentin expression, and caspase activity, which are considered hallmarks of previously established EMT subtype. The segregation of 19,392 protein expression time courses by sensitive and resistant cell lines for the drugs tested revealed that 5FU-resistant cell lines had lower changes in global protein dynamics, suggesting their robust protein level regulation, than their sensitive counterparts, whereas the cell lines that are resistant to other drugs showed increased protein dynamics in response to each drug. Despite faint global protein dynamics, 5FU-resistant cell lines showed increased signal transducer and activator of transcription 1 phosphorylation and PD-L1 expression in response to 5FU. In publicly available cohort data, expression of signal transducer and activator of transcription 1 and NFκB target genes induced by proinflammatory cytokines was associated with prolonged survival in GC. In our validation cohort, total lymphocyte count, rather than PD-L1 positivity, predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, total lymphocyte count+ patients who had no survival benefit from adjuvant chemotherapy were discriminated by expression of IκBα, a potent negative regulator of NFκB. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.

Stomach Neoplasms↗

PubMed2006

Comparasite: a database for comparative study of transcriptomes of parasites defined by full-length cDNAs.

Comparasite is a database for comparative studies of transcriptomes of parasites. In this database, each data is defined by the full-length cDNAs from various apicomplexan parasites. It integrates seven individual databases, Full-Parasites, consisting of numerous full-length cDNA clones that we have produced and sequenced: 12,484 cDNA sequences from Plasmodium falciparum, 11,262 from Plasmodium yoelii, 9633 from Plasmodium vivax, 1518 from Plasmodium berghei, 7400 from Toxoplasma gondii, 5921 from Cryptosporidium parvum and 10,966 from the tapeworm Echinococcus multilocularis. Putatively counterpart gene groups are clustered and comparative analysis of any combination of six apicomplexa species is implemented, such as interspecies comparisons regarding protein motifs (InterPro), predicted subcellular localization signals (PSORT), transmembrane regions (SOSUI) or upstream promoter elements. By specifying keywords and other search conditions, Comparasite retrieves putative counterpart gene groups containing a given feature in common or in a species-specific manner. By enabling multi-faceted comparative analyses of genes of apicomplexa protozoa, monophyletic organisms that have evolved to diversify to parasitize various hosts by adopting complex life cycles, Comparasite should help elucidate the mechanism behind parasitism. Our full-length cDNA databases and Comparasite are accessible from http://fullmal.ims.u-tokyo.ac.jp.

Animals↗

PubMed2006

H-DBAS: alternative splicing database of completely sequenced and manually annotated full-length cDNAs based on H-Invitational.

The Human-transcriptome DataBase for Alternative Splicing (H-DBAS) is a specialized database of alternatively spliced human transcripts. In this database, each of the alternative splicing (AS) variants corresponds to a completely sequenced and carefully annotated human full-length cDNA, one of those collected for the H-Invitational human-transcriptome annotation meeting. H-DBAS contains 38,664 representative alternative splicing variants (RASVs) in 11,744 loci, in total. The data is retrievable by various features of AS, which were annotated according to manual annotations, such as by patterns of ASs, consequently invoked alternations in the encoded amino acids and affected protein motifs, GO terms, predicted subcellular localization signals and transmembrane domains. The database also records recently identified very complex patterns of AS, in which two distinct genes seemed to be bridged, nested or degenerated (multiple CDS): in all three cases, completely unrelated proteins are encoded by a single locus. By using AS Viewer, each AS event can be analyzed in the context of full-length cDNAs, enabling the user's empirical understanding of the relation between AS event and the consequent alternations in the encoded amino acid sequences together with various kinds of affected protein motifs. H-DBAS is accessible at http://jbirc.jbic.or.jp/h-dbas/.

Alternative Splicing↗

PubMed2006

Impact of prophylactic mupirocin for radical esophagectomy.

The preoperative intranasal application of mupirocin significantly decreases the rate of nosocomial S. aureus infections among patients who are S. aureus carriers. However, it remains unclear whether the routine preoperative use of mupirocin would reduce postoperative S. aureus infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infections, and who would benefit from the prophylactic use of mupirocin. Ninety-six consecutive patients who had undergone elective radical esophagectomy with right thoracotomy and laparotomy were evaluated. Fifty-one patients were given 2% mupirocin calcium ointment 3 times daily over 3 consecutive days before surgery. Uni- and multivariate analyses were performed to identify factors affecting the following three issues: postoperative MRSA infection, postoperative pneumonia, and the length of postoperative hospital stay. In univariate analyses, the preoperative application of mupirocin significantly reduced MRSA infection, postoperative pneumonia, and length of postoperative hospital stay. Multivariate analyses indicated significant associations between mupirocin administration and reductions in both MRSA infection and postoperative pneumonia, but not in length of postoperative hospital stay. Radical esophagectomy with right thoracotomy and laparotomy for esophageal carcinoma warranted the preoperative prophylactic administration of mupirocin in order to reduce postoperative infectious complications from MRSA. Its routine use for such a high-risk procedure is entirely reasonable.

Administration, Intranasal↗

PubMed2006

Diverse DNA methylation statuses at alternative promoters of human genes in various tissues.

We characterized the DNA methylation status at 144 tissue-biased and 37 non-tissue-biased alternative promoters of 61 human genes in five normal tissues. Analysis of the collected data revealed that (i) DNA methylation status differed greatly among alternative promoters belonging to the same gene; (ii) DNA methylation status differed between tissues for the majority of the individual promoters, and (iii) 80-90% of CpG-island-containing promoters were not methylated on either allele throughout the five tissues examined. Furthermore, although the statistical significance was not as clear as for the above features, we also found that (iv) the DNA methylation patterns of tissue-biased promoters changed more drastically than those of non-tissue-biased promoters; (v) tissue-biased promoters tended to be less methylated than their respective alternative promoters in the tissues where they were preferentially expressed, and (vi) the 'null' methylation pattern of a given promoter was enriched in the tissues where the transcription was most active. These findings together indicate that there are dynamic physiological changes of DNA methylation. DNA methylation appears to play a significant role in differential usage of alternative promoters and may be related to functional diversification between CpG-island-containing promoters and CpG-island-less promoters.

Brain↗

PubMed2006

Large-scale identification and characterization of alternative splicing variants of human gene transcripts using 56,419 completely sequenced and manually annotated full-length cDNAs.

We report the first genome-wide identification and characterization of alternative splicing in human gene transcripts based on analysis of the full-length cDNAs. Applying both manual and computational analyses for 56,419 completely sequenced and precisely annotated full-length cDNAs selected for the H-Invitational human transcriptome annotation meetings, we identified 6877 alternative splicing genes with 18 297 different alternative splicing variants. A total of 37,670 exons were involved in these alternative splicing events. The encoded protein sequences were affected in 6005 of the 6877 genes. Notably, alternative splicing affected protein motifs in 3015 genes, subcellular localizations in 2982 genes and transmembrane domains in 1348 genes. We also identified interesting patterns of alternative splicing, in which two distinct genes seemed to be bridged, nested or having overlapping protein coding sequences (CDSs) of different reading frames (multiple CDS). In these cases, completely unrelated proteins are encoded by a single locus. Genome-wide annotations of alternative splicing, relying on full-length cDNAs, should lay firm groundwork for exploring in detail the diversification of protein function, which is mediated by the fast expanding universe of alternative splicing variants.

Alternative Splicing↗

PubMed2006

Common inheritance of chromosome Ia associated with clonal expansion of Toxoplasma gondii.

Toxoplasma gondii is a globally distributed protozoan parasite that can infect virtually all warm-blooded animals and humans. Despite the existence of a sexual phase in the life cycle, T. gondii has an unusual population structure dominated by three clonal lineages that predominate in North America and Europe, (Types I, II, and III). These lineages were founded by common ancestors approximately10,000 yr ago. The recent origin and widespread distribution of the clonal lineages is attributed to the circumvention of the sexual cycle by a new mode of transmission-asexual transmission between intermediate hosts. Asexual transmission appears to be multigenic and although the specific genes mediating this trait are unknown, it is predicted that all members of the clonal lineages should share the same alleles. Genetic mapping studies suggested that chromosome Ia was unusually monomorphic compared with the rest of the genome. To investigate this further, we sequenced chromosome Ia and chromosome Ib in the Type I strain, RH, and the Type II strain, ME49. Comparative genome analyses of the two chromosomal sequences revealed that the same copy of chromosome Ia was inherited in each lineage, whereas chromosome Ib maintained the same high frequency of between-strain polymorphism as the rest of the genome. Sampling of chromosome Ia sequence in seven additional representative strains from the three clonal lineages supports a monomorphic inheritance, which is unique within the genome. Taken together, our observations implicate a specific combination of alleles on chromosome Ia in the recent origin and widespread success of the clonal lineages of T. gondii.

Animals↗

PubMed2006

DBTSS: DataBase of Human Transcription Start Sites, progress report 2006.

DBTSS was first constructed in 2002 based on precise, experimentally determined 5' end clones. Several major updates and additions have been made since the last report. First, the number of human clones has drastically increased, going from 190,964 to 1,359,000. Second, information about potential alternative promoters is presented because the number of 5' end clones is now sufficient to determine several promoters for one gene. Namely, we defined putative promoter groups by clustering transcription start sites (TSSs) separated by <500 bases. A total of 8308 human genes and 4276 mouse genes were found to have putative multiple promoters. Third, DBTSS provides detailed sequence comparisons of user-specified TSSs. Finally, we have added TSS information for zebrafish, malaria and schyzon (a red algae model organism). DBTSS is accessible at http://dbtss.hgc.jp.

Animals↗

PubMed2006

Covering the percutaneous endoscopic gastrostomy (PEG) tube prevents peristomal infection.

BACKGROUND: Because oropharyngeal bacteria can be brought through the abdominal wall during percutaneous endoscopic gastrostomy (PEG), peristomal infection is one of the most frequent complications in patients who undergo the procedure. This study aimed to determine whether covering the PEG tube with a sheath that could be detached in the stomach could help prevent peristomal infection. METHODS: In three community hospitals in Japan, data from 449 patients with swallowing dysfunction were prospectively collected between March 2000 and February 2002 for non-covered PEG (n=206) and between March 2002 and February 2004 for covered PEG (n=243). RESULTS: After adjusting for hospital, age, gender, and underlying diseases, covering the PEG significantly reduced peristomal purulent infection compared with non-covered PEG (odds ratio: 0.05; 95% confidence interval: 0.02-0.13). Body temperature, white blood cell count, and C-reactive protein at day 3 after PEG placement, as well as duration of antibiotics usage, were significantly lower or shorter in patients treated with covered PEG than non-covered PEG. In spite of the same frequencies in the two groups of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in oropharyngeal cultures before PEG placement, these organisms were detected significantly less frequently in peristomal lesions of patients who underwent covered PEG. Moreover, 28 patients treated with covered PEG received no antibiotic therapy, and 27 of them had no signs of peristomal infection. CONCLUSIONS: These results suggest that covering the PEG tube, with or without providing antibiotic therapy, may prevent peristomal infection in spite of the presence of oropharyngeal bacterial flora after percutaneous endoscopic gastrostomy.

Aged↗

PubMed2006

Therapeutic effects of a laparoscopic Heller myotomy and Dor fundoplication on the chest pain associated with achalasia.

PURPOSE: The therapeutic effects of a laparoscopic Heller myotomy and Dor fundoplication (LHD) on the chest pain associated with achalasia were investigated. METHODS: Sixty-six patients who were diagnosed to have achalasia underwent LHD. The degree of dilatation was assessed based on the maximum horizontal diameter of the esophagus (Grades I-III). The type of dilatation was assessed based on the shape of the distal esophagus, namely, spindle type (Sp), flask type (Fk), and sigmoid type (Sig). The degree of improvement was classified into three grades as follows: A (complete disappearance), B (partial response), and C (unchanged). RESULTS: Chest pain improved (A or B) in 22 patients (92%). The statistical results revealed that the improvement of postoperative A or B was significantly better in patients with Sp than in those with Fk or Sig (P = 0.0213). In addition, the results revealed that the improvement of postoperative A or B was significantly better in patients with grade I and grade II than in those with grade III (P = 0.004). CONCLUSION: LHD is an effective therapeutic technique for the treatment of chest pain associated with achalasia. These results suggest that both the morphological type and esophageal dilatation are useful predictors for the improvement of chest pain after surgical therapy.

Adolescent↗

PubMed2006

Therapeutic effects of laparoscopic fundoplication for nonerosive gastroesophageal reflux disease.

PURPOSE: Surgical treatments for nonerosive gastroesophageal reflux disease (NERD) have not been investigated sufficiently. We examined the results of laparoscopic fundoplication for patients with NERD. METHODS: We performed laparoscopic fundoplication for NERD in 22 patients. The severity of esophageal hiatal hernia, morphology of the cardiac orifice, and results of 24-hour continuous esophageal and gastric pH were evaluated. We used a four-point scale for the improvement rating of postoperative symptoms. RESULTS: There were 20 patients (91%) with a sliding hiatal hernia, and 21 patients (95%) with a loose cardiac orifice. Seven patients had acid reflux with 4.0% or higher esophageal fraction of time pH below 4. The surgical techniques used were Nissen fundoplication in 10 patients and Toupet fundoplication in 12 patients. Improvement of postoperative heartburn was rated as excellent in 16 patients, good in 5, and fair in 1. The overall efficacy rating was 95%, and discontinuation of proton pump inhibitor (PPI) was possible in 21 patients. CONCLUSION: Our results of performing laparoscopic fundoplication in patients with NERD were excellent. Even if abnormal acid reflux cannot be confirmed preoperatively, sufficient therapeutic efficacy can be expected for patients with esophageal hiatal hernia or a loose cardiac orifice.

Adult↗