Publications by authors named "Makoto Iimori"

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  • Trifluridine (FTD) is a chemotherapy drug used for cancer treatment, but its cytotoxic mechanism is not fully understood, particularly in relation to mutations in the TP53 gene, which are known to impact cancer progression and drug resistance.
  • This study uncovered that FTD leads to DNA damage and abnormal cell division (mitosis) in both cells lacking p53 and those with gain-of-function TP53 mutations, though it failed to enforce a proper cell cycle checkpoint during G2/M transition.
  • The research indicates that FTD's effectiveness as an anti-tumor agent operates independently of p53 functionality, suggesting that it can be effective even in the presence of the mutant forms of p53 that typically enhance resistance to chemotherapy
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  • Prof. Setsuro Fujii made major contributions to drug discovery in Japan, creating nine impactful medications.
  • Among these are notable anticancer drugs like FT, UFT, S-1, and FTD/TPI, as well as therapeutic drugs for other conditions including cetraxate hydrochloride and pravastatin sodium.
  • His work continues to inspire ongoing research in drug discovery, providing hope to patients worldwide.
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  • CD44 is a versatile adhesion molecule involved in development and cancer progression, with various mRNA isoforms due to alternative splicing, but their specific functions are still not entirely clear.
  • In gastric cancer cells, specific CD44 variant isoforms (CD44v8-10 and CD44v3,8-10) enhance the expression of vimentin during TGF-β1-induced epithelial-mesenchymal transition (EMT), leading to increased migration and invasion.
  • In clinical samples from gastric cancer patients, the presence of CD44v9 correlates with EMT characteristics and indicates worse prognosis due to associations with deeper tumor invasion and lymph node metastasis.
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  • DNA replication stress (DRS) is a major factor in genome instability and cancer progression, and certain chemotherapy drugs worsen this stress in tumor cells.
  • The study reveals that trifluridine, a nucleoside analogue, disrupts DNA synthesis and raises DRS by altering nucleotide levels and acting as an obstacle during replication.
  • Results suggest that DRS leads to different outcomes based on p53 status in tumor cells, promoting either cellular senescence or apoptosis, highlighting the potential effectiveness of chemotherapeutics that induce DRS.
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Chromosomal instability, one of the most prominent features of tumour cells, causes aneuploidy. Tetraploidy is thought to be an intermediate on the path to aneuploidy, but the mechanistic relationship between the two states is poorly understood. Here, we show that spindle polarity (e.

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Introduction: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them.

Materials And Methods, And Results: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability.

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Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because TK1-specific-deficient human cancer cell lines have not been established.

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Background: It is essential to establish a strategy for second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer; however, HER2 expression status after chemotherapy treatment is not routinely determined.

Materials And Methods: We analyzed 25 cases of gastric cancer that received preoperative chemotherapy and selected the six pre-treatment samples that were HER2-positive. Pre- and post-treatment tumor samples were examined for HER2 expression, and for HER2, epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (MET) gene amplification.

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  • * MDC1 is identified as a key adapter in the DNA damage response, and its methylation, regulated by EHMT1 and EHMT2, is necessary for recruiting repair factors to sites of DNA double-strand breaks.
  • * The interaction between MDC1 and EHMT1 is strengthened by DNA damage signals, allowing EHMT2 to modify MDC1, which in turn enhances the recruitment of other DNA repair proteins and promotes genomic stability.
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Background: E-cadherin and vimentin are regarded as major conventional canonical markers of the epithelial-mesenchymal transition. It is commonly assumed that E-cadherin is uniformly lost during the process of epithelial-mesenchymal transition. Breast tumor cells typically invade as a cohesive multicellular unit in a process called collective invasion.

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  • Trifluridine/tipiracil (TFTD) is an oral anti-cancer drug effective for metastatic colorectal cancer (mCRC), with its active ingredient, trifluridine (FTD), integrating into DNA to exert its effects.
  • Researchers successfully identified FTD in various tissues, including bone marrow and spleen cells from mice, as well as in the blood of mCRC patients treated with TFTD, suggesting it's incorporated into their cells.
  • The study found fluctuations in FTD-positive cells in mCRC patients, indicating that monitoring these levels could help predict the treatment's effectiveness and potential side effects.
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Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood.

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DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS).

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Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H.

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  • Chromosomal instability (CIN), marked by aneuploidy, is a key molecular type of gastric cancer, with the deubiquitinase USP44 playing a vital role in regulating proper chromosome separation.
  • A study of 207 gastric cancer patients revealed that higher USP44 expression in tumors (39.6%) compared to normal tissue (14.6%) correlates strongly with DNA aneuploidy and poorer overall survival rates.
  • Specifically, high USP44 expression serves as a significant poor prognostic factor for patients with aneuploid gastric cancer, influencing progression-free survival and overall survival outcomes.
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MutT homolog-1 (MTH1) is a pyrophosphatase that acts on oxidized nucleotides and hydrolyzes 8-oxo-2'-deoxyguanosine triphosphate in deoxynucleoside triphosphate pool to prevent its incorporation into nuclear and mitochondrial DNA, result in reduce cytotoxicity in tumor cells. MTH1 is overexpressed in various cancers and is considered as a therapeutic target. Environmental factors such as cigarette smoking and alcohol consumption are critical risk factors for the development and progression of esophageal squamous cell carcinoma (ESCC), suggesting that oxidative stress contributes to the pathogenesis of ESCC.

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5-fluorouracil(5-FU)therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation(BCM)with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur(FT), followed by tegafur-uracil(UFT)and tegafurgimeracil- potassium oxonate(S-1)as combined products based on BCM.

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  • Platinum-based drugs, like oxaliplatin (L-OHP), are commonly used in combination chemotherapy to treat cancer, particularly advanced colorectal cancer.
  • Oxaliplatin, when combined with 5-FU and Leucovorin, shows a synergistic effect that enhances treatment effectiveness.
  • The review aims to summarize new findings on how oxaliplatin works in human tumor cells and explore the mechanisms behind its synergistic effect with 5-FU.
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Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients.

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Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2'-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA.

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Temporal regulation of microtubule dynamics is essential for proper progression of mitosis and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Here we show that Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the amino terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules.

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Treatment options for patients with metastatic colorectal cancer (mCRC), who are refractory to standard chemotherapy, are limited. In a global multicenter randomized double-blind phase III study (RECOURSE study), TAS-102 (TFTD) administration significantly improved overall survival rate with favorable safety profile in mCRC patients refractory to standard chemotherapy (HR=0.68, p<0.

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  • LGR5 is a key molecule that marks stem cells in various organs and is significant in colon cancer, but it is expressed at very low levels.
  • The study developed enhanced immunofluorescence staining techniques, comparing the tyramide method and the Qdot method for better detection of LGR5 protein.
  • Results showed the tyramide method is better for increasing detection sensitivity, while the Qdot method excels at pinpointing subcellular localization, which can aid in understanding and targeting cancer stem cells.
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Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity.

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