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Article ; Online: Mitochondrial calcium uniporter as biomarker and therapeutic target for breast cancer: Prognostication, immune microenvironment, epigenetic regulation and precision medicine.

Lin, Hung-Yu / Chu, Pei-Yi

2024

Abstract: Introduction: Mitochondrial calcium uniporter (MCU) is a central subunit of MCU complex that regulate the levels of calcium ions within mitochondria. A comprehensive understanding the implications of MCU in clinical prognostication, biological ... ...

Abstract	Introduction: Mitochondrial calcium uniporter (MCU) is a central subunit of MCU complex that regulate the levels of calcium ions within mitochondria. A comprehensive understanding the implications of MCU in clinical prognostication, biological understandings and therapeutic opportunity of breast cancer (BC) is yet to be determined. Objectives: This study aims to investigate the role of MCU in predictive performance, tumor progression, epigenetic regulation, shaping of tumor immune microenvironment, and pharmacogenetics and the development of anti-tumor therapy for BC. Methods: The downloaded TCGA datasets were used to identify predictive ability of MCU expressions via supervised learning principle. Functional enrichment, mutation landscape, immunological profile, drug sensitivity were examined using bioinformatics analysis and confirmed by experiments exploiting human specimens, in vitro and in vivo models. Results: MCU copy numbers increase with MCU gene expression. MCU expression, but not MCU genetic alterations, had a positive correlation with known BC prognostic markers. Higher MCU levels in BC showed modest efficacy in predicting overall survival. In addition, high MCU expression was associated with known BC prognostic markers and with malignancy. In BC tumor and sgRNA-treated cell lines, enrichment pathways identified the involvement of cell cycle and immunity. miR-29a was recognized as a negative epigenetic regulator of MCU. High MCU levels were associated with increased mutation levels in oncogene TP53 and tumor suppression gene CDH1, as well as with an immunosuppressive microenvironment. Sigle-cell sequencing indicated that MCU mostly mapped on to tumor cell and CD8 T-cells. Inter-databases verification further confirmed the aforementioned observation. miR-29a-mediated knockdown of MCU resulted in tumor suppression and mitochondrial dysfunction, as well as diminished metastasis. Furthermore, MCU present pharmacogenetic significance in cellular docetaxel sensitivity and in prediction of patients' response to chemotherapeutic regimen. Conclusion: MCU shows significant implication in prognosis, outcome prediction, microenvironmental shaping and precision medicine for BC. miR-29a-mediated MCU inhibition exerts therapeutic effect in tumor growth and metastasis.
Language	English
Publishing date	2024-04-24
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2541849-X
ISSN	2090-1224 ; 2090-1224
ISSN (online)	2090-1224
ISSN	2090-1224
DOI	10.1016/j.jare.2024.04.015
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Article: Current and Developing Liquid Biopsy Techniques for Breast Cancer.

Wu, Hsing-Ju / Chu, Pei-Yi

Cancers

2022 Volume 14, Issue 9

Abstract: Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography ... ...

Abstract	Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With the development of novel techniques, such as personalized medicine and genetic profiling, liquid biopsy is emerging as the less invasive tool for diagnosing and monitoring breast cancer. Liquid biopsy is performed by sampling biofluids and extracting tumor components, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free mRNA (cfRNA) and microRNA (miRNA), proteins, and extracellular vehicles (EVs). In this review, we summarize and focus on the recent discoveries of tumor components and biomarkers applied in liquid biopsy and novel development of detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and microfluidic devices.
Language	English
Publishing date	2022-04-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14092052
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Article ; Online: Multi-omics and experimental analysis unveil theragnostic value and immunological roles of inner membrane mitochondrial protein (IMMT) in breast cancer.

Lin, Hung-Yu / Wu, Hsing-Ju / Chu, Pei-Yi

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 189

Abstract: Background: The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating ... ...

Abstract	Background: The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. Methods: Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. Results: High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. Conclusion: This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/pathology ; Multiomics ; Neoplasm Recurrence, Local ; Precision Medicine ; Mitochondrial Proteins/genetics ; Tumor Microenvironment ; Muscle Proteins/metabolism
Chemical Substances	Mitochondrial Proteins ; IMMT protein, human ; Muscle Proteins
Language	English
Publishing date	2023-03-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-023-04035-4
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Article ; Online: Supervised Learning and Multi-Omics Integration Reveals Clinical Significance of Inner Membrane Mitochondrial Protein (IMMT) in Prognostic Prediction, Tumor Immune Microenvironment and Precision Medicine for Kidney Renal Clear Cell Carcinoma.

Chen, Chun-Chi / Chu, Pei-Yi / Lin, Hung-Yu

International journal of molecular sciences

2023 Volume 24, Issue 10

Abstract: Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10% surviving five years after diagnosis. Inner membrane mitochondrial protein (IMMT) ... ...

Abstract	Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10% surviving five years after diagnosis. Inner membrane mitochondrial protein (IMMT) plays a crucial role in shaping the inner mitochondrial membrane (IMM), regulation of metabolism and innate immunity. However, the clinical relevance of IMMT in KIRC is not yet fully understood, and its role in shaping the tumor immune microenvironment (TIME) remains unclear. This study aimed to investigate the clinical significance of IMMT in KIRC using a combination of supervised learning and multi-omics integration. The supervised learning principle was applied to analyze a TCGA dataset, which was downloaded and split into training and test datasets. The training dataset was used to train the prediction model, while the test and the entire TCGA dataset were used to evaluate its performance. Based on the risk score, the cutoff between the low and high IMMT group was set at median value. A Kaplan-Meier curve, receiver operating characteristic (ROC) curve, principal component analysis (PCA) and Spearman's correlation were conducted to evaluate the prediction ability of the model. Gene Set Enrichment Analysis (GSEA) was used to investigate the critical biological pathways. Immunogenicity, immunological landscape and single-cell analysis were performed to examine the TIME. Databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were employed for inter-database verification. Pharmacogenetic prediction was analyzed via single-guide RNA (sgRNA)-based drug sensitivity screening using Q-omics v.1.30. Low expressions of IMMT in tumor predicted dismal prognosis in KIRC patients and correlated with KIRC progression. GSEA revealed that low expressions of IMMT were implicated in mitochondrial inhibition and angiogenetic activation. In addition, low IMMT expressions had associations with reduced immunogenicity and an immunosuppressive TIME. Inter-database verification corroborated the correlation between low IMMT expressions, KIRC tumors and the immunosuppressive TIME. Pharmacogenetic prediction identified lestaurtinib as a potent drug for KIRC in the context of low IMMT expressions. This study highlights the potential of IMMT as a novel biomarker, prognostic predictor and pharmacogenetic predictor to inform the development of more personalized and effective cancer treatments. Additionally, it provides important insights into the role of IMMT in the mechanism underlying mitochondrial activity and angiogenesis development in KIRC, which suggests IMMT as a promising target for the development of new therapies.
MeSH term(s)	Humans ; Precision Medicine ; Prognosis ; Clinical Relevance ; Multiomics ; Proteomics ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/genetics ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/genetics ; Mitochondrial Proteins ; Supervised Machine Learning ; Kidney ; Tumor Microenvironment/genetics ; Muscle Proteins
Chemical Substances	Mitochondrial Proteins ; IMMT protein, human ; Muscle Proteins
Language	English
Publishing date	2023-05-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24108807
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Article: The Efficacy of

Chu, Pei-Yi / Yu, Ying-Chun / Pan, Yi-Cheng / Dai, Yun-Hao / Yang, Juan-Cheng / Huang, Kuo-Chin / Wu, Yang-Chang

Metabolites

2024 Volume 14, Issue 2

Abstract: This study aimed to evaluate the efficacy ... ...

Abstract	This study aimed to evaluate the efficacy of
Language	English
Publishing date	2024-02-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo14020129
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Article: Cure the Incurable? Recent Breakthroughs in Immune Checkpoint Blockade for Hepatocellular Carcinoma.

Chu, Pei-Yi / Chan, Shih-Hsuan

Cancers

2021 Volume 13, Issue 21

Abstract: HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to ... ...

Abstract	HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, the use of ICI therapy has revolutionized the systemic treatment of advanced HCC. For the first time, clinical trials testing ICIs, anti-CTLA-4 and anti-PD1/PDL1 reported a survival benefit in patients with sorafenib resistance. However, it took four more years to find the right combination regimen to use ICI in combination with the anti-angiogenic agent bevacizumab to substantially prolong overall survival (OS) of patients with advanced HCC after sorafenib. This review provides a comprehensive history of ICI therapy in HCC, up-to-date information on the latest ICI clinical trials, and discusses the recent development of novel ICIs that would potentially lead to a new checkpoint blockade therapy for advanced HCC.
Language	English
Publishing date	2021-10-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13215295
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Article ; Online: Epigenetic Regulation of Breast Cancer Stem Cells Contributing to Carcinogenesis and Therapeutic Implications.

Wu, Hsing-Ju / Chu, Pei-Yi

International journal of molecular sciences

2021 Volume 22, Issue 15

Abstract: Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of ... ...

Abstract	Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of treatments. Breast cancer stem cells (BCSCs), a small subset of cancer cells with stem cell-like properties, play essential roles in breast cancer progression, recurrence, metastasis, chemoresistance and treatments. Epigenetics is defined as inheritable changes in gene expression without alteration in DNA sequence. Epigenetic regulation includes DNA methylation and demethylation, as well as histone modifications. Aberrant epigenetic regulation results in carcinogenesis. In this review, the mechanism of epigenetic regulation involved in carcinogenesis, therapeutic resistance and metastasis of BCSCs will be discussed, and finally, the therapies targeting these biomarkers will be presented.
MeSH term(s)	Animals ; Biomarkers, Tumor/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; DNA Methylation/drug effects ; Epigenesis, Genetic/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Histone Code/drug effects ; Histone Code/genetics ; Humans ; Molecular Targeted Therapy/methods ; Neoplastic Stem Cells/metabolism
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-07-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22158113
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Article ; Online: Recent Discoveries of Macromolecule- and Cell-Based Biomarkers and Therapeutic Implications in Breast Cancer.

Wu, Hsing-Ju / Chu, Pei-Yi

International journal of molecular sciences

2021 Volume 22, Issue 2

Abstract: Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related mortality in women worldwide. Breast cancer is fairly heterogeneous and reveals six molecular subtypes: luminal A, luminal B, HER2+, basal-like subtype (ER-, ...

Abstract	Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related mortality in women worldwide. Breast cancer is fairly heterogeneous and reveals six molecular subtypes: luminal A, luminal B, HER2+, basal-like subtype (ER-, PR-, and HER2-), normal breast-like, and claudin-low. Breast cancer screening and early diagnosis play critical roles in improving therapeutic outcomes and prognosis. Mammography is currently the main commercially available detection method for breast cancer; however, it has numerous limitations. Therefore, reliable noninvasive diagnostic and prognostic biomarkers are required. Biomarkers used in cancer range from macromolecules, such as DNA, RNA, and proteins, to whole cells. Biomarkers for cancer risk, diagnosis, proliferation, metastasis, drug resistance, and prognosis have been identified in breast cancer. In addition, there is currently a greater demand for personalized or precise treatments; moreover, the identification of novel biomarkers to further the development of new drugs is urgently needed. In this review, we summarize and focus on the recent discoveries of promising macromolecules and cell-based biomarkers for the diagnosis and prognosis of breast cancer and provide implications for therapeutic strategies.
MeSH term(s)	Animals ; Biomarkers, Tumor ; Breast Neoplasms/diagnosis ; Breast Neoplasms/immunology ; Breast Neoplasms/therapy ; Cell- and Tissue-Based Therapy ; Early Detection of Cancer ; Female ; Humans ; Immunotherapy ; Neoplasm Proteins/analysis ; Prognosis
Chemical Substances	Biomarkers, Tumor ; Neoplasm Proteins
Language	English
Publishing date	2021-01-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22020636
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Article ; Online: Advances in Understanding Mitochondrial MicroRNAs (mitomiRs) on the Pathogenesis of Triple-Negative Breast Cancer (TNBC).

Lin, Hung-Yu / Chu, Pei-Yi

Oxidative medicine and cellular longevity

2021 Volume 2021, Page(s) 5517777

Abstract: Triple-negative breast cancer (TNBC) is characterized by poor outcome and the most challenging breast cancer type to treat worldwide. TNBC manifests distinct profile of mitochondrial functions, which dictates reprogrammed metabolism, fosters tumor ... ...

Abstract	Triple-negative breast cancer (TNBC) is characterized by poor outcome and the most challenging breast cancer type to treat worldwide. TNBC manifests distinct profile of mitochondrial functions, which dictates reprogrammed metabolism, fosters tumor progression, and notably serves as therapeutic targets. Mitochondrial microRNAs (mitomiRs) are a group of microRNAs that critically modulate mitochondrial homeostasis. By a pathway-centric manner, mitomiRs tightly orchestrate metabolic reprogramming, redox status, cell apoptosis, mitochondrial dynamics, mitophagy, mitochondrial DNA (mtDNA) maintenance, and calcium balance, leading to an emerging field of study in various cancer types, including TNBC. We herein review the recent insights into the roles and mechanism of mitomiRs in TNBC and highlight its clinical value in diagnosis and prognosis as well as vital advances on therapeutics of preclinical and clinical studies.
MeSH term(s)	Animals ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Mitochondrial Dynamics ; Oxidative Stress ; RNA, Mitochondrial/genetics ; RNA, Mitochondrial/metabolism ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology
Chemical Substances	Biomarkers, Tumor ; MicroRNAs ; RNA, Mitochondrial
Language	English
Publishing date	2021-03-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2021/5517777
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Article ; Online: Translocation of Methionine Adenosyl Transferase MAT2A and Its Prognostic Relevance for Liver Hepatocellular Carcinoma.

Chu, Pei-Yi / Chou, Dev-Aur / Chen, Po-Ming / Chiang, En-Pei Isabel

International journal of molecular sciences

2023 Volume 24, Issue 10

Abstract: Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of ... ...

Abstract	Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the
MeSH term(s)	Humans ; Male ; Female ; Carcinoma, Hepatocellular/metabolism ; Liver Neoplasms/metabolism ; Prognosis ; S-Adenosylmethionine/metabolism ; Transferases ; Methionine Adenosyltransferase/metabolism
Chemical Substances	S-Adenosylmethionine (7LP2MPO46S) ; Transferases (EC 2.-) ; Methionine Adenosyltransferase (EC 2.5.1.6) ; MAT2A protein, human (EC 2.5.1.6)
Language	English
Publishing date	2023-05-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24109103
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