IU Indianapolis ScholarWorks :: Browsing by Author "Sato, Keisaku"

Browsing by Author "Sato, Keisaku"

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Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies
(MDPI, 2024-06-21) Zarlashat, Yusra; Mushtaq, Hassan; Pham, Linh; Abbas, Wasim; Sato, Keisaku; Medicine, School of Medicine
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal-7 microRNA
(Wiley, 2019-02-05) McDaniel, Kelly; Wu, Nan; Zhou, Tianhao; Huang, Li; Sato, Keisaku; Venter, Julie; Ceci, Ludovica; Chen, Demeng; Ramos‐Lorenzo, Sugeily; Invernizzi, Pietro; Bernuzzi, Francesca; Wu, Chaodong; Francis, Heather; Glaser, Shannon; Alpini, Gianfranco; Meng, Fanyin; Medicine, School of Medicine
Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)−/− mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2−/− mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2−/− mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.
Biliary Epithelial Senescence in Liver Disease: There Will Be SASP
(Frontiers Media, 2021-12-21) Meadows, Vik; Baiocchi, Leonardo; Kundu, Debjyoti; Sato, Keisaku; Fuentes, Yessenia; Wu, Chaodong; Chakraborty, Sanjukta; Glaser, Shannon; Alpini, Gianfranco; Kennedy, Lindsey; Francis, Heather; Medicine, School of Medicine
Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.
Bioinformatic analysis identified novel candidate genes with the potentials for diagnostic blood testing of primary biliary cholangitis
(Public Library of Science, 2023-10-16) Pham, Hoang Nam; Pham, Linh; Sato, Keisaku; Medicine, School of Medicine
Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers.
Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy
(Taylor & Francis, 2021) Baiocchi, Leonardo; Sato, Keisaku; Ekser, Burcin; Kennedy, Lindsey; Francis, Heather; Ceci, Ludovica; Lenci, Ilaria; Alvaro, Domenico; Franchitto, Antonio; Onori, Paolo; Gaudio, Eugenio; Wu, Chaodong; Chakraborty, Sanjukta; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
Introduction: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA. Areas covered: In this review, we discuss CCA-related: i) experimental systems used in preclinical studies; ii) pharmacological targets identified by genetic analysis; iii) results obtained in preliminary trials in human with their pros and cons; and iv) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term “cholangiocarcinoma” with “experimental model”, “preclinical model”, “genetic target”, “targeted therapy”, “clinical trial” or “translational research” was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing. Expert opinion: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.
Cholangiocarcinoma: novel therapeutic targets
(Taylor & Francis, 2020-04) Sato, Keisaku; Glaser, Shannon; Alvaro, Domenico; Meng, Fanyin; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
Introduction: Cholangiocarcinoma (CCA) is a liver cancer derived from the biliary tree with a less than 30% five-year survival rate. Early diagnosis of CCA is challenging and treatment options are limited. Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins. However, CCA is heterogeneous and patients often present with drug resistance which is attributed to multiple mutations or other factors. Novel approaches and methodologies for CCA treatments are in demand.Area covered: This review summarizes current approaches for CCA treatments leading to the development of novel therapeutic drugs or tools for human CCA patients. A literature search was conducted in PubMed utilizing the combination of the searched term 'cholangiocarcinoma' with other keywords such as 'miRNA', 'FGFR', 'immunotherapy' or 'microenvironment'. Papers published within 2015-2019 were obtained for reading.Expert opinion: Preclinical studies have demonstrated promising therapeutic approaches that target various cells or pathways. Recent studies have revealed that hepatic cells coordinate to promote CCA tumor progression in the tumor microenvironment, which may be a new therapeutic target. Although further studies are required, novel therapeutic tools such as extracellular vesicles could be utilized to manage CCA and its microenvironment.
Concise Review: Functional Roles and Therapeutic Potentials of Long Non-coding RNAs in Cholangiopathies
(Frontiers Media, 2020-02) Sato, Keisaku; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
Long non-coding RNAs (lncRNAs) are RNAs with lengths exceeding 200 nucleotides that are not translated into proteins. It is well-known that small non-coding RNAs, such as microRNAs (miRNAs), regulate gene expression and play an important role in cholangiopathies. Recent studies have demonstrated that lncRNAs may also play a key role in the pathophysiology of cholangiopathies. Patients with cholangiopathies often develop cholangiocarcinoma (CCA), which is cholangiocyte-derived cancer, in the later stage. Cholangiocytes are a primary target of therapies for cholangiopathies and CCA development. Previous studies have demonstrated that expression levels of lncRNAs are altered in the liver of cholangiopathies or CCA tissues. Some lncRNAs regulate gene expression by inhibiting functions of miRNAs leading to diseased liver conditions or CCA progression, suggesting that lncRNAs could be a novel therapeutic target for those disorders. This review summarizes current understandings of functional roles of lncRNAs in cholangiopathies and seek their potentials for novel therapies.
Current Advances in Basic and Translational Research of Cholangiocarcinoma
(MDPI, 2021-06-01) Sato, Keisaku; Baiocchi, Leonardo; Kennedy, Lindsey; Zhang, Wenjun; Ekser, Burcin; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are limited since early diagnosis is challenging, and the efficacy of chemotherapy or radiotherapy is also limited because CCA is a heterogeneous malignancy. Basic research is important for CCA to establish novel diagnostic testing and more effective therapies. Previous studies have introduced new techniques and methodologies for animal models, in vitro models, and biomarkers. Recent experimental strategies include patient-derived xenograft, syngeneic mouse models, and CCA organoids to mimic heterogeneous CCA characteristics of each patient or three-dimensional cellular architecture in vitro. Recent studies have identified various novel CCA biomarkers, especially non-coding RNAs that were associated with poor prognosis or metastases in CCA patients. This review summarizes current advances and limitations in basic and translational studies of CCA.
Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?
(MDPI, 2021-07-04) Baiocchi, Leonardo; Lenci, Ilaria; Milana, Martina; Kennedy, Lindsey; Sato, Keisaku; Zhang, Wenjun; Ekser, Burcin; Ceci, Ludovica; Meadows, Vik; Glaser, Shannon; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes' injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes' proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.
Deconvolution analysis identified altered hepatic cell landscape in primary sclerosing cholangitis and primary biliary cholangitis
(Frontiers Media, 2024-05-15) Pham, Hoang Nam; Pham, Linh; Sato, Keisaku; Medicine, School of Medicine
Introduction: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are characterized by ductular reaction, hepatic inflammation, and liver fibrosis. Hepatic cells are heterogeneous, and functional roles of different hepatic cell phenotypes are still not defined in the pathophysiology of cholangiopathies. Cell deconvolution analysis estimates cell fractions of different cell phenotypes in bulk transcriptome data, and CIBERSORTx is a powerful deconvolution method to estimate cell composition in microarray data. CIBERSORTx performs estimation based on the reference file, which is referred to as signature matrix, and allows users to create custom signature matrix to identify specific phenotypes. In the current study, we created two custom signature matrices using two single cell RNA sequencing data of hepatic cells and performed deconvolution for bulk microarray data of liver tissues including PSC and PBC patients. Methods: Custom signature matrix files were created using single-cell RNA sequencing data downloaded from GSE185477 and GSE115469. Custom signature matrices were validated for their deconvolution performance using validation data sets. Cell composition of each hepatic cell phenotype in the liver, which was identified in custom signature matrices, was calculated by CIBERSORTx and bulk RNA sequencing data of GSE159676. Deconvolution results were validated by analyzing marker expression for the cell phenotype in GSE159676 data. Results: CIBERSORTx and custom signature matrices showed comprehensive performance in estimation of population of various hepatic cell phenotypes. We identified increased population of large cholangiocytes in PSC and PBC livers, which is in agreement with previous studies referred to as ductular reaction, supporting the effectiveness and reliability of deconvolution analysis in this study. Interestingly, we identified decreased population of small cholangiocytes, periportal hepatocytes, and interzonal hepatocytes in PSC and PBC liver tissues compared to healthy livers. Discussion: Although further studies are required to elucidate the roles of these hepatic cell phenotypes in cholestatic liver injury, our approach provides important implications that cell functions may differ depending on phenotypes, even in the same cell type during liver injury. Deconvolution analysis using CIBERSORTx could provide a novel approach for studies of specific hepatic cell phenotypes in liver diseases.

Browsing by Author "Sato, Keisaku"

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