Publications by authors named "Alexander Wu"

129 Publications

Bruton's tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma.

Oncogenesis 2021 Jul 27;10(7):56. Epub 2021 Jul 27.

Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton's tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTK cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.
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http://dx.doi.org/10.1038/s41389-021-00345-8DOI Listing
July 2021

Bayesian information sharing enhances detection of regulatory associations in rare cell types.

Bioinformatics 2021 07;37(Suppl_1):i349-i357

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Motivation: Recent advances in single-cell RNA-sequencing (scRNA-seq) technologies promise to enable the study of gene regulatory associations at unprecedented resolution in diverse cellular contexts. However, identifying unique regulatory associations observed only in specific cell types or conditions remains a key challenge; this is particularly so for rare transcriptional states whose sample sizes are too small for existing gene regulatory network inference methods to be effective.

Results: We present ShareNet, a Bayesian framework for boosting the accuracy of cell type-specific gene regulatory networks by propagating information across related cell types via an information sharing structure that is adaptively optimized for a given single-cell dataset. The techniques we introduce can be used with a range of general network inference algorithms to enhance the output for each cell type. We demonstrate the enhanced accuracy of our approach on three benchmark scRNA-seq datasets. We find that our inferred cell type-specific networks also uncover key changes in gene associations that underpin the complex rewiring of regulatory networks across cell types, tissues and dynamic biological processes. Our work presents a path toward extracting deeper insights about cell type-specific gene regulation in the rapidly growing compendium of scRNA-seq datasets.

Supplementary Information: Supplementary data are available at Bioinformatics online.

Availability And Implementation: The code for ShareNet is available at http://sharenet.csail.mit.edu and https://github.com/alexw16/sharenet.
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http://dx.doi.org/10.1093/bioinformatics/btab269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275330PMC
July 2021

Prevalence and Factors Associated with Bone Stress Injury in Middle School Runners.

PM R 2021 Jul 12. Epub 2021 Jul 12.

California State University, Long Beach, California.

Introduction: Bone stress injury (BSI) in youth runners are clinically important during times of skeletal growth and are not well studied.

Objective: Evaluate the prevalence, anatomical distribution, and factors associated with running-related BSI in boy and girl middle school runners.

Design: Retrospective cross-sectional study.

Setting: Online survey distributed to middle school runners.

Methods: Survey evaluated BSI history, age, grade, height, weight, eating behaviors, menstrual function, exercise training, and other health characteristics.

Main Outcome Measurements: Prevalence and characteristics associated with history of BSI, stratified by cortical-rich (eg, tibia) and trabecular-rich (pelvis and femoral neck) locations.

Participants: 2107 runners (n = 1250 boys, n = 857 girls), age 13.2 ± 0.9y.

Results: One hundred-five (4.7%) runners reported a history of 132 BSIs, with higher prevalence in girls than boys (6.7% vs 3.8%, P = 0.004). The most common location was the tibia (n = 51). Most trabecular-rich BSIs (n = 16, 94% total) were sustained by girls (pelvis: n = 6; femoral neck: n = 6; sacrum: n = 4). In girls, consuming <3 daily meals (OR = 18.5, 95%CI = 7.3, 47.4), eating disorder (9.8, 95%CI = 2.0, 47.0), family history of osteoporosis (OR = 6.9, 95%CI = 2.6, 18.0), and age (OR = 1.6, 95%CI = 1.0, 2.6) were associated with BSI. In boys, family history of osteoporosis (OR = 3.2, 95%CI = 1.2, 8.4), prior non-BSI fracture (OR = 3.2, 95%CI = 1.6, 6.7), and running mileage (OR = 1.1, 95%CI = 1.0, 1.1) were associated with BSI. Participating in soccer or basketball ≥2 years was associated with lower odds of BSI for both sexes.

Conclusion: While family history of osteoporosis and prior fracture (non-BSI) were most strongly related to BSI in the youth runners, behaviors contributing to an energy deficit, such as eating disorder and consuming<3 meals daily, also emerged as independent factors associated with BSI. While cross-sectional design limits determining causality, our findings suggest promoting optimal skeletal health through nutrition and participation in other sports including soccer and basketball may address factors associated with BSI in this population. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/pmrj.12673DOI Listing
July 2021

A preclinical report of a cobimetinib-inspired novel anticancer small-molecule scaffold of isoflavones, NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple cancers.

Am J Cancer Res 2021 15;11(6):2590-2617. Epub 2021 Jun 15.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica Taipei 11031, Taiwan.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways are critical for normal human physiology, and any alteration in their regulation leads to several human cancers. These pathways are well interconnected and share a survival mechanism for escaping the depressant effect of antagonists. Therefore, novel small molecules capable of targeting both pathways with minimal or no toxicity are better alternatives to current drugs, which are disadvantaged by their accompanying resistance and toxicity. In this study, we demonstrate that the PI3K/AKT/mTOR/MEK is a crucial oncoimmune signature in multiple cancers. Moreover, we describe NSC777213, a novel isoflavone core and cobimetinib-inspired small molecule, which exhibit both antiproliferative activities against all panels of NCI60 human tumor cell lines (except COLO205 and HT29) and a selective cytotoxic preference for melanoma, non-small-cell lung cancer (NSCLC), brain, renal, and ovarian cancer cell lines. Notably, for NSC777213 treatment, chemoresistant ovarian cancer cell lines, including SK-OV-3, OVCAR-3, OVCAR-4, and NCI/ADR-RES, exhibited a higher antiproliferative sensitivity (total growth inhibition (TGI) = 7.62-31.50 µM) than did the parental cell lines OVCAR-8 and IGROV1 (TGI > 100 µM). NSC777213 had a mechanistic correlation with clinical inhibitors of PI3K/AKT/mTOR/MEK. NSC777213 demonstrates robust binding interactions and higher affinities for AKT and mTOR than did isoflavone, and also demonstrate a higher affinity for human MEK-1 kinase than some MEK inhibitors under clinical developments. In addition, treatment of U251 and U87MG cells with NSC777213 significantly downregulated the expression levels of the total and phosphorylated forms of PI3K/AKT/mTOR/MEK. Our study suggests that NSC777213 is a promising PI3K/AKT/mTOR/MEK inhibitor for further preclinical and clinical evaluation as a chemotherapeutic agent, particularly for the treatment of NSCLC, melanoma, and brain, renal, and ovarian cancers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263676PMC
June 2021

Galectin-3 as a Biomarker for Stratifying Abdominal Aortic Aneurysm Size in a Taiwanese Population.

Front Cardiovasc Med 2021 31;8:663152. Epub 2021 May 31.

Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Abdominal aortic aneurysm (AAA) ruptures are unpredictable and lethal. A biomarker predicting AAA rupture risk could help identify patients with small, screen-detected AAAs. Galectin-3 (Gal-3), a β-galactosidase-binding lectin, is involved in inflammatory processes and may be associated with AAA incidence. We investigated whether Gal-3 can be used as a biomarker of AAA size. Plasma Gal-3 protein concentrations were examined in patients with AAA ( = 151) and control patients ( = 195) using Human ProcartaPlex multiplex and simplex kits. Circulating Gal-3 levels were significantly higher in patients with AAA than in control patients. The area under the receiver operating characteristic curve for Gal-3 was 0.91. Multivariate logistic regression analysis revealed a significant association between Gal-3 level and the presence of AAA. Circulating Gal-3 levels were significantly correlated with aortic diameter in a concentration-dependent manner. In conclusion, higher plasma Gal-3 concentrations may be a useful biomarker of AAA progression.
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http://dx.doi.org/10.3389/fcvm.2021.663152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200414PMC
May 2021

In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Academia Sinica, Taipei 11031, Taiwan.

Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease's pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI = 1.6 µM~1.82 µM and TGI = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.
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http://dx.doi.org/10.3390/ijms22115895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198179PMC
May 2021

Network Pharmacological Analysis through a Bioinformatics Approach of Novel NSC765600 and NSC765691 Compounds as Potential Inhibitors of /// in Cancer Types.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.

Cyclin D1 () and cyclin-dependent kinase 4 () both play significant roles in regulating cell cycle progression, while polo-like kinase 1 () regulates cell differentiation and tumor progression, and activates cancer stem cells (CSCs), with the cluster of differentiation 44 () surface marker mostly being expressed. These oncogenes have emerged as promoters of metastasis in a variety of cancer types. In this study, we employed comprehensive computational and bioinformatics analyses to predict drug targets of our novel small molecules, NSC765600 and NSC765691, respectively derived from diflunisal and fostamatinib. The target prediction tools identified as target genes for NSC765600 and NSC765691 compounds. Additionally, the results of our in silico molecular docking analysis showed unique ligand-protein interactions with putative binding affinities of NSC765600 and NSC765691 with oncogenic signaling pathways. Moreover, we used drug-likeness precepts as our guidelines for drug design and development, and found that both compounds passed the drug-likeness criteria of molecular weight, polarity, solubility, saturation, flexibility, and lipophilicity, and also exhibited acceptable pharmacokinetic properties. Furthermore, we used development therapeutics program (DTP) algorithms and identified similar fingerprints and mechanisms of NSC765600 and NSC765691 with synthetic compounds and standard anticancer agents in the NCI database. We found that NSC765600 and NSC765691 displayed antiproliferative and cytotoxic effects against a panel of NCI-60 cancer cell lines. Based on these finding, NSC765600 and NSC765691 exhibited satisfactory levels of safety with regard to toxicity, and met all of the required criteria for drug-likeness precepts. Currently, further in vitro and in vivo investigations in tumor-bearing mice are in progress to study the potential treatment efficacies of the novel NSC765600 and NSC765691 small molecules.
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http://dx.doi.org/10.3390/cancers13112523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196568PMC
May 2021

Running-related injuries in middle school cross-country runners: Prevalence and characteristics of common injuries.

PM R 2021 May 30. Epub 2021 May 30.

Spaulding Rehabilitation Hospital, Charlestown, Massachusetts, USA.

Background: Understanding the prevalence and factors associated with running-related injuries in middle school runners may guide injury prevention.

Objective: To determine the prevalence of running-related injuries and describe factors related to a history of injury.

Design: Retrospective cross-sectional study.

Setting: Survey distributed online to middle school runners.

Methods: Participants completed a web-based survey regarding prior running-related injuries, training, sleep, diet, and sport participation.

Main Outcome Measurements: Prevalence and characteristics differentiating girls and boys with and without running-related injury history adjusted for age.

Participants: Youth runners (total: 2113, average age,  13.2 years; boys: n = 1255, girls: n = 858).

Results: Running-related injuries were more prevalent in girls (56% vs. 50%, p = .01). Ankle sprain was the most common injury (girls: 22.5%, boys: 21.6%), followed by patellofemoral pain (20.4% vs. 7.8%) and shin splints (13.6% vs. 5.9%); both were more prevalent in girls (p < .001). Boys more frequently reported plantar fasciitis (5.6% vs. 3.3%, p = .01), iliotibial band syndrome (4.1% vs. 1.4%, p = .001) and Osgood-Schlatter disease (3.8% vs. 1.2%, p = .001). Runners with history of running-related injuries were older, ran greater average weekly mileage, ran faster, had fewer average hours of sleep on weekends, skipped more meals, missed breakfast, and consumed less milk (all p < .05). Girls with history of running-related injuries reported higher dietary restraint scores, later age of menarche, more menstrual cycle disturbances, and higher likelihood of following vegetarian diets and an eating disorder diagnosis (all p < .05). Runners with no history of running-related injuries were more likely to have participated in ≥2 years of soccer or basketball (p < .001).

Conclusions: Most middle school runners reported a history of running-related injuries and certain injuries differing by gender. Modifiable factors with the greatest association with running-related injuries included training volume, dietary restraint, skipping meals, and less sleep. Sport sampling, including participation in ball sports, may reduce running-related injury risk in this population.
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http://dx.doi.org/10.1002/pmrj.12649DOI Listing
May 2021

COVID-19 Surveillance for Local Decision Making : An Academic, School District, and Public Health Collaboration.

Public Health Rep 2021 Jul-Aug;136(4):403-412. Epub 2021 May 12.

443323 Franklin County Public Health, Columbus, OH, USA.

Objective: Data-informed decision making is valued among school districts, but challenges remain for local health departments to provide data, especially during a pandemic. We describe the rapid planning and deployment of a school-based COVID-19 surveillance system in a metropolitan US county.

Methods: In 2020, we used several data sources to construct disease- and school-based indicators for COVID-19 surveillance in Franklin County, an urban county in central Ohio. We collected, processed, analyzed, and visualized data in the COVID-19 Analytics and Targeted Surveillance System for Schools (CATS). CATS included web-based applications (public and secure versions), automated alerts, and weekly reports for the general public and decision makers, including school administrators, school boards, and local health departments.

Results: We deployed a pilot version of CATS in less than 2 months (August-September 2020) and added 21 school districts in central Ohio (15 in Franklin County and 6 outside the county) into CATS during the subsequent months. Public-facing web-based applications provided parents and students with local information for data-informed decision making. We created an algorithm to enable local health departments to precisely identify school districts and school buildings at high risk of an outbreak and active SARS-CoV-2 transmission in school settings.

Practice Implications: Piloting a surveillance system with diverse school districts helps scale up to other districts. Leveraging past relationships and identifying emerging partner needs were critical to rapid and sustainable collaboration. Valuing diverse skill sets is key to rapid deployment of proactive and innovative public health practices during a global pandemic.
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http://dx.doi.org/10.1177/00333549211018203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203033PMC
June 2021

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2',4'-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications.

Front Oncol 2021 26;11:656738. Epub 2021 Mar 26.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.

Background: The application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities

Methods: We used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.

Results: We identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non-small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI) = 1.12-3.95 µM; total growth inhibition (TGI) = 3.72-16.60 μM), leukemia (GI = 1.20-3.10 µM; TGI = 3.90-12.70 μM), melanoma (GI = 1.45-3.59 µM), and renal cancer (GI = 1.38-3.40 µM; TGI = 4.84-13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = -11.0 kcal/mol), NOS2 (ΔG = -11.0 kcal/mol), and mTOR (ΔG = -8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.

Conclusion: NSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.
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http://dx.doi.org/10.3389/fonc.2021.656738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034425PMC
March 2021

An Integrated Bioinformatics Study of a Novel Niclosamide Derivative, NSC765689, a Potential /// Suppressor with Anti-Glioblastoma Properties.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.

Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified (), , signal transducer and activator of transcription 3 (), and cluster of differentiation 44 () as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of , and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; , , and , and the stem cell marker, , to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI) values ranged 0.23~5.13 μM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (//) signaling and upregulate the tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic.
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http://dx.doi.org/10.3390/ijms22052464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957701PMC
February 2021

Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.

Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it's associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy.
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http://dx.doi.org/10.3390/cancers13050954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956610PMC
February 2021

Robust Formation of an Epithelial Layer of Human Intestinal Organoids in a Polydimethylsiloxane-Based Gut-on-a-Chip Microdevice.

Front Med Technol 2020 Aug 7;2. Epub 2020 Aug 7.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, United States.

Polydimethylsiloxane (PDMS) is a silicone polymer that has been predominantly used in a human organ-on-a-chip microphysiological system. The hydrophobic surface of a microfluidic channel made of PDMS often results in poor adhesion of the extracellular matrix (ECM) as well as cell attachment. The surface modification by plasma or UV/ozone treatment in a PDMS-based device produces a hydrophilic surface that allows robust ECM coating and the reproducible attachment of human intestinal immortalized cell lines. However, these surface-activating methods have not been successful in forming a monolayer of the biopsy-derived primary organoid epithelium. Several existing protocols to grow human intestinal organoid cells in a PDMS microchannel are not always reproducibly operative due to the limited information. Here, we report an optimized methodology that enables robust and reproducible attachment of the intestinal organoid epithelium in a PDMS-based gut-on-a-chip. Among several reported protocols, we optimized a method by performing polyethyleneimine-based surface functionalization followed by the glutaraldehyde cross linking to activate the PDMS surface. Moreover, we discovered that the post-functionalization step contributes to provide uniform ECM deposition that allows to produce a robust attachment of the dissociated intestinal organoid epithelium in a PDMS-based microdevice. We envision that our optimized protocol may disseminate an enabling methodology to advance the integration of human organotypic cultures in a human organ-on-a-chip for patient-specific disease modeling.
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http://dx.doi.org/10.3389/fmedt.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849371PMC
August 2020

Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines.

Biomedicines 2021 Jan 19;9(1). Epub 2021 Jan 19.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein-ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy.
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http://dx.doi.org/10.3390/biomedicines9010092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832910PMC
January 2021

Chronic stress affects tyrosine phosphorylated protein expression and secretion of male rat epididymis.

Andrologia 2021 Apr 20;53(3):e13981. Epub 2021 Jan 20.

Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Chronic stress (CS) is shown to decrease the semen quality with changed expression of tyrosine phosphorylated (TyrPho) proteins in testicular and seminal tissues. However, the alterations of such proteins and fluid contents in the epididymis, producing sperm maturation factors, have never been reported. Sixteen adult rats were randomly divided into 2 groups (n = 8). The control animals were not subjected to stressors whereas CS rats were immobilised within restraint cage (4 hr/day) before cold forced-water swimming (15 min/day) for 60 days. Corticosterone, testosterone, blood glucose level (BGL), malondialdehyde (MDA) and biochemical components in epididymal fluid were assayed. Expressions of heat shock protein 70 (HSP-70), androgen receptor (AR) and TyrPho protein were investigated in epididymal tissue and fluid. Significantly, CS increased the corticosterone and BGL but decreased testosterone and epididymal substance levels. MDA level in tail epididymal fluid and HSP-70 expression in both regions of epididymal tissues and fluids, except in head epididymal fluid of CS were increased. Epididymal tissues showed the decrease of AR expression. Presence and changes of many TyrPho proteins were observed in CS. In conclusion, CS could affect functional proteins particularly TyrPho in epididymis, resulted in low semen quality.
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http://dx.doi.org/10.1111/and.13981DOI Listing
April 2021

The effect of Dolichandrone serrulata (wall. ex DC.) Seem. flower extract containing antioxidant capacity and terpenoids on the male reproductive system.

Andrologia 2021 Apr 11;53(3):e13966. Epub 2021 Jan 11.

Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Although the fruit extract of Dolichandrone genus was shown to inhibit spermatogenesis, the reproductive toxicity of Dolichandrone serrulata flowers (DSFs) is not documented. Recent study aimed to evaluate the sub-chronic toxicity of DSF on male reproductive system. Antioxidant capacity and total phenolic contents of DSF extract were determined using Folin-Ciocalteu's, 2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power assays. The terpenoid components were determined using nuclear magnetic resonance spectrum. Adult male rats were treated orally with DSF (100, 300 or 600 mg/kg) for 48 days. Histopathology of testis and epididymis was observed. Sperm concentration, viability, acrosome status and morphology were also examined. Expressions of heat shock protein 70 (Hsp70), tyrosine-phosphorylated (TyrPho) proteins, androgen receptor (AR) and steroidogenic acute regulatory (StAR) protein in testis were investigated. Results showed that DSF contained phenolic compounds and terpenoids (phytoandrogens; rengyolone and cleroindicin B). No reproductive histopathology was observed in DSF-treated rats. Although DSF decreased the serum testosterone level, the sperm qualities were not affected. Particularly, sperm concentration of DSF-treated animals was significantly increased. DSF changed the testicular TyrPho proteins but the expression of AR, StAR or Hsp70 was not altered. In conclusion, DSF possesses antioxidant capacity with no toxicity on male reproductive system.
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http://dx.doi.org/10.1111/and.13966DOI Listing
April 2021

Erratum: Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal β-catenin/STAT3/miR-1246 cargoes.

Am J Cancer Res 2020 1;10(12):4640-4642. Epub 2020 Dec 1.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.

[This corrects the article on p. 2337 in vol. 10, PMID: 32905416.].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783745PMC
December 2020

Corrigendum to "Effects of laparoscopic vs robotic-assisted mesorectal excision for rectal cancer: An update systematic review and meta-analysis of randomized controlled trials". [Asian J Surg. 42 (6) 2019 Jun 657-666].

Asian J Surg 2021 Jan;44(1):429

Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan, Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, Division of Colorectal Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.asjsur.2020.12.010DOI Listing
January 2021

HNC0014, a Multi-Targeted Small-Molecule, Inhibits Head and Neck Squamous Cell Carcinoma by Suppressing c-Met/STAT3/CD44/PD-L1 Oncoimmune Signature and Eliciting Antitumor Immune Responses.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.

Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exo- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development.
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http://dx.doi.org/10.3390/cancers12123759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764918PMC
December 2020

Galectin-3 Modulates Macrophage Activation and Contributes Smooth Muscle Cells Apoptosis in Abdominal Aortic Aneurysm Pathogenesis.

Int J Mol Sci 2020 Nov 4;21(21). Epub 2020 Nov 4.

Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.

Galectin-3 (Gal-3) is a 26-kDa lectin that regulates many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels of Gal-3 contribute to abdominal aortic aneurysm (AAA) progression by enhancing monocyte chemoattraction through macrophage activation. We analyzed the plasma levels of Gal-3 in 76 patients with AAA (AAA group) and 97 controls (CTL group) as well as in angiotensin II (Ang-II)-infused ApoE knockout mice. Additionally, conditioned media (CM) were used to polarize THP-1 monocyte to M1 macrophages with or without Gal-3 inhibition through small interfering RNA targeted deletion to investigate whether Gal-3 inhibition could attenuate macrophage-induced inflammation and smooth muscle cell (SMC) apoptosis. Our results showed a markedly increased expression of Gal-3 in the plasma and aorta in the AAA patients and experimental mice compared with the CTL group. An in vitro study demonstrated that the M1 cells exhibited increased Gal-3 expression. Gal-3 inhibition markedly decreased the quantity of macrophage-induced inflammatory regulators, including IL-8, TNF-α, and IL-1β, as well as messenger RNA expression and MMP-9 activity. Moreover, Gal-3-deficient CM weakened SMC apoptosis through Fas activation. These findings prove that Gal-3 may contribute to AAA progression by the activation of inflammatory macrophages, thereby promoting SMC apoptosis.
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http://dx.doi.org/10.3390/ijms21218257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663490PMC
November 2020

Biomechanical comparison of four tibial fixation techniques for meniscal root sutures in posterior medial meniscus root repair: A porcine study.

J Orthop Translat 2020 Sep 17;24:144-149. Epub 2020 Feb 17.

Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Objective: This study hypothesized that the suture anchor of tibial fixation method of PMMR repair technique is the main factor which reduce the gap formation or over displacement of tear site in initial healing, and then investigated the fixation stability of 4 different tibial fixations through cyclic and ultimate failure load testing of meniscal root sutures.

Methods: Twenty-four porcine tibiae with intact medial meniscus roots were randomly assigned into 4 groups: transosseous suture, washer, suture anchor, or screw with washer. Each sample underwent cyclic loading followed by a load-to-failure test. Displacement, maximum load to failure, stiffness, and elongation at failure load were recorded.

Results: The maximum average load and displacement at failure for each of the repair groups were as follows: transosseous suture, 232.8 N and 12.16 mm; washer, 189.9 N and 21.5 mm; suture anchor, 140.6 N and 13.8 mm; and screw with washer, 167.9 N and 18.9 mm. The maximum stiffness values for each of the repair groups were as follows: transosseous suture, 19.5 ± 0.7 N/mm; washer, 21.5 ± 1.4 N/mm; suture anchor, 13.8 ± 0.7 N/mm; and screw with washer, 18.9 ± 3.9 N/mm. The mean elongation across the repairs for each of the repair groups after 1000 loading cycles was: transosseous suture, 3.74 ± 0.28 mm; washer, 3.04 ± 0.13 mm; suture anchor, 2.25 ± 0.33 mm; and screw with washer, 2.43 ± 0.19 mm. The mean elongation was significantly less with the suture anchor than with the other techniques ( < .05).

Conclusion: Under physiological loading, our results indicate that a slower rehabilitation program with limited flexion and only partial weight bearing is advised when using a suture anchor because of the lower maximum load and stiffness.

The Translational Potential Of This Article: Tibial fixation using a washer or a screw with a washer is an effective and cost-saving technique when an option is required with high stiffness and low displacement at failure.
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http://dx.doi.org/10.1016/j.jot.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548383PMC
September 2020

Successful Management of Life-threatening Pelvic Hemorrhage From Acquired Factor V Deficiency With immunosuppressive Therapy.

Cureus 2020 Aug 23;12(8):e9972. Epub 2020 Aug 23.

Hematology/Oncology, St. Joseph's University Medical Center, Paterson, USA.

Acquired Factor V deficiency is a rare and challenging condition to treat. It has been associated with major surgeries, antibiotics, blood transfusions, infections, autoimmune disorders, malignancy and exposure to bovine thrombin. The clinical presentation can be heterogeneous and can manifest as asymptomatic laboratory abnormalities to fatal hemorrhage with mortality rates around 15-20% . We report a case of acquired factor V deficiency in which the patient developed a life-threatening bleeding coagulopathy with elevated prothrombin time, activated partial thromboplastin time and factor V inhibitor titers following multiple surgical procedures that were performed after a motor vehicle accident. The patient was successfully treated with immunosuppressive therapy including steroids and cyclophosphamide resulting in the complete elimination of inhibitor levels.
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http://dx.doi.org/10.7759/cureus.9972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510508PMC
August 2020

Localization (and profiles) of tyrosinephosphorylated proteins in female reproductive organs of adult rats.

Clin Exp Reprod Med 2020 Sep 1;47(3):180-185. Epub 2020 Sep 1.

Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Objective: Tyrosine phosphorylation is an essential process in many biological systems, including the male reproductive system. The presence of tyrosine-phosphorylated (TyrPho) proteins has been well documented in male reproductive organs, but research in fertile females is still limited.

Methods: The ovary, oviduct, and uterus of adult female Sprague-Dawley rats in the estrus phase were used to localize TyrPho proteins using an immunohistochemical technique. These proteins were separated and their expression patterns were examined by sodium dodecyl sulfatepolyacrylamide gel electrophoresis and Western blot analysis, respectively.

Results: TyrPho proteins were localized in the cytoplasm of the oocyte except the antral fluid; in the granulosa cells, theca cells, and stromal cells of the ovary; at the apical surface of oviductal epithelial cells; and in the basal epithelium and submucosa of the uterine wall. Moreover, we found that 72-, 43-, and 28-kDa TyrPho proteins were localized in the ovary, while 170-, 55-, and 43-kDa proteins were localized in the oviduct. In the uterus, we detected four major bands, corresponding to 61-, 55-, 54-, and 43-kDa TyrPho proteins.

Conclusion: Given that these TyrPho proteins were found in major reproductive organs in the estrus phase, these proteins may play important roles in female fertility.
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http://dx.doi.org/10.5653/cerm.2020.03573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482952PMC
September 2020

Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal β-catenin/STAT3/miR-1246 cargoes.

Am J Cancer Res 2020 1;10(8):2337-2354. Epub 2020 Aug 1.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.

Patients with advanced-stage colon cancer often exhibit resistance against treatment and distant metastasis, both key contributors to poor prognosis. Emerging evidence indicates that cancer stem cells (CSCs), characterized by the enhanced ability to self-renew, resist therapeutics, and promote metastasis, represents a clinical challenge to target. Alternative therapeutic approaches are urgently required. Here, we explored the feasibility of disrupting the intracellular communications between CSCs and the tumor microenvironment by way of exosomes. First, we demonstrated that exosomes secreted by colon tumorspheres (Exo) promoted 5-FU resistance, migration, and tumorsphere formation. Exo also increased the generation of cancer-associated fibroblasts and M2 polarized macrophages . Oncogenic molecules, including IL-6, p-STAT3, TGF-β1, and β-catenin, were identified as the cargoes of Exo. Furthermore, the public database revealed the high abundance of miR-1246 in serum exosomes from colon cancer patients, and we verified in the Exo from HCT116 and HT29 cells. Therapeutically, we demonstrated the ovatodiolide treatment reduced exosomal cargoes from tumorspheres (Exo_OV). Exo_OV were significantly less capable of promoting 5-FU resistance, migration, and tumorsphere formation when co-cultured with HCT116 and HT29 cells. Notably, Exo_OV was less CAF- and M2 TAM-transformative. Computational docking analysis revealed that OV could bind and significantly reduced β-catenin activity. Finally, mouse xenograft data indicated that ovatodiolide suppressed tumor growth via down-regulating IL-6, STAT3, β-catenin expression, and serum exosomal miR-1246. In conclusion, our findings provided preclinical supports for ovatodiolide as a colon CSC inhibitor by reducing β-catenin/STAT3/miR-1246 signaling conveyed by CSC derived exosomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471366PMC
August 2020

Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer.

J Ovarian Res 2020 Aug 21;13(1):95. Epub 2020 Aug 21.

Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, P.R. China.

Background: Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer.

Methods: We applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy.

Results: We found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo.

Conclusions: This study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials.
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http://dx.doi.org/10.1186/s13048-020-00703-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442990PMC
August 2020

Effect of chronic stress on expression and secretion of seminal vesicle proteins in adult rats.

Andrologia 2021 Feb 20;53(1):e13800. Epub 2020 Aug 20.

Department of Anatomy, School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand.

Chronic stress (CS) is known to affect men's health especially fertility by reducing semen quality. Although the effects of CS on testicular function and sperm parameters are documented, changes of substances and secreting proteins in the seminal vesicle (SV) have never been reported. This study aimed to demonstrate the alterations of contents and expressions of proteins in seminal vesicle fluid (SVF) under CS. Fourteen adult rats were divided into control and CS groups (n = 7/each). Control rats were not exposed to stressor, while the CS animals were immobilised by restraint cage (4 hr/day) and followed by forced swimming (15 min/day) for consecutive 60 days. Biochemical substances and malondialdehyde (MDA) level in SVF were examined. Expressions of heat-shock protein 70 (Hsp70), caspases (Casp) 3 and 9, and tyrosine-phosphorylated (TyrPho) proteins were investigated in seminal vesicle tissue (SVT) and SVF. It was found that CS caused reductions of seminal epithelial height and secreted substance levels. Significantly, MDA levels in SVF and expressions of Hsp70, Casp and TyrPho proteins were increased in of CS animals. It was concluded that CS affected seminal secretion. Low quality of CS seminal plasma may associate with increase of MDA and expressions of secreted proteins.
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http://dx.doi.org/10.1111/and.13800DOI Listing
February 2021

NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer.

Cells 2020 08 3;9(8). Epub 2020 Aug 3.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. The was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibit expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 ( mutant) xenograft experiment. Gefitinib might suppress expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.
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http://dx.doi.org/10.3390/cells9081830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464180PMC
August 2020

Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids.

iScience 2020 Aug 16;23(8):101372. Epub 2020 Jul 16.

Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USA; Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address:

In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-shaped hydrogel show significant size heterogeneity in different locations inside the hydrogel. Computational simulations revealed that the instability and diffusion limitation of Wnt3a constitutively generate a concentration gradient inside the hydrogel. The location-dependent heterogeneity of organoids in a hydrogel dome substantially perturbed the transcriptome profile associated with epithelial functions, cytodifferentiation including mucin 2 expression, and morphological characteristics. This heterogeneous phenotype was significantly mitigated when the Wnt3a was frequently replenished in the culture medium. Our finding suggests that the morphological, transcriptional, translational, and functional heterogeneity in conventional organoid cultures may lead to a false interpretation of the experimental results in organoid-based studies.
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http://dx.doi.org/10.1016/j.isci.2020.101372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398973PMC
August 2020

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip.

Micromachines (Basel) 2020 Jul 7;11(7). Epub 2020 Jul 7.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.

The regeneration of the mucosal interface of the human intestine is critical in the host-gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn's disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic-oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host-microbiome crosstalk to target a patient-specific disease modeling.
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http://dx.doi.org/10.3390/mi11070663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408321PMC
July 2020

Preclinical Evaluation of the Novel Small-Molecule MSI-N1014 for Treating Drug-Resistant Colon Cancer via the LGR5/β-catenin/miR-142-3p Network and Reducing Cancer-Associated Fibroblast Transformation.

Cancers (Basel) 2020 Jun 16;12(6). Epub 2020 Jun 16.

Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Colorectal cancer represents one of the most prevalent malignancies globally, with an estimated 140,000 new cases in the United States alone in 2019. Despite advancements in interventions, drug resistance occurs in virtually all patients diagnosed with late stages of colon cancer. Amplified epidermal growth factor receptor (EGFR) signaling is one of the most prevalent oncogenic drivers in patients and induces increased Janus kinase (JAK)/signal transduction and activator of transcription (STAT) and β-catenin functions, all of which facilitate disease progression. Equally important, cancer-associated fibroblasts (CAFs) transformed by cancer cells within the tumor microenvironment (TME) further facilitate malignancy by secreting interleukin (IL)-6 and augmenting STAT3 signaling in colon cancer cells and promoting the generation of cancer stem-like cells (CSCs). Based on these premises, single-targeted therapeutics have proven ineffective for treating malignant colon cancer, and alternative multiple-targeting agents should be explored. Herein, we synthesized a tetracyclic heterocyclic azathioxanthone, MSI-N1014, and demonstrated its therapeutic potential both in vitro and in vivo. First, we used a co-culture system to demonstrate that colon cancer cells co-cultured with CAFs resulted in heightened 5-fluorouracil (5-FU) resistance and tumor sphere-forming ability and increased side populations, accompanied by elevated expression of cluster of differentiation 44 (CD44), β-catenin, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), and ATP-binding cassette super-family G member 2 (ABCG2). MSI-N1014 suppressed cell viability, colony formation, and migration in both DLD1 and HCT116 cells. MSI-N1014 treatment led to decreased expressions of oncogenic markers, including mammalian target of rapamycin (mTOR), EGFR, and IL-6 and stemness markers such as CD44, β-catenin, and LGR5. More importantly, MSI-N1014 treatment suppressed the transformation of CAFs, and was associated with decreased secretion of IL-6 and vascular endothelial growth factor (VEGF) by CAFs. Furthermore, MSI-N1014 treatment resulted in significantly reduced oncogenic properties, namely the migratory ability, tumor-sphere generation, and resistance against 5-FU. Notably, an increased level of the tumor suppressor, miR-142-3p, whose targets include LGR5, IL-6, and ABCG2, was detected in association with MSI-N1014 treatment. Finally, we demonstrated the therapeutic potential of MSI-N1014 in vivo where combined treatment with MSI-N1014 and 5-FU led to the lowest tumor growth, followed by MSI-N1014 only, 5-FU, and the vehicle control. Tumor samples from the MSI-N1014 group showed markedly reduced expressions of LGR5, β-catenin, IL-6, and mTOR, but increased expression of the tumor suppressor, miR-142-3p, according to qRT-PCR analysis. Collectively, we present preclinical support for the application of MSI-N1014 in treating 5-FU-resistant colon cancer cells. Further investigation is warranted to translate these findings into clinical settings.
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http://dx.doi.org/10.3390/cancers12061590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352915PMC
June 2020
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