• BMB Reports
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• v.44 no.1
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• pp.11-21
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• 2011

During the last decade small regulatory RNA (srRNA) emerged as central players in the regulation of gene expression in all kingdoms of life. Multiple pathways for srRNA biogenesis and diverse mechanisms of gene regulation may indicate that srRNA regulation evolved independently multiple times. However, small RNA pathways share numerous properties, including the ability of a single srRNA to regulate multiple targets. Some of the mechanisms of gene regulation by srRNAs have significant effect on the abundance of free srRNAs that are ready to interact with new targets. This results in indirect interactions among seemingly unrelated genes, as well as in a crosstalk between different srRNA pathways. Here we briefly review and compare the major srRNA pathways, and argue that the impact of srRNA is always at the system level. We demonstrate how a simple mathematical model can ease the discussion of governing principles. To demonstrate these points we review a few examples from bacteria and animals.

• Genes and Genomics
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• v.40 no.12
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• pp.1339-1349
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• 2018

Cerebral palsy (CP) is a non-progressive neurological disease, of which susceptibility is linked to genetic and environmental risk factors. More and more studies have shown that CP might be caused by multiple genetic factors, similar to other neurodevelopmental disorders. Due to the high genetic heterogeneity of CP, we focused on investigating related molecular pathways. Ten children with CP were collected for whole-exome sequencing by next-generation sequencing (NGS) technology. Customized processes were used to identify potential pathogenic pathways and variants. Three pathways (axon guidance, transmission across chemical synapses, protein-protein interactions at synapses) with twenty-three genes were identified to be highly correlated with CP. This study showed that the three pathways associated with CP might be the molecular mechanism of pathogenesis. These findings could provide useful clues for developing pathway-based pharmacotherapies. Further studies are required to confirm potential roles for these pathways in the pathogenesis of CP.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3905-3909
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• 2012

Ovarian cancer is the fifth leading cause of cancer death in women aged 35 to 74 years. Although there are several popular hypothesis of ovarian cancer pathogenesis, the genetic mechanisms are far from being clear. Recently, systems biology approaches such as network-based methods have been successfully applied to elucidate the mechanisms of diseases. In this study, we constructed a crosstalk network among ovarian cancer related pathways by integrating protein-protein interactions and KEGG pathway information. Several significant pathways were identified to crosstalk with each other in ovarian cancer, such as the chemokine, Notch, Wnt and NOD-like receptor signaling pathways. Results from these studies will provide the groundwork for a combination therapy approach targeting multiple pathways which will likely be more effective than targeting one pathway alone.

• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.213-221
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• 2020

Acute kidney injury (AKI) is a common disease with a complex pathophysiology which significantly contributes to the development of chronic kidney disease and end stage kidney failure. Preventing AKI can consequently reduce mortality, morbidity, and healthcare burden. However, there are no effective drugs in use for either prevention or treatment of AKI. Developing therapeutic agents with pleiotropic effects covering multiple pathophysiological pathways are likely to be more effective in attenuating AKI. Fyn, a non-receptor tyrosine kinase, has been acknowledged to integrate multiple injurious stimuli in the kidney. Limited studies have shown increased Fyn transcription level and activation under experimental AKI. Activated Fyn kinase propagates various downstream signaling pathways associated to the progression of AKI, such as oxidative stress, inflammation, endoplasmic reticulum stress, as well as autophagy dysfunction. The versatility of Fyn kinase in mediating various pathophysiological pathways suggests that its inhibition can be a potential strategy in attenuating AKI.

• Journal of Chest Surgery
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• v.29 no.12
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• pp.1373-1376
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• 1996

From October 1993 to February 1996, 9 patients with Wolfr-Parkinson-White syndrome underwent surgical ablation of the accessory atrioventricular conduction pathways. The indications for surgical ablation we e radiofrequency ablation failure in 6 cases, multiple accessory pathways in 1 case, catheter tip fracture ducting catheter ablation in 1 case and additional procedure(redo mitral valve replacement due to valve thrombosis) in 1 case. There was no operative mortality. The postoperative complications were noted In 2 cases pericardial effusion and wound Infection. All patients had accessory atrioventricular connections ablated which were proven by surface ECG and follow-up electrophysiologic study and have remained free of symptomatic tachycardia. The indications for surgical treatment of Wolff-Parkinson-White syndrome are radiofrequency ablation failure, multiple pathways, or when additional procedures are required The present results were satisfactory.

• BMB Reports
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• v.47 no.10
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• pp.540-545
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• 2014

Balanced cell growth is crucial in animal development as well as tissue homeostasis. Concerted cross-regulation of multiple signaling pathways is essential for those purposes, and the dysregulation of signaling may lead to a variety of human diseases such as cancer. The time-honored Wnt/${\beta}$-catenin and recently identified Hippo signaling pathways are evolutionarily conserved in both Drosophila and mammals, and are generally considered as having positive and negative roles in cell proliferation, respectively. While most mainstream regulators of the Wnt/${\beta}$-catenin signaling pathway have been fairly well identified, the regulators of the Hippo pathway need to be more defined. The Hippo pathway controls organ size primarily by regulating cell contact inhibition. Recently, several cross-regulations occurring between the Wnt/${\beta}$-catenin and Hippo signaling pathways were determined through biochemical and genetic approaches. In the present mini-review, we mainly discuss the signal transduction mechanism of the Hippo signaling pathway, along with cross-talk between the regulators of the Wnt/${\beta}$-catenin and Hippo signaling pathways.

• Genomics & Informatics
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• v.6 no.4
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• pp.210-222
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• 2008

Due to the polygenic nature of cancer, it is believed that breast cancer is caused by the perturbation of multiple genes and their complex interactions, which contribute to the wide aspects of disease phenotypes. A systems biology approach for the identification of subnetworks of interconnected genes as functional modules is required to understand the complex nature of diseases such as breast cancer. In this study, we apply a 3-step strategy for the interpretation of microarray data, focusing on identifying significantly perturbed metabolic pathways rather than analyzing a large amount of overexpressed and underexpressed individual genes. The selected pathways are considered to be dysregulated functional modules that putatively contribute to the progression of disease. The subnetwork of protein-protein interactions for these dysregulated pathways are constructed for further detailed analysis. We evaluated the method by analyzing microarray datasets of breast cancer tissues; i.e., normal and invasive breast cancer tissues. Using the strategy of microarray analysis, we selected several significantly perturbed pathways that are implicated in the regulation of progression of breast cancers, including the extracellular matrix-receptor interaction pathway and the focal adhesion pathway. Moreover, these selected pathways include several known breast cancer-related genes. It is concluded from this study that the present strategy is capable of selecting interesting perturbed pathways that putatively play a role in the progression of breast cancer and provides an improved interpretability of networks of protein-protein interactions.

• BMB Reports
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• v.36 no.1
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• pp.78-81
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• 2003

The prevention of cancer is one of the most important public health and medical practices of the $21^{st}$ century. We have made much progress in this new emerging field, but so much remains to be accomplished before widespread use and practice become common place. Cancer chemoprevention encompasses the concepts of inhibition, reversal, and retardation of the cancer process. This process, called carcinogenesis, requires 20-40 years to reach the endpoint called invasive cancer. It typically follows multiple, diverse and complex pathways in a stochastic process of clonal evolution. These pathways appear amenable to inhibition, reversal or retardation at various points. We must therefore identify key pathways in the evolution of the cancer cell that can be exploited to prevent this carcinogenesis process. Basic research is identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes are active during early development and are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes are mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. Thus there is a wide range of defects in cellular machinery which can lead to evolution of the cancer phenotype. Mistakes may not have to appear in a certain order for cells to progress along the cancer pathway. To conquer this diverse disease, we must attack multiple key pathways at once for a predetermined period of time. Thus, agent combination prevention strategies are essential to decrease cancer morbidity. Furthermore, each cancer type may require custom combination of prevention strategies to be successful.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.2
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• pp.109-120
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• 2014

The epothilones are a class of microtubule inhibitors that exhibit a strong antitumor activity. UTD2 is a novel epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This study investigated the effects of UTD2 on the actin cytoskeleton and its critical regulators, and the signaling pathways which are essential for cell motility, growth and survival in MCF-7 breast cancer cells. Results showed that UTD2 inhibited the cellular functions of actin cytoskeleton, such as wound-closure, migration and invasion, as well as adhesion. Our study further demonstrated that UTD2 suppressed Rac1 GTPase activation and reduced the activity of PAK1, which is a downstream effector of Rac1, while the activity of Cdc42 was not affected. Additionally, the phosphorylation of p38 and ERK were significantly inhibited, but the phosphorylation of JNK remained the same after UTD2 treatment. Moreover, UTD2 inhibited the activity and mRNA expression of MMP-2, which plays a key role in cell motility. UTD2 also reduced the phosphorylation of Akt, which is an important signaling kinase regulating the cell survival through Rac1. Furthermore, UTD2 interrupted the synergy between Rac1 and Raf in focus formation assays. Taken together, these results indicated that UTD2 exerted multiple effects on the actin cytoskeleton and signaling pathways associated with Rac1. This study provided novel insights into the molecular mechanism of the antineoplastic and antimetastatic activities of epothilones. Our findings also suggest that the signaling pathways regulated by Rac1 may be evaluated as biomarkers for the response to therapy in clinical trials of epothilones.

• Genomics & Informatics
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• v.17 no.4
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• pp.45.1-45.3
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• 2019

To identify pathways associated with survival phenotypes using gene expression data, we recently proposed the hierarchical structural component model for pathway analysis of gene expression data (HisCoM-PAGE) method. The HisCoM-PAGE software can consider hierarchical structural relationships between genes and pathways and analyze multiple pathways simultaneously. It can be applied to various types of gene expression data, such as microarray data or RNA sequencing data. We expect that the HisCoM-PAGE software will make our method more easily accessible to researchers who want to perform pathway analysis for survival times.