Contractility assessment using aligned human iPSC-derived cardiomyocytes.

Introduction: Cardiac safety assessment, such as lethal arrhythmias and contractility dysfunction, is critical during drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been shown to be useful in predicting drug-induced proarrhythmic risk through international validation studies. Although cardiac contractility is another key function, fit-for-purpose hiPSC-CMs in evaluating drug-induced contractile dysfunction remain poorly understood.

Contractility assessment of human iPSC-derived cardiomyocytes by using a motion vector system and measuring cell impedance.

Predicting drug-induced cardiotoxicity during the non-clinical stage is important to avoid severe consequences in the clinical trials of new drugs. Human iPSC-derived cardiomyocytes (hiPSC-CMs) hold great promise for cardiac safety assessments in drug development. To date, multi-electrode array system (MEA) has been a widely used as a tool for the assessment of proarrhythmic risk with hiPSC-CMs.

Proarrhythmia Risk Assessment Using Electro-Mechanical Window in Human iPS Cell-Derived Cardiomyocytes.

Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation.

Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes.

Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs).

Assessment of Contractility in Human iPS Cell-Derived Cardiomyocytes Using Motion Vector Analysis.

Human-induced pluripotent stem cell (iPSC) technology paves the way for next-generation drug-safety assessment. In particular, human iPSC-derived cardiomyocytes, which exhibit electrical activity, are useful as a human cell model for assessing QT-interval prolongation and the risk of the lethal arrhythmia Torsade de Pointes (TdP). In addition to proarrhythmia assay, contractile behavior has received increased attention in drug development.

[Current challenges and future perspectives of pharmacological testing using new approach methodologies].

The mission of regulatory science is to promote human longevity by providing safer and more effective drugs and ensuring human health. At present, various in vitro and in vivo evaluation methods are used for drug development, and no major problems have been observed. However, there is still room for improvement in terms of risk prediction in humans.

Comprehensive Cardiotoxicity Assessment of COVID-19 Treatments Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment.

Optimizing the Direction and Order of the Motion Unveiled the Ability of Conventional Monolayers of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Show Frequency-Dependent Enhancement of Contraction and Relaxation Motion.

Contractility of the human heart increases as its beating rate is elevated, so-called positive force-frequency relationship; however, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been reported to exert a negative force-frequency relationship. We tested the hypothesis that the regulation of motion directions by electrical pacing and/or oxygen supply may improve the electro-mechanical properties of hiPSC-CMs monolayers. To better evaluate the spatial and temporal relationship between electrical excitation and contractile motion, we simultaneously observed the field potential and motion vector of hiPSC-CMs sheets.

[Development of a new assessment for cardio-oncology and its international trend].

Cardiac safety assessments play a key role in drug development. New non-clinical cardiac safety risk assessments, such as the use of iPSC-derived cardiomyocytes, have been validated by several consortiums both in Japan and abroad. The emerging multidisciplinary field of cardio-oncology has been recognized more important.

Cardiotoxicity Assessment of Drugs Using Human iPS Cell-Derived Cardiomyocytes: Toward Proarrhythmic Risk and Cardio-Oncology.

Growing evidence suggests that Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) can be used as a new human cell-based platform to assess cardiac toxicity/safety during drug development. Cardiotoxicity assessment is highly challenging due to species differences and various toxicities, such as electrophysiological and contractile toxicities, which can result in proarrhythmia and heart failure. To explore proarrhythmic risk, the Multi-Electrode Array (MEA) platform is widely used to assess QT-interval prolongation and the proarrhythmic potential of drug candidates using hiPSC-CMs.

Human papillomaviruses activate and recruit SMC1 cohesin proteins for the differentiation-dependent life cycle through association with CTCF insulators.

Human papillomaviruses infect stratified epithelia and link their productive life cycle to the differentiation state of the host cell. Productive viral replication or amplification is restricted to highly differentiated suprabasal cells and is dependent on the activation of the ATM DNA damage pathway. The ATM pathway has three arms that can act independently of one another.

p38MAPK and MK2 pathways are important for the differentiation-dependent human papillomavirus life cycle.

Amplification of human papillomaviruses (HPV) is dependent on the ATM DNA damage pathway. In cells with impaired p53 activity, DNA damage repair requires the activation of p38MAPK along with MAPKAP kinase 2 (MK2). In HPV-positive cells, phosphorylation of p38 and MK2 proteins was induced along with relocalization to the cytoplasm.

HPV18 E1^E4 is assembled into aggresome-like compartment and involved in sequestration of viral oncoproteins.

Papillomavirus is the etiological agent for warts and several squamous carcinomas. Skin cancer induced by cottontail rabbit papillomavirus was the first animal model for virus-induced carcinogenesis. The target organ of the virus infection is stratified epithelium and virus replication is tightly regulated by the differentiation program of the host cell.

Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation.

Human papillomaviruses (HPVs) target the stratified epidermis, and can causes diseases ranging from benign condylomas to malignant tumors. Infections of HPVs in the genital tract are among the most common sexually transmitted diseases, and a major risk factor for cervical cancer. The virus targets epithelial cells in the basal layer of the epithelium, while progeny virions egress from terminally differentiated cells in the cornified layer, the surface layer of the epithelium.

Neucrin, a novel secreted antagonist of canonical Wnt signaling, plays roles in developing neural tissues in zebrafish.

Wnt signaling plays crucial roles in neural development. We previously identified Neucrin, a neural-specific secreted antagonist of canonical Wnt/β-catenin signaling, in humans and mice. Neucrin has one cysteine-rich domain, in which the positions of 10 cysteine residues are similar to those in the second cysteine-rich domain of Dickkopfs, secreted Wnt antagonists.

Novel human papillomavirus type 18 replicon and its application in screening the antiviral effects of cytokines.

Human papillomaviruses (HPVs) infect the stratified epithelial organ. The infection induces benign tumors, which occasionally progress into malignant tumors. To elucidate the virus-induced tumorigenesis, an understanding of the lifecycle of HPV is crucial.

[Life cycle of HPV governed by the differentiation program of epithelial cell].

Papillomavirus is a pathogenic virus that induces benign tumor at the infected lesion, and its association with malignant tumor was first identified by R. Shope using animal model. A variety of cancers have been reported to be associated with the infection of human papillomavirus since the report by H.

Ras modifies proliferation and invasiveness of cells expressing human papillomavirus oncoproteins.

Infection by human papillomavirus (HPV) is a major risk factor for human cervical carcinoma. However, the HPV infection alone is not sufficient for cancer formation. Cervical carcinogenesis is considered a multistep process accompanied by genetic alterations of the cell.