Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma.

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development.

Most clinically used drugs are metabolized in the body via oxidation, reduction, or hydrolysis reactions, which are considered phase I reactions. Cytochrome P450 (P450) enzymes, which primarily catalyze oxidation reactions, contribute to the metabolism of over 50% of clinically used drugs. In the last few decades, the function and regulation of P450s have been extensively studied, whereas the characterization of non-P450 phase I enzymes is still incomplete.

Plasma miR-218a-5p as a biomarker for acute cholestatic liver injury in rats and investigation of its pathophysiological roles.

MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug-induced liver injury. We recently reported that the plasma levels of miR-143-3p and miR-218a-5p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity-dependent manner and to elucidate their pathophysiological roles in cholestasis.

Recent progress in the use of microRNAs as biomarkers for drug-induced toxicities in contrast to traditional biomarkers: A comparative review.

microRNAs (miRNAs) are small non-coding RNAs with 18-25 nucleotides. They play key regulatory roles in versatile biological process including development and apoptosis, and in disease pathogenesis, for example carcinogenesis, by negatively regulating gene expression. miRNAs often exhibit characteristics suitable for biomarkers such as tissue-specific expression patterns, high stability in serum/plasma, and change in abundance in circulation immediately after toxic injury.

Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance.

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance.

Models of Idiosyncratic Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a leading cause of attrition during the early and late stages of drug development and after a drug is marketed. DILI is generally classified as either intrinsic or idiosyncratic. Intrinsic DILI is dose dependent and predictable (e.

[Recent advances in evaluation studies for drug-induced liver injury].

With the recent progress in drug metabolism and pharmacokinetics studies, the attrition due to pharmacokinetics in clinical trials and post-marketing was reduced to less than 1%. On the other hand, attrition of clinical trials due to adverse effects and toxicity has remained high. In particular, drug-induced liver injury (DILI) is a major cause of discontinuation of clinical trials and withdrawal of drug candidates after marketing.

An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury.

Preventing clinical drug-induced liver injury (DILI) remains a major challenge, because DILI develops via multifactorial mechanisms. Immune and inflammatory reactions are considered important mechanisms of DILI; however, biomarkers from in vitro systems using immune cells have not been comprehensively studied. The aims of this study were (1) to identify promising biomarker genes for predicting DILI in an in vitro coculture model of peripheral blood mononuclear cells (PBMCs) with a human liver cell line, and (2) to evaluate these genes as predictors of DILI using a panel of drugs with different clinical DILI risk.

Pharmacological evidence for the involvement of ryanodine receptors in halothane-induced liver injury in mice.

Drug-induced liver injury (DILI) is a major safety concern in drug development. Halothane (HAL), an inhaled anesthetic, induces severe and idiosyncratic liver injury. Ryanodine receptors (RyR) are major intracellular calcium release channels found on the plasma membrane of the endoplasmic reticulum (ER).

Associations between hemodynamic parameters at rest and exercise capacity in patients with implantable left ventricular assist devices.

Background: Hemodynamic parameters at rest are known to correlate poorly with peak oxygen uptake (VO) in heart failure. However, we hypothesized that hemodynamic parameters at rest could predict exercise capacity in patients with left ventricular assist device (LVAD), because LVAD pump rotational speed does not respond during exercise. Therefore, we investigated the relationships between hemodynamic parameters at rest (measured with right heart catheterization) and exercise capacity (measured with cardiopulmonary exercise testing) in patients with implantable LVAD.

Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.

Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown.

Macrophage-derived extracellular vesicles regulate concanavalin A-induced hepatitis by suppressing macrophage cytokine production.

Acute liver failure is a clinical syndrome of severe hepatic dysfunction. Immune cells play an important role in acute liver failure. In recent years, the immunoregulatory function of extracellular vesicles (EVs) has been reported; therefore, it is inferred that EVs play a role in immune-mediated hepatitis.

Exploration of small RNA biomarkers for testicular injury in the serum exosomes of rats.

Testicular injury is often observed in drug development. Serum hormones are usually used as noninvasive biomarkers for testicular injury; however, their sensitivities are low. Therefore, it is difficult to monitor testicular injury in drug development.

Pathological changes of the myocardium in reworsening of anthracycline-induced cardiomyopathy after explant of a left ventricular assist device.

We herein report the long-term changes in cardiac function and pathological findings after successful explantation of a left ventricular assist device in a 42-year-old patient with anthracycline-induced cardiomyopathy with reworsening heart failure. Endomyocardial biopsy samples revealed that the cardiomyocyte diameter decreased and collagen volume fraction increased just after left ventricular assist device explantation. The collagen volume fraction decreased after 6 months, despite preserved systolic function.

Pulmonary artery pressure may be a predictor of closed aortic valve in patients managed by venoarterial extracorporeal membrane oxygenation.

In the management of venoarterial extracorporeal membrane oxygenation, some patients present persistently closed aortic valve. However, little is known about the variables that contribute to persistently closed aortic valve. We investigated the factors that could predict persistently closed aortic valve at the time of venoarterial extracorporeal membrane oxygenation initiation.

Giant cell myocarditis with central diabetes insipidus: A case report.

A 51-year-old male, previously diagnosed with central diabetes insipidus due to lymphocytic hypophysitis, presented with fever and dyspnea for 1 week. On arrival, he exhibited hypotension (85/60 mmHg) and sinus tachycardia (110 bpm). His electrocardiogram revealed mild ST elevation on V2-V4.

Potential prognostic implications of myocardial thallium-201 and iodine-123-beta-methylpentadecanoic acid dual scintigraphy in patients with Anderson-Fabry disease.

Objectives: Information on the relationship between myocardial damage assessed by myocardial scintigraphy and prognosis in patients with Anderson-Fabry disease (AFD) is lacking. We therefore aimed to investigate the prognostic impacts of myocardial thallium-201 (Tl) and iodine-123 beta-methyl 15-para-iodophenyl 3(R, S)-methylpentadecanoic acid (I-BMIPP) dual scintigraphy in patients with AFD.

Methods: Eighteen consecutive patients with AFD underwent resting myocardial Tl/I-BMIPP dual scintigraphy.

Unique miRNA profiling of squamous cell carcinoma arising from ovarian mature teratoma: comprehensive miRNA sequence analysis of its molecular background.

Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues.

Early Blood Pressure Reduction by Intravenous Vasodilators Is Associated With Acute Kidney Injury in Patients With Hypertensive Acute Decompensated Heart.

Background: Intravenous vasodilators are commonly used in patients with hypertensive acute decompensated heart failure (ADHF), but little is known about their optimal use in blood pressure (BP) management to avoid acute kidney injury (AKI). The purpose of this study was to investigate the association between systolic BP (SBP) changes and the incidence of AKI in patients with hypertensive ADHF.

Methods and results: Post-hoc analysis was performed on a prospectively enrolled cohort.

Establishment of a mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism.

Drug-induced liver injury is a major problem in drug development and clinical drug therapy. Troglitazone (TGZ), a thiazolidinedione antidiabetic drug for the treatment of type II diabetes mellitus, was found to induce rare idiosyncratic severe liver injury in patients, which led to its withdrawal in 2000. However, in normal experimental animals in vivo TGZ has never induced liver injury.

Characterization of human UGT2A3 expression using a prepared specific antibody against UGT2A3.

UDP-Glucuronosyltransferase (UGT) 2A3 belongs to a UGT superfamily of phase II drug-metabolizing enzymes that catalyzes the glucuronidation of many endobiotics and xenobiotics. Previous studies have demonstrated that UGT2A3 is expressed in the human liver, small intestine, and kidney at the mRNA level; however, its protein expression has not been determined. Evaluation of the protein expression of UGT2A3 would be useful to determine its role at the tissue level.

A survival case of a young adult patient with ST-elevated myocardial infarction with high levels of lipoprotein(a).

A 23-year-old Japanese man presented to a nearby hospital with a complaint of chest pain. In terms of the risk factors for cardiovascular events, there were no abnormal findings in past medical examinations and no smoking history. The 12-lead　electrocardiogram revealed ST-elevation in V1-V6, I, and aVL, and he was diagnosed with acute myocardial infarction.

Prognostic impact of mitral L-wave in patients with hypertrophic cardiomyopathy without risk factors for sudden cardiac death.

Hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction is a major cause of heart failure and sudden cardiac death (SCD) associated with lethal arrhythmia. Although various risk factors for cardiac events have been reported in HCM patients, previous studies have reported that some HCM patients exhibit either no risk or a low risk of SCD experienced cardiac events. The mid-diastolic transmitral flow velocity curve (mitral L-wave) is an echocardiographic index of left ventricular compliance, and it has been reported as one of the parameters of advanced diastolic dysfunction assessed noninvasively.

Left Ventricular Relaxation Half-Time as a Predictor of Cardiac Events in Idiopathic Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy With Left Ventricular Systolic and/or Diastolic Dysfunction.

Purpose: Diastolic dysfunction preceding systolic dysfunction is considered an important interaction in cardiomyopathy with poor prognosis. The aim of this study was to compare left ventricular (LV) isovolumic relaxation with the other parameters as a potential prognostic marker for patients with idiopathic dilated cardiomyopathy (IDC) and hypertrophic cardiomyopathy (HC).

Methods: A total of 145 patients with IDC and 116 with HC were evaluated for hemodynamic parameters; LV pressure was directly measured by a micromanometer catheter, and relaxation half-time (T) was used to determine LV isovolumic relaxation.