Advancing Cardiovascular Drug Screening Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a promising tool for studying cardiac physiology and drug responses. However, their use is largely limited by an immature phenotype and lack of high-throughput analytical methodology. In this study, we developed a high-throughput testing platform utilizing hPSC-CMs to assess the cardiotoxicity and effectiveness of drugs. Following an optimized differentiation and maturation protocol, hPSC-CMs exhibited mature CM morphology, phenotype, and functionality, making them suitable for drug testing applications. We monitored intracellular calcium dynamics using calcium imaging techniques to measure spontaneous calcium oscillations in hPSC-CMs in the presence or absence of test compounds. For the cardiotoxicity test, hPSC-CMs were treated with various compounds, and calcium flux was measured to evaluate their effects on calcium dynamics. We found that cardiotoxic drugs withdrawn due to adverse drug reactions, including encainide, mibefradil, and cetirizine, exhibited toxicity in hPSC-CMs but not in HEK293-hERG cells. Additionally, in the effectiveness test, hPSC-CMs were exposed to ATX-II, a sodium current inducer for mimicking long QT syndrome type 3, followed by exposure to test compounds. The observed changes in calcium dynamics following drug exposure demonstrated the utility of hPSC-CMs as a versatile model system for assessing both cardiotoxicity and drug efficacy. Overall, our findings highlight the potential of hPSC-CMs in advancing drug discovery and development, which offer a physiologically relevant platform for the preclinical screening of novel therapeutics.

Toxicological evidence integration to confirm the biological plausibility of the association between humidifier disinfectant exposure and respiratory diseases using the AEP-AOP framework.

Objectives: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. Methods: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into 3 lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway-adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. Results: The integration of each AEP-AOP component for PHMG and CMIT/MIT led to the development of an AEP-AOP model, wherein disinfectants released from humidifiers in aerosol or gaseous form reached target sites, causing respiratory damage through molecular initiating events and key events. The model demonstrated high reliability and relevance to the pathogenesis of respiratory diseases. Conclusion: The AEP-AOP model developed in this study provides strong evidence that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Next generation risk assessment of biocides (PHMG-p and CMIT/MIT)-induced pulmonary fibrosis using adverse outcome pathway-based transcriptome analysis.

Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled toxicants. In this study, NGRA was used to assess the inhalation risks of two biocides commonly used as humidifier disinfectants: polyhexamethylene guanidine phosphate (PHMG-p) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Human bronchial epithelial cell transcriptomic data were processed based on adverse outcome pathways and used to establish transcriptome-based points of departure (tPODs) for each biocide. tPOD values were 0.00500-0.0510 µg/cm2 and 0.0342-0.0544 µg/cm2 for PHMG-p and CMIT/MIT, respectively. tPODs may provide predictive power comparable to that of traditional animal-based PODs (aPODs). The tPOD-based NGRA determined that both PHMG-p and CMIT/MIT present a high inhalation risk. Moreover, the identified PHMG-p posed a higher risk than CMIT/MIT, and children were identified as more susceptible population compared to adults. This finding is consistent with observations from actual exposure events. Our findings suggest that NGRA with transcriptomics offers a reliable approach for risk assessment of specific humidifier disinfectant biocides, while acknowledging the limitations of current models and in vitro systems, particularly regarding uncertainties in pharmacokinetics (PK) and pharmacodynamics (PD).

Primary cutaneous mucinous carcinoma in a periorbital lesion: two case reports and literature review.

Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy of the sweat glands that most commonly affects the periorbital area. It is characterized by slow growth over a prolonged period, and its morphology can be easily confused with a benign tumor, such as an epidermal cyst. Consequently, many patients experience recurrence after undergoing multiple resections. However, there are few reports concerning the surgical management of PCMC. We present two cases of PCMC originating in the periorbital area. The first case involved a 76-year-old man with a mass measuring 3.0× 1.5 cm that had been increasing in size. The second case was a 61-year-old man with two masses, each measuring 1.0× 1.0 cm, that were also growing. Both patients underwent wide excision with a 5-mm safety margin, which was determined based on the widest view of the cross-section of the mass on the magnetic resonance imaging. Subsequently, based on the intraoperative frozen biopsy results, both patients underwent additional excision with a 5-mm safety margin in only one direction. This report shows that, when determining the surgical margin of PCMC in periorbital area, employing imaging modalities and intraoperative frozen biopsies can be helpful for narrowing the surgical margin.

Python-Based Algorithm for Estimating the Parameters of Physical Property Models for Substances Not Available in Database.

An in-house Python-based algorithm was developed using simplified molecular-input line-entry specification (SMILES) strings and a dipole moment for estimating the normal boiling point, critical properties, standard enthalpy, vapor pressure, liquid molar volume, enthalpy of vaporization, heat capacity, viscosity, thermal conductivity, and surface tension of molecules. Normal boiling point, critical properties, and standard enthalpy were estimated by using the Joback group contribution method. Vapor pressure, liquid molar volume, enthalpy of vaporization, heat capacity, and surface tension were estimated by using the Riedel model, Gunn-Yamada model, Clausius-Clapeyron equation, Joback group contribution method, and Brock-Bird model, respectively. Viscosities of liquid and gas were estimated by using the Letsou-Stiel model and the Chapman-Enskog-Brokaw model, respectively. Thermal conductivities of liquid and gas were estimated by using the Sato-Riedel model and Stiel-Thodos model, respectively. Dipole moment was calculated through molecular dynamics simulation using the MMFF94 force field, performed with Avogadro software. A case study was conducted with dihydro-2-methyl-3-furanone (DHMF), 2-furaldehyde diethyl acetal (FDA), 1,1-diethoxy-3-methyl butane (DEMB), glutathione (GSH), vitamin B5 (VITB5), homocysteine (HCYS), and O-acetyl-l-homoserine (AH), which are not present in the existing property database. Cross-validation indicated that the developed Python-based algorithm provided pure component model parameters nearly identical with those obtained with the Aspen Property Constant Estimation System (PCES) method, except for the enthalpy of vaporization. The parameters for estimating the enthalpy of vaporization using the current Python-based algorithm accurately represented the behavior of the actual substances, as determined using the Clausius-Claperyon equation. This Python-based algorithm provides a detailed and clear reference for estimating pure property parameters.

Clinical outcomes of preimplantation genetic testing for aneuploidy in high-risk patients: a retrospective cohort study.

OBJECTIVE: The purpose of this study was to evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on clinical outcomes among high-risk patients. METHODS: This retrospective study involved 1,368 patients and the same number of cycles, including 520 cycles with PGT-A and 848 cycles without PGT-A. The study participants comprised women of advanced maternal age (AMA) and those affected by recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), or severe male factor infertility (SMF). RESULTS: PGT-A was associated with significant improvements in the implantation rate (IR) and the ongoing pregnancy rate/live birth rate (OPR/LBR) per embryo transfer cycle in the AMA (39.3% vs. 16.2% [p<0.001] and 42.0% vs. 21.8% [p<0.001], respectively), RIF (41.7% vs. 22.0% [p<0.001] and 47.0% vs. 28.6% [p<0.001], respectively), and RPL (45.6% vs. 19.5% [p<0.001] and 49.1% vs. 24.2% [p<0.001], respectively) groups, as well as the IR in the SMF group (43.3% vs. 26.5%, p=0.011). Additionally, PGT-A was associated with lower overall incidence rates of early pregnancy loss in the AMA (16.7% vs. 34.3%, p=0.001) and RPL (16.7% vs. 50.0%, p<0.001) groups. However, the OPR/LBR per total cycle across all PGT-A groups did not significantly exceed that for the non-PGT-A groups. CONCLUSION: PGT-A demonstrated beneficial effects in high-risk patients. However, our findings indicate that these benefits are more pronounced in carefully selected candidates than in the entire high-risk patient population.

Clinical characteristics of pediatric nasal bone fractures by age group.

BACKGROUND: The clinical characteristics of pediatric nasal fractures can vary depending on the child's age, social activities, and environment. Therefore, this study aimed to analyze these characteristics in different age groups. METHODS: We retrospectively reviewed of a series of patients aged under 12 years who received treatment between 2013 and 2021. The initial study design involved dividing the patients into four age groups, corresponding to different developmental ages, but there were no cases in infants aged 0 to 1 year. Therefore, the patients were divided into three groups: group I, between 2 and 5; group II, between 6 and 9; and group III, between 10 and 12 years of age. The following parameters were evaluated: sex, age, etiology, fracture type and severity, and the incidence of septal injuries. RESULTS: In total, 98 patients were included in this study. In group III, the ratio of boys to girls was 3.88:1, exceeding the overall ratio of 1.97:1. The most common cause varied with age: slipping down in group I, bumping accidents in group II, and sports accidents in group III. Concomitant septal injuries were present in 4.17% of patients in group I, 5.71% of patients in group II, and 28.21% of patients in group III. CONCLUSION: Increasing age was accompanied by a greater tendency for male predominance and a higher prevalence of sports-related causes and septal injuries. Violence was infrequent but started to become a contributing factor during school age. These varying environmental factors across age groups can offer valuable insights into the epidemiology and clinical characteristics of pediatric nasal bone fractures.