Analysis of Mechanisms of T-2 Toxin Toxicity Using Yeast DNA Microarrays

T-2 toxin is a mycotoxin that belongs to a group of type A tricothecenes found in agricultural products. The cytotoxicity of T-2 toxin was characterized by analysis of the yeast transcriptome upon challenge with T-2 toxin. Interestingly, T-2 toxin-induced yeast gene expression profiles were found to be similar to profiles obtained following cycloheximide treatment. Moreover, T-2 toxin treatment was found to activate facilitators, gluconeogenesis and cell arrest related genes such as mitogen-activated protein kinase genes (FUS3). T-2 toxin attacks the membrane and as a result the membrane transport system was disturbed. A large number of genes are induced to restore the toxicity caused by T-2 toxin. However, the data did not suggest that DNA damage by alkylation (Mag1, a gene 3-methyl-adenine DNA glycosylase, 0.46-fold down regulated), no induction of DNA repair mechanisms such as recombination (RAD26, RAD52 and etc.) and excision repair (RAD7, RAD14, RAD16, RAD23 and etc.). These results suggested that the toxicity of the T-2 toxin was due to the disturbance of the cell membrane of the yeast cell and that T-2 toxin caused mild mutagenesis

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis

Ono Sawako, Hirose Katsutoshi, Sukegawa Shintaro, et al. Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis. Diagnostic Pathology 19, 63 (2024); https://doi.org/10.1186/s13000-024-01487-0.Background: Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. Methods: Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes.Results: We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1–4) were one woman and three men with a mean age of 53.75 years (range: 15–74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1–3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. Conclusions: We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated

FMD, PWV, and Cardiovascular Events

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD‐J (Flow‐Mediated Dilation Japan) Study A

BackgroundThe usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known.Methods and ResultsWe measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed.ConclusionsIn patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

Effects of Melatonin on the Transcriptome of Human Granulosa Cells, Fertilization and Blastocyst Formation

Melatonin is a promising reagent that can improve assisted reproductive technology (ART) outcomes in infertility patients. However, melatonin is not effective for all infertile patients, and it remains unclear for which patients melatonin would be effective. This study examined the effects of melatonin on ART outcomes and examined its mechanisms. Melatonin increased the fertilization rate in patients whose fertilization rates in the previous cycle were less than 50%, but not in patients whose fertilization rates were more than 50% in the previous cycle. Melatonin increased the blastocyst formation rate in patients whose embryo development rates in the previous cycle were less than 50%, but not in patients whose embryo development rates were more than 50% in the previous cycle. To clarify its mechanisms, transcriptome changes by melatonin treatment in granulosa cells (GCs) of the patients were examined by RNA-sequence. Melatonin treatment altered the transcriptomes of GCs of patients with poor ART outcomes so that they were similar to the transcriptomes of patients with good ART outcomes. The altered genes were associated with the inhibition of cell death and T-cell activity, and the activation of steroidogenesis and angiogenesis. Melatonin treatment was effective for patients with poor fertilization rates and poor embryo development rates in the previous ART cycle. Melatonin alters the GCs transcriptome and, thus, their functions, and this could improve the oocyte quality, leading to good ART outcomes

A novel quantitative hemolytic assay coupled with restriction fragment length polymorphisms analysis enabled early diagnosis of atypical hemolytic uremic syndrome and identified unique predisposing mutations in Japan.

For thrombotic microangiopathies (TMAs), the diagnosis of atypical hemolytic uremic syndrome (aHUS) is made by ruling out Shiga toxin-producing Escherichia coli (STEC)-associated HUS and ADAMTS13 activity-deficient thrombotic thrombocytopenic purpura (TTP), often using the exclusion criteria for secondary TMAs. Nowadays, assays for ADAMTS13 activity and evaluation for STEC infection can be performed within a few hours. However, a confident diagnosis of aHUS often requires comprehensive gene analysis of the alternative complement activation pathway, which usually takes at least several weeks. However, predisposing genetic abnormalities are only identified in approximately 70% of aHUS. To facilitate the diagnosis of complement-mediated aHUS, we describe a quantitative hemolytic assay using sheep red blood cells (RBCs) and human citrated plasma, spiked with or without a novel inhibitory anti-complement factor H (CFH) monoclonal antibody. Among 45 aHUS patients in Japan, 24% (11/45) had moderate-to-severe (≥50%) hemolysis, whereas the remaining 76% (34/45) patients had mild or no hemolysis (<50%). The former group is largely attributed to CFH-related abnormalities, and the latter group has C3-p.I1157T mutations (16/34), which were identified by restriction fragment length polymorphism (RFLP) analysis. Thus, a quantitative hemolytic assay coupled with RFLP analysis enabled the early diagnosis of complement-mediated aHUS in 60% (27/45) of patients in Japan within a week of presentation. We hypothesize that this novel quantitative hemolytic assay would be more useful in a Caucasian population, who may have a higher proportion of CFH mutations than Japanese patients

Correction: A Novel Quantitative Hemolytic Assay Coupled with Restriction Fragment Length Polymorphisms Analysis Enabled Early Diagnosis of Atypical Hemolytic Uremic Syndrome and Identified Unique Predisposing Mutations in Japan.

[This corrects the article DOI: 10.1371/journal.pone.0124655.]

Differential gene expression in decidualized human endometrial stromal cells induced by different stimuli

Abstract Decidualization can be induced by culturing human endometrial stromal cells (ESCs) with several decidualization stimuli, such as cAMP, medroxyprogesterone acetate (MPA) or Estradiol (E2). However, it has been unclear how decidualized cells induced by different stimuli are different. We compared transcriptomes and cellular functions of decidualized ESCs induced by different stimuli (MPA, E2 + MPA, cAMP, and cAMP + MPA). We also investigated which decidualization stimulus induces a closer in vivo decidualization. Differentially expressed genes (DEGs) and altered cellular functions by each decidualization stimuli were identified by RNA-sequence and gene-ontology analysis. DEGs was about two times higher for stimuli that use cAMP (cAMP and cAMP + MPA) than for stimuli that did not use cAMP (MPA and E2 + MPA). cAMP-using stimuli altered the cellular functions including angiogenesis, inflammation, immune system, and embryo implantation whereas MPA-using stimuli (MPA, E2 + MPA, and cAMP + MPA) altered the cellular functions associated with insulin signaling. A public single-cell RNA-sequence data of the human endometrium was utilized to analyze in vivo decidualization. The altered cellular functions by in vivo decidualization were close to those observed by cAMP + MPA-induced decidualization. In conclusion, decidualized cells induced by different stimuli have different transcriptome and cellular functions. cAMP + MPA may induce a decidualization most closely to in vivo decidualization