Long noncoding RNA EIF1AX-AS1 promotes endometrial cancer cell apoptosis by affecting EIF1AX mRNA stabilization.

Long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of endometrial carcinoma (EC). Here, using RNA sequencing analysis, we systemically screened and identified the lncRNA eukaryotic translation initiation factor 1A, X-linked (EIF1AX)-AS1, which is aberrantly downregulated in clinical EC tissues and closely correlated with tumor type. EIF1AX-AS1 markedly inhibited EC cell proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, EIF1AX-AS1 interacts with EIF1AX mRNA and poly C binding protein 1 (PCBP1), which promote EIF1AX mRNA degradation. Intriguingly, by interacting with internal ribosome entry site-related protein Y-box binding protein 1 (YBX-1), EIF1AX promotes c-Myc translation through the internal ribosome entry site pathway. c-Myc promotes EIF1AX transcription and thus forms a feed-forward loop to regulate EC cell proliferation. Taken together, these data reveal new insights into the biology driving EC proliferation and highlights the potential of lncRNAs as biomarkers for prognosis and future therapeutic targets for cancer.

Icariin promotes mouse Leydig cell testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 pathway.

Icariin (ICA), extracted from Epimedium, is a flavonoid used in traditional Chinese medicine. Di(2-ethylhexyl) phthalate (DEHP) is a phthalate used in commercial products as a plasticizer that can influence the human endocrine and reproduction system. We previously found that ICA reversed DEHP-induced damage through the prevention of reactive oxygen species accumulation and promotion of testosterone secretion. Here we investigated the mechanisms of ICA in promoting testosterone secretion from murine Leydig cells. We used ICA, DEHP, the Akt agonist SC-79, the Akt inhibitor MK2206, and the Creb inhibitor KG501 to determine the effect of these treatments on the expression levels of the steroidogenic enzymes, Cyp11a1 and Hsd3b, which play critical roles in androgen production, in Leydig cells. Bioinformatic analysis was used to search for ICA-targeted proteins and their associated pathways. We found that icariin interacted with estrogen receptor on the cell membrane, leading to increased phosphorylation levels of Akt and Creb proteins and enhanced transcription of genes encoding steroidogenic enzymes and testosterone synthesis. We further investigated ICA activity in vivo using male mice pretreated with 100 mg/kg ICA and then treated with 750 mg/kg DEHP. ICA pretreatment reversed the reduced protein expression levels of Cyp11a1 and Hsd3b induced by DEHP in Leydig cells in vivo. Furthermore, while the phosphorylation levels of Akt and Creb were decreased in testes of mice exposed to DEHP alone, these effects were reversed by ICA pretreatment. These findings indicate that ICA promotes testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 signaling pathway.

Marijuana use in acute coronary syndromes.

BACKGROUND: Cannabis is one of the most widely used illicit substances worldwide, and it has the highest prevalence among drugs used in Egypt. OBJECTIVES: The aims were to evaluate whether the use of cannabis is a risk factor of acute coronary heart disease in low-risk, young males and to compare the cardiac pathological changes between cannabis exposed and non-exposed ischemic patients. METHODS: This was a cross-sectional study that was performed on 138 male patients, aged ≤ 40 years, with acute myocardial infarction who were admitted to the Cardiac Care Unit at the University Hospital. Urine samples were submitted for toxicological analysis using a homogenous enzyme immunoassay technique to determine the substance of use. The patients were divided into three groups: group 1 (n = 23), cannabis-positive only patients; group 2 (n = 28), patients positive for any other substance of use; and group 3 (n = 34), patients negative for any substance of use. RESULTS: Smoking was prominent, whereas group 1 had no other risk factors. In groups 1 and 2, ST-segment elevation myocardial infarction (STEMI) was dominant, whereas no ST-segment elevation myocardial infarction (NSTEMI) was prominent in group 3. Ischemic resting wall motion abnormalities were presented in 47.8% of group 1 and in only 11.8% of group 3. None of group 1 had normal coronaries, whereas 14.3% of group 3 had normal coronaries. Significant changes in echocardiography and angiography were observed between group 1 and other groups. CONCLUSION: Cannabis smoking could be a potential risk factor for the development of cardiac ischemia.

The possible therapeutic role of intravenous lipid emulsion in acute aluminium phosphide poisoning: a randomized controlled clinical trial.

Introduction: Aluminum phosphide (ALP) is a highly toxic rodenticide and the mortality rates caused by it have been demonstrated up to 70-100% in various studies. Unfortunately, there is no specific antidote to manage its toxic effects. This study aimed to assess the biochemical and clinical efficacy and safety of intravenous lipid emulsion as an adjuvant therapy in acute aluminum phosphide poisoning. Patients and methods: Sixty-four cases with acute ALP poisoning were stratified according to severity by the Poison Severity Score into severe and moderate groups (32 patients each). Patients were then randomly allocated into either receiving intravenous lipid emulsion in addition to the conventional treatment or receiving the conventional treatment only by using block randomization. Results: Treatment by ILE resulted in a significant improvement in the survival time, the mean arterial blood pressure, arterial blood gases, and a significant reduction in serum lactate levels. The need for intubation and mechanical ventilation was insignificantly lower in the intervention groups compared to control groups. However, the reduction in mortality rate in the patients of intervention groups compared with control groups was found to be non-significant. Intravenous lipid emulsion use in acute ALP poisoning significantly prolonged the survival time, improved the metabolic acidosis, decreased the serum lactate levels and increased the mean arterial blood pressure and hospital stay in the intervention groups. And insignificantly decreased the mortality rate, need of intubation and mechanical ventilation, and the total dose of vasopressors.

Multicenter validation of an artificial intelligence (AI)-based platform for the diagnosis of acute appendicitis.

BACKGROUND: The current scores used to help diagnose acute appendicitis have a "gray" zone in which the diagnosis is usually inconclusive. Furthermore, the universal use of CT scanning is limited because of the radiation hazards and/or limited resources. Hence, it is imperative to have an accurate diagnostic tool to avoid unnecessary, negative appendectomies. METHODS: This was an international, multicenter, retrospective cohort study. The diagnostic accuracy of the artificial intelligence platform was assessed by sensitivity, specificity, negative predictive value, the area under the receiver curve, precision curve, F1 score, and Matthews correlation coefficient. Moreover, calibration curve, decision curve analysis, and clinical impact curve analysis were used to assess the clinical utility of the artificial intelligence platform. The accuracy of the artificial intelligence platform was also compared to that of CT scanning. RESULTS: Two data sets were used to assess the artificial intelligence platform: a multicenter real data set (n = 2,579) and a well-qualified synthetic data set (n = 9736). The platform showed a sensitivity of 92.2%, specificity of 97.2%, and negative predictive value of 98.7%. The artificial intelligence had good area under the receiver curve, precision, F1 score, and Matthews correlation coefficient (0.97, 86.7, 0.89, 0.88, respectively). Compared to CT scanning, the artificial intelligence platform had a better area under the receiver curve (0.92 vs 0.76), specificity (90.9 vs 53.3), precision (99.8 vs 98.9), and Matthews correlation coefficient (0.77 vs 0.72), comparable sensitivity (99.2 vs 100), and lower negative predictive value (67.6 vs 99.5). Decision curve analysis and clinical impact curve analysis intuitively revealed that the platform had a substantial net benefit within a realistic probability range from 6% to 96%. CONCLUSION: The current artificial intelligence platform had excellent sensitivity, specificity, and accuracy exceeding 90% and may help clinicians in decision making on patients with suspected acute appendicitis, particularly when access to CT scanning is limited.

Deep Neural Network for the Prediction of KRAS Genotype in Rectal Cancer.

BACKGROUND: KRAS mutation can alter the treatment plan after resection of colorectal cancer. Despite its importance, the KRAS status of several patients remains unchecked because of the high cost and limited resources. This study developed a deep neural network (DNN) to predict the KRAS genotype using hematoxylin and eosin (H&E)-stained histopathological images. STUDY DESIGN: Three DNNs were created (KRAS_Mob, KRAS_Shuff, and KRAS_Ince) using the structural backbone of the MobileNet, ShuffleNet, and Inception networks, respectively. The Cancer Genome Atlas was screened to extract 49,684 image tiles that were used for deep learning and internal validation. An independent cohort of 43,032 image tiles was used for external validation. The performance was compared with humans, and a virtual cost-saving analysis was done. RESULTS: The KRAS_Mob network (area under the receiver operating curve [AUC] 0.8, 95% CI 0.71 to 0.89) was the best-performing model for predicting the KRAS genotype, followed by the KRAS_Shuff (AUC 0.73, 95% CI 0.62 to 0.84) and KRAS_Ince (AUC 0.71, 95% CI 0.6 to 0.82) networks. Combing the KRAS_Mob and KRAS_Shuff networks as a double prediction approach showed improved performance. KRAS_Mob network accuracy surpassed that of two independent pathologists (AUC 0.79 [95% CI 0.64 to 0.93], 0.51 [95% CI 0.34 to 0.69], and 0.51 (95% CI 0.34 to 0.69]; p < 0.001 for all comparisons). CONCLUSION: The DNN has the potential to predict the KRAS genotype directly from H&E-stained histopathological slide images. As an algorithmic screening method to prioritize patients for laboratory confirmation, such a model might possibly reduce the number of patients screened, resulting in significant test-related time and economic savings.

Trps1 targets Ccnd1 to regulate mouse Leydig cell proliferation.

BACKGROUND: The tricho-rhino-phalangeal syndrome-1 gene (Trps1) is an atypical GATA family member. Although current studies of Trps1 mainly focus on tumors, whether Trps1 plays a role in the male reproductive system remains unknown. OBJECTIVES: The purpose of this study was to elucidate the function of Trps1 in Leydig cells, indicating its regulatory mechanism on the cell cycle. METHODS: Gene-silencing technology, RNA-seq, RT-qPCR, and western blotting were used to evaluate the function of Trps1 in mouse primary Leydig cells and MLTC-1 cells. In addition, ChIP-base sets and ChIP-qPCR were employed to further assess the regulatory mechanism of Trps1 in MLTC-1 cells. RESULTS: Knockdown of Trps1 in Leydig cells significantly suppressed phosphorylation of Src and Akt and expression of Ccnd1, which was accompanied by impairment of cell proliferative ability. Trps1 may affect the cell cycle through the Src/Akt/Ccnd1 signaling pathway. In addition, Trps1 may bind to the promoter of Srcin1 to regulate its transcription, thus influencing Src phosphorylation levels and the proliferation of Leydig cells. DISCUSSION AND CONCLUSION: Src increases in Leydig cells during pubertal development, suggesting its functional involvement in differentiated adult Leydig cells. Inhibition of the Src/Akt pathway would reduce Ccnd1 expression. In the present study, we found that Trps1 may regulate the phosphorylation level of Src and Akt through Srcin1, targeting Ccnd1 to influence mouse Leydig cell proliferation. These findings shed light on the regulation of Trps1 on cell proliferation and differentiation of mouse Leydig cells.

Evaluation of pelvic inflammatory disease potential in cholinesterase inhibitor pesticide-exposed females.

Cholinesterase inhibitor pesticides, mainly organophosphates and carbamates, are commonly used in Egypt. Chronic exposure of males and females working in agriculture is expected. The study aimed to relate exposure to cholinesterase inhibitor pesticides to the development of pelvic inflammatory disease (PID). This is a case-control study that was conducted among 84 females. Seventy patients complained of pelvic inflammatory disease visited the outpatient Gynecology and Obstetrics Clinic. Fourteen females were not suffering from PID and were chosen as a control group. Red blood cells' cholinesterase activity was measured in blood. Cervical swaps were collected, and cultures were submitted for microbiological examination. The results showed that cholinesterase activities were significantly depressed in exposed females (6.36 ± 0.8 µmoles/min/ml red cells) when compared to non-exposed (7.5 ± 1.2 µmoles/min/ml red cells), and both were significantly depressed when compared with healthy females (9.17 ± 0.7 µmoles/min/ml red cells). The correlation coefficient (r) between previous exposure and the laboratory confirmed cervical infection was 0.31, with a P value of 0.009. The study concluded that exposure to cholinesterase inhibitor pesticides could increase the occurrence of pelvic inflammatory disease.

Immunotoxicological study of one of the most common over-the-counter pyrethroid insecticide products in Egypt.

A commonly available aerosolized pyrethroid insecticide containing deltamethrin and imiprothrin is widely used for hygienic control in Egypt. The immunotoxic effects after inhalation exposures to the preparation of each for 2, 10, and 30 days were investigated in rats. For each exposure, the insecticide (containing 0.2% imiprothrin and 2.5% deltamethrin) was sprayed in all directions in a room (using a special attachment located in the ceiling in the center of the room) for 30 s each minute for 15 min; the room was then kept closed for 15 min. After each spray interval, the rats were introduced for 30 min and then removed to a clean room. The exposure process was repeated a total of three times on each day of the respective regimens. The interval between the 15-min spray/15-min pause/30-min rat exposure cycles was 120 min. Twenty-four hours after the final exposure in each particular regimen, the cohort rats in the regimen (air and exposed) were weighed, sacrificed, and their tissues were removed for analyses. Immunological tests performed included assessments of potential changes in immunopathology (determined from body and splenic weights), humoral-mediated immunity (based on plaque-forming activity of spleen cells), cell-mediated immunity (determined from splenic lymphocyte responsiveness to stimulation with phytohemagglutinin and immune cell (sub)type profile analyses), and nonspecific immunity (based on phagocytic activity of peritoneal macrophages). The results indicated that of all the endpoints examined, among the rats exposed over a 2-day period to the imiprothrin- and deltamethrin-containing insecticide aerosol, the only significant change noted (relative to values from time-matched controls) was in the levels of splenic CD4+CD8- and CD4+ CD8+ cells. In contrast, exposures on each day of a 10-day period led to significant decreases in several endpoints; exceptions to this were values for body and spleen weight (unaffected), splenic OX12-OX19+ levels (significant increase), and CD4+CD8- levels (unaffected, relative to control). Rats exposed for 30 days displayed significant decreases in each test applied, except for increases in both splenic OX12-OX19+ and CD4+CD8- cell levels relative to corresponding control rat values. The present study findings indicate that repeated noncontinuous inhalation of a commonly utilized insecticide that contains imiprothrin and deltamethrin can cause a variety of immunotoxic effects in sites distal to the lungs.

Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs.

BACKGROUND: Despite that gentamicin is a very effective aminoglycoside, its potential ototoxicity which is of irreversible nature makes a challenge and limitation for its use. This study was designed to investigate possible neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity. METHODS AND RESULTS: Twenty pigmented guinea pigs were divided into four equal groups, where group I served as normal control group. The other groups received gentamicin (120 mg/kg/day, ip) for 19 days where group II given vehicle of 1% CMC, group III and group IV were pre-treated 2h before gentamicin by 4-methylcatechol (10 µg/kg, ip) and silymarin (100mg/kg, oral gavage), respectively. The main findings indicated that silymarin exhibited restoration of nerve growth factor (NGF) levels and increased tropomyosin-related kinase receptors-A (Trk-A) m-RNA expression in cochlear tissue and preservation of hair cells of organ of Corti by scanning electron microscopy (SEM) with significant decrease in auditory brainstem response (ABR) threshold compared to 4-methylcatechol. Only silymarin caused significant amelioration in oxidative stress state by reducing malondialdehyde (MDA) levels and increasing catalase activity. CONCLUSIONS: Silymarin exerts superiority over 4-methylcatechol when recommended as protective agent against gentamicin ototoxicity based on its efficient neurotrophic and antioxidant activities.