Dose ingested, vomiting, and outcome in patients ingesting a standard paraquat 20SL formulation.

BACKGROUND: FAO specifications for liquid paraquat dichloride SL formulations require the use of an emetic agent to stimulate vomiting within 30 min of ingestion. To date, there is no high-quality evidence of efficacy, despite use of the PP796 emetic since 1979. We first examined the validity of patients' self-reported dose of paraquat ingested by examining the relationship with blood paraquat concentration and time to death for patients ingesting the standard paraquat SL formulation in a Sri Lankan cohort. As a secondary outcome, we assessed whether ingestion resulted in vomiting within 30 min and whether vomiting was associated with good outcome. METHODS: Patients presenting with paraquat SL self-poisoning were prospectively studied in ten Sri Lankan hospitals in 2003-08. Data on reported dose ingested, incidence and timing of vomiting after ingestion, treatment received, plasma paraquat concentration, and outcome were collected prospectively on presentation to hospital. Time between ingestion and blood sampling was incorporated by covariate adjustment. RESULTS: 441 patients were recruited to the case series, presenting a median (IQR) of 3.0 (1.5-8.1] h post ingestion. Outcome was known for 435 patients of whom 322 (74.0%) died within 42 days, a median of 1.3 (0.6-4.4) days post ingestion. Median reported dose ingested was 15 to <30 mL. There was a highly significant linear trend between log plasma paraquat and reported dose ingested (p < .001); adjustment for the log of the time from ingestion to sampling further improved the model fit. Case fatality and median time to death also showed good agreement with estimated ingestion amount. 347/438 patients (79.2%) were stated to have vomited before reaching the study hospital with 300 (68.5%) vomiting within 30 min of ingestion; time to vomiting was unknown for a further 12 (2.7%). The proportion vomiting was strongly associated with reported dose ingested (p < .001); of note the proportion vomiting within 30 min only increased to 83.3% for the highest ingestion group. Patients vomiting within 30 min had higher plasma paraquat concentrations (p = .008), and higher hazard ratio in the adjusted Cox regression model of 2.01 (95% CI 1.45-2.77) compared to those who did not. Vomiting within 30 min was associated with a higher case fatality (241/295 [81.7%] vs 68/125 [54.4%], p < .001). Forty-three (47.3%) of the 91 patients who did not vomit before reaching hospital died (one had unknown outcome). CONCLUSION: Importantly, we found good agreement between reported dose ingested and plasma paraquat concentration, case fatality, and time to death, suggesting that the reported dose is a valid marker for the dose ingested. Vomiting occurred within 30 min for 68.5% of patients, exceeding the characteristics for a purported effective emetic in the FAO specifications. However, vomiting within 30 min was associated with approximately double the risk of death compared to those who did not vomit, larger paraquat ingestions, and higher blood paraquat concentrations. In addition, death occurred in many patients who did not vomit, and the proportion vomiting within 30 min only reached 82.1% for the highest ingested dose group. Overall, we found no evidence of benefit resulting from incorporation of the emetic, suggesting that the current FAO specification is not effective at preventing deaths after ingestion of the paraquat SL formulation.

Staying on the ball during COVID-19 pandemic: impact on training modalities in football players.

BACKGROUND: COVID-19 pandemic has affected worldwide sports competitions and training in both amateur and professional leagues. We thus aimed to investigate changes in different training modalities in elite and amateur football players following COVID-19 lockdown in March 2020. METHODS: In this cross-sectional study, we applied a Likert Scale-based questionnaire with 20 items to quantify and classify time spent at standard training methods in 47 professional and 54 amateur football players from 12 Austrian clubs before and during lockdown. Additionally, McLean Score was calculated to assess perceived training fatigue. RESULTS: Weekly amount of training time at endurance exercises (cycling) increased in both professional (37.5 [IQR 46.5] min/week vs. 187.5 [IQR 127.5] min/week, P<0.001), and amateur players (0.0 [IQR 45.0] min/week vs. 37.5 [IQR 112.5] min/week, P=0.015) during COVID-19 lockdown. Time on diverse muscle strengthening workouts was significantly elevated in both cohorts. Total training time at ball declined for professionals (from 472.5 [IQR 150] min/week to 15.0 [IQR 112.5] min/week, P<0.001) and amateurs (from 337.5 [IQR 285] min/week to 0.0 [IQR 37.5] min/week, P<0.001). Video-guided training was intensified in both groups (P<0.001 each). Location shifted from football fields and gyms to home and outdoors. Overall McLean Score remained unchanged in amateurs (P=0.42) while elite players showed a trend towards an increase (P=0.056). CONCLUSIONS: COVID-19 lockdown compromised football training, especially training concepts with ball. Consequently, resulting changes in exercise loads and muscular burden might impact susceptibility for injuries and impair performances especially in amateur players, especially as they lacked training supervision and professional training plans. Minimum effective dose of training workload to maintain endurance- and neuromuscular-related performance parameters should be prescribed.

The Platelet-Activating Factor Receptor's Association with the Outcome of Ovarian Cancer Patients and Its Experimental Inhibition by Rupatadine.

The platelet-activating factor receptor (PAFR) and its ligand (PAF) are important inflammatory mediators that are overexpressed in ovarian cancer. The receptor is an important player in ovarian cancer development. In this study, we aimed to evaluate the prognostic value of PAFR in epithelial ovarian cancer (EOC) and the potential use of its antagonist, rupatadine, as an experimental treatment. Tissue microarrays of ovarian cancer patients, most markedly those with a non-mucinous subtype, immunohistochemically overexpressed PAFR. Elevated cytoplasmic PAFR expression was found to significantly and independently impair patients' overall and recurrence-free survival (OS: median 83.48 vs. 155.03 months; p = 0.022; RFS: median 164.46 vs. 78.03 months; p = 0.015). In vitro, the serous ovarian cancer subtypes especially displayed an elevated PAFR gene and protein expression. siRNA knockdown of PAFR decreased cell proliferation significantly, thus confirming the receptor's protumorigenic effect on ovarian cancer cells. The clinically approved PAFR antagonist rupatadine effectively inhibited in vitro cell proliferation and migration of ovarian cancer cells. PAFR is a prognostic marker in ovarian cancer patients and its inhibition through rupatadine may have important therapeutic implications in the therapy of ovarian cancer patients.

Platelet-Activating Factor Acetylhydrolase Expression in BRCA1 Mutant Ovarian Cancer as a Protective Factor and Potential Negative Regulator of the Wnt Signaling Pathway.

Aberrantly activated Wnt/ß-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3ß, and ß-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and ß-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3ß (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and ß-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of ß-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/ß-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/ß-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored.

Prostaglandin E2 receptor 3 (EP3) signaling promotes migration of cervical cancer via urokinase-type plasminogen activator receptor (uPAR).

PURPOSE: Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2). As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy. Now, we aimed to investigate the pathological mechanism of EP3 in modulating cervical cancer carcinogenesis. METHODS: Bioinformatics analysis was used to identify PAI-1 and uPAR correlations with EP3 expression, as well as the prognosis of cervical cancer patients. In vitro analyses were carried out to investigate the role of EP3 on cervical cancer proliferation and migration. RESULTS: In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration. Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression. Bioinformatics analysis showed that both PAI-1 and uPAR were correlated with EP3 expression, as well as the prognosis of cervical cancer patients. The survival analysis further showed that uPAR overexpression (IRS≥2) was correlated with a lower overall survival rate of cervical cancer patients with advanced stages (FIGO III-IV). CONCLUSION: These results indicated that EP3 signaling pathway might facilitate the migration of cervical cancer cells through modulating uPAR expression. Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of cervical cancer in advantaged stages.

Cytoplasmic VDR expression as an independent risk factor for ovarian cancer.

The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013; Cc = 0.203), positive lymph node status (p = 0.023; Cc = 0.236), high-grade serous histology (p = 0.000; Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006; Cc = - 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached; p < 0.001) and was confirmed as a statistically independent prognostic factor in the Cox regression multivariate analysis. Additional knowledge of VDR as a biomarker and its interactions within the mitogen-activated protein kinase (MAPK) signaling pathway could potentially improve the prognosis of therapeutic approaches for specific subgroups in EOC.

Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients.

Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone receptor (FSHR), and their functional role in ovarian cancer. By immunohistochemistry, AhR staining was analyzed in a subset of 156 samples of ovarian cancer patients. AhR staining was assessed in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score (IRS), and the scores were grouped into high- and low-level expression. AhR expression was detected in all histological subtypes, with clear cell ovarian cancer displaying the highest staining intensity. Low cytoplasmic expression of AhR was associated with longer overall survival (median 183.46 vs. 85.07 months; p = 0.021). We found a positive correlation between AhR and FSHR (p = 0.005). Ovarian cancer patients with high cytoplasmic AhR and concurrent FSHR expression had the worst outcome (median 69.72 vs. 43.32 months; p = 0.043). Consequently, low cytoplasmic AhR expression seems to be associated with improved survival in ovarian cancer patients. Our data suggest that AhR and FSHR levels correlate with each other, and their concurrent expression was observed in ovarian cancer patients with the worst outcome. Further investigation of the interaction of both receptors and their functional role might better predict the impact of endocrine therapy in ovarian cancer.

Vitamin D and VDR in Gynecological Cancers-A Systematic Review.

In recent years, a vast amount of studies have centered on the role of vitamin D in the pathogenesis of certain types of cancers such as breast, colorectal and lung cancer. Increasing evidence suggests that vitamin D and its receptor play a crucial role in the development of gynecological cancers. In this review, we systematically analyzed the effect of vitamin D and the vitamin D receptor on endometrial, ovarian, cervical, vulvar and vaginal cancer. Our literature research shows that vitamin D levels and vitamin-D-related pathways affect the risk of gynecological cancers. Numerous ecological studies give evidence on the inverse relationship between UVB exposure and gynecological cancer risk. However, epidemiologic research is still inconclusive for endometrial and ovarian cancer and insufficient for rarer types of gynecological cancers. The vitamin D receptor (VDR) is upregulated in all gynecological cancers, indicating its influence on cancer etiology. The VDR polymorphism FokI (rs2228570) seems to increase the risk of ovarian cancer. Other nuclear receptors, such as the RXR, also influence gynecological cancers. Although there is limited knowledge on the role of the VDR/RXR on the survival of endometrial, cervical, vulvar or vaginal cancer patients, some studies showed that both receptors influence survival. Therefore, we suggest that further studies should focus on the vitamin D- and its hetero dimer receptor RXR in gynecological cancers.