Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma

Background Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC). Methods Differentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples. Results Based on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml−1) from high risk population (AUC=0.93; 95% CI 0.892–0.969). Conclusions We have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort. Trial registration The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(#NCT04383353).

Prescreening of biological and biorational fungicides against common hemp pathogens using in vitro analyses

Upon reintroduction of hemp in 2014 and legalization in 2018, labeled pesticides have remained limited. Further, consumer demand has aimed the market toward organic or chemical-free production systems. In efforts to manage diseases and pests in fields and greenhouses, producers turn toward biological and biorational formulations. Efficacy of these fungicides against common aerial diseases of hemp is largely unpublished. Challenges of efficacy testing, however, further delay or discourage research. In this study, we evaluated screening methods against some common biological products. The aim was to test a screening model in order to examine products against fungal pathogens and to identify demonstrable differences under controlled conditions. Thus, in this study, we prescreen 11 biological and biorational fungicides against four common fungal leaf and flower pathogens using three bioassays. Confirmation that the major modes of action for these products have measurable activity against major pathogens of hemp serves as a first step toward more complex field studies.

Development of the simulation-based German albuminuria screening model (S-GASM) for estimating the cost-effectiveness of albuminuria screening in Germany

Background Chronic kidney disease is often asymptomatic in its early stages but constitutes a severe burden for patients and causes major healthcare systems costs worldwide. While models for assessing the cost-effectiveness of screening were proposed in the past, they often presented only a limited view. This study aimed to develop a simulation-based German Albuminuria Screening Model (S-GASM) and present some initial applications. Methods The model consists of an individual-based simulation of disease progression, considering age, gender, body mass index, systolic blood pressure, diabetes, albuminuria, glomerular filtration rate, and quality of life, furthermore, costs of testing, therapy, and renal replacement therapy with parameters based on published evidence. Selected screening scenarios were compared in a cost-effectiveness analysis. Results Compared to no testing, a simulation of 10 million individuals with a current age distribution of the adult German population and a follow-up until death or the age of 90 shows that a testing of all individuals with diabetes every two years leads to a reduction of the lifetime prevalence of renal replacement therapy from 2.5% to 2.3%. The undiscounted costs of this intervention would be 1164.10 € / QALY (quality-adjusted life year). Considering saved costs for renal replacement therapy, the overall undiscounted costs would be—12581.95 € / QALY. Testing all individuals with diabetes or hypertension and screening the general population reduced the lifetime prevalence even further (to 2.2% and 1.8%, respectively). Both scenarios were cost-saving (undiscounted, - 7127.10 €/QALY and—5439.23 €/QALY). Conclusions The S-GASM can be used for the comparison of various albuminuria testing strategies. The exemplary analysis demonstrates cost savings through albuminuria testing for individuals with diabetes, diabetes or hypertension, and for population-wide screening.

Quantum-chemical investigation of interactions in supramolecular systems: cholesterol - bile acids - silica in aqueous solutions

Hypercholesterolemia significantly increases the risk of myocardial infarction associated with COVID-19. Along with pharmacological treatment, the possibility of the excretion of excess cholesterol from an organism by adsorption is also of great interest. The interaction of cholesterol with the surface of partially hydrophobized silica in aqueous solutions of bile acids was investigated by the PM7 method using the COSMO (COnductor-like Screening MOdel) solvation model. The distribution of electrostatic and hydrophobic potentials of molecules and complexes was calculated. The values of free Gibbs energy adsorption of bile acids on the surface of silica correlate with the distribution coefficients in the n-octanol-water system. The energy of interaction of cholesterol with bile acids affects its adsorption on silica. The stronger the bond of cholesterol with the molecules of bile acids, the less it is released from the primary micelles in solution and adsorbed on the surface.

The Effect of Mushroom Manager Behavior on Organizational Charlatan and Organizational Loneliness

The mushroom-type manager expects employees not to have much knowledge on organizational issues, but to follow the instructions and directives without question. This study aims to examine the effect of the mushroom-type management approach on the loneliness levels of the employees and organizational charlatan behaviors. Therefore, the research is designed in a relational screening model. The research was carried out in the province of Denizli in Turkey with 464 participants. In the research, the mushroom type management scale, UCLA loneliness scale-3, and organizational charlatan scale were used. Validity and reliability studies of the Turkish mushroom-type management scale for schools have been reconstructed. UCLA loneliness scale-3 and organizational charlatan scale were adapted to Turkish by the researcher. The data were collected with the help of electronic forms. Regression analysis was carried out to determine the extent to which mushroom type management predicted teachers’ organizational loneliness behaviors and teachers' organizational charlatan behaviors. As a result of the research, it has been found that mushroom management positively affects the other two variables. For this reason, school principals can be suggested mushroom management behavior.

Comparison of Synthetic Membranes to Heat-Separated Human Epidermis in Skin Permeation Studies In Vitro

In recent years, the study of dermal preparations has received increased attention. There are more and more modern approaches to evaluate transdermal formulations, which are crucial in proving the efficacy of a formulation. The aim of this study was to compare permeation across innovative synthetic membranes (Strat-M and Skin PAMPA membranes) and heat-separated human epidermis (HSE, gold standard membrane) using four different dermal formulations. The Strat-M and Skin PAMPA membranes were designed to mimic the stratum corneum layer of the human epidermis. There have also been some publications on their use in dermal formulation development, but further information is needed. Drug permeation was measured using formulations containing diclofenac sodium (two hydrogels and two creams). The HSE, Strat-M, and Skin PAMPA membranes proved to be significantly different, but based on the results, the Strat-M membrane showed the greatest similarity to HSE. The permeation data of the different formulations across different membranes showed good correlations with formulations similar to these four, which allows the prediction of permeation across HSE using these synthetic membranes. In addition, Strat-M and Skin PAMPA membranes have the potential to select and differentiate a dermal formulation containing diclofenac sodium as an early screening model.