Miracle-dz/UniFAR-FTUs huggingface dataset:
Diagnostic and Prognostic Performance of Liquid Biopsy-Derived Exosomal MicroRNAs in Thyroid Cancer Patients: A Systematic Review and Meta-Analysis

Simple Summary Circulatory tumor-derived exosomal miRNAs play key roles in cancer development and progression. Studies have shown that serum and plasma miRNAs have the potential to be promising biomarkers for cancer diagnosis. This meta-analysis aimed to assess the diagnostic and prognostic performance of exosomal miRNAs in thyroid cancer. Our study analysis included 12 articles. We found that specific exosomal miRNAs found in blood provide high diagnostic value with high sensitivity and specificity. Furthermore, certain panels of exosomal microRNAs showed remarkable diagnostic value. The best discriminative ability to differentiate between cancer and non-cancer individuals were for miR-146b-5p + miR-223-5p + miR-182-5p. The novel and non-invasive use of miRNAs to diagnose TC can significantly improve patient outcomes by preventing the burden of unnecessary surgery and providing prognosis information on thyroid cancer. Abstract Circulatory tumor-derived exosomal microRNAs (miRNAs) play key roles in cancer development/progression. We aimed to assess the diagnostic/prognostic value of circulating exosomal miRNA in thyroid cancer (TC). A search in PubMed, Scopus, Web of Science, and Science Direct up to 22 May 2021 was performed. The true/false positive (TP/FP) and true/false negative (TN/FN) rates were extracted from each eligible study to obtain the pooled sensitivity, specificity, positive/negative likelihood ratios (PLR/NLR), diagnostic odds ratio (DOR), and their 95% confidence intervals (95%CIs). The meta-analysis included 12 articles consisting of 1164 Asian patients and 540 controls. All miRNAs were quantified using qRT-PCR assays. The pooled sensitivity was 82% (95%CI = 77–86%), pooled specificity was 76% (95%CI = 71–80%), and pooled DOR was 13.6 (95%CI = 8.8–21.8). The best biomarkers with high sensitivity were miR-16-2-3p (94%), miR-223-5p (91%), miR-130a-3p (90%), and miR182-5p (94%). Similarly, they showed high specificity, in addition to miR-34c-5p. Six panels of two to four exosomal miRNAs showed higher diagnostic values with an area under the curve (AUC) ranging from 0.906 to 0.981. The best discriminative ability to differentiate between cancer and non-cancer individuals was observed for miR-146b-5p + miR-223-5p + miR-182-5p (AUC = 0.981, sensitivity = 93.8% (84.9–98.3), specificity = 92.9% (76.5–99.1)). In conclusion, the expression levels of exosomal miRNAs could predict TC.
Timing of Aspirin Use Among Patients With Colorectal Cancer in Relation to Mortality: A Systematic Review and Meta-Analysis

Abstract Background Exposure of aspirin has been associated with reduced risk of colorectal cancer (CRC) incidence, but aspirin use in relation to CRC patients’ mortality remains undetermined. It is necessary to quantify the association between aspirin use and CRC mortality. Methods Two authors independently searched the electronic databases (PubMed, Embase, and the Cochrane Library) from 1947 through April 25, 2020. All observational studies assessing the association between different timing of aspirin use and CRC mortality were included. The effect size on study outcomes was calculated using random-effect model and presented as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity, publication bias, and quality of included studies were also assessed. Results A total of 34 studies were included in this systematic review and meta-analysis. Prediagnosis aspirin use was not associated with CRC-specific mortality (RR = 0.91, 95% CI = 0.79 to 1.05) and all-cause mortality (RR = 0.87, 95% CI = 0.57 to 1.31). A statistically significant association between continued aspirin use and improvement in both CRC-specific mortality (RR = 0.76, 95% CI = 0.70 to 0.81) and all-cause mortality (RR = 0.83, 95% CI = 0.74 to 0.93) was observed. Postdiagnosis use of aspirin was associated only with reduced all-cause mortality (RR = 0.80, 95% CI = 0.69 to 0.94). Conclusions Continued aspirin use before and after CRC diagnosis has the most advantage regarding the improvement of CRC mortality. Nevertheless, further prospective trials and mechanistic studies are highly warranted.
Fungi Associated With Woody Tissues of European Beech and Their Impact on Tree Health

Filamentous fungi associated with woody tissues of European Beech (Fagus sylvatica) and isolated from diseased trees and healthy trees were examined in relation to their impact on tree health. To this end, classical culture-based isolation methods, in planta inoculations and fungal identification using ITS-barcode and morphological characters were used. Stem endophytes of healthy beech saplings collected in German forests were isolated to determine endophyte communities in woody stem tissues. Pathogenicity tests were performed on living potted beech saplings using twelve selected fungal pathogens and wood inhabiting fungi (Hypocreales, Botryosphaeriales, and Xylariales) originating mainly from European beech with symptoms of the complex disease Vitality loss, or from bark necroses, or known to be common endophytes of beech. The impact of these ascomycetous fungi with respect to tree health was discussed. The potential influences of endophytic fungi of beech and of test conditions are discussed in relation to the success of inoculation. All tested fungal strains except for Neonectria ditissima were able to establish themselves post inoculation in the beech stems and caused necroses when there was sufficient water, but at different severities. Under the experimental conditions, Botryosphaeria corticola was shown to be the most virulent tested latent pathogen against F. sylvatica. In the context of climate change and global warming, the tested Botryosphaeriaceae are able to play a primary role in the disease progress of Vitality loss of Beech. The key role of Neonectria coccinea in causing bark necroses and the loss of vitality in beech was confirmed because the tested strain induced large lesions on the beech saplings.
Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy

Simple Summary Factors impacting the response to CAR T-cell therapies are not fully understood. In this monocentric prospective study, we describe the outcome of 60 patients with relapsed/refractory diffuse large B-cell lymphoma and transformed follicular lymphoma infused with CD19-directed CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel. We obtained a 40% complete metabolic response and a 27% partial metabolic response with a median progression-free survival of 3.1 months and a median of overall survival of 12.3 months. We also found that age-adjusted IPI at the time of infusion, product features, in vivo expansion, and CAR T-cell exhaustion phenotype were significatively associated with the efficacy of the CAR T-cell therapy. Abstract CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.
The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer

The dysregulation of androgen receptor (AR) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 (NDRG1) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro. Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 (DNMT1) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.
Application of Surgical Decision Model for Patients With Childhood Cataract: A Study Based on Real World Data

Reliable validated methods are necessary to verify the performance of diagnosis and therapy-assisted models in clinical practice. However, some validated results have research bias and may not reflect the results of real-world application. In addition, the conduct of clinical trials has executive risks for the indeterminate effectiveness of models and it is challenging to finish validated clinical trials of rare diseases. Real world data (RWD) can probably solve this problem. In our study, we collected RWD from 251 patients with a rare disease, childhood cataract (CC) and conducted a retrospective study to validate the CC surgical decision model. The consistency of the real surgical type and recommended surgical type was 94.16%. In the cataract extraction (CE) group, the model recommended the same surgical type for 84.48% of eyes, but the model advised conducting cataract extraction and primary intraocular lens implantation (CE + IOL) surgery in 15.52% of eyes, which was different from the real-world choices. In the CE + IOL group, the model recommended the same surgical type for 100% of eyes. The real-recommended matched rates were 94.22% in the eyes of bilateral patients and 90.38% in the eyes of unilateral patients. Our study is the first to apply RWD to complete a retrospective study evaluating a clinical model, and the results indicate the availability and feasibility of applying RWD in model validation and serve guidance for intelligent model evaluation for rare diseases.
The sequence–ensemble relationship in fuzzy protein complexes

Significance Intrinsically disordered proteins (IDPs) do not possess a stable three-dimensional structure but populate partially folded, transient structures. They are involved in numerous cellular processes, often in cooperation with globular proteins. In such complexes, the protein-bound IDPs can be structurally very heterogeneous ranging from folded, stable conformations to those that are dynamic and disordered. The underlaying principles governing this heterogeneity, known also as fuzziness, are obscure. We developed a simple statistical thermodynamic model based on the helix–coil theory that rationalizes diversity of the target-bound IDP ensembles. The model successfully reproduces bound-state IDP dynamics and explains how ensembles modulate their structure and interaction affinity due to mutations. Collectively, this sheds light on the sequence–ensemble relationship of fuzzy IDP–protein complexes. Intrinsically disordered proteins (IDPs) interact with globular proteins through a variety of mechanisms, resulting in the structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural characteristics of IDPs bound to their targets. Using a statistical thermodynamic model, we show that the target-bound ensembles are determined by a simple code that combines the IDP sequence and the distribution of IDP–target interaction hotspots. These two parameters define the conformational space of target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces the dynamical signatures of target-bound IDPs from the NMR relaxation experiments as well as the changes of interaction affinity and the IDP helicity induced by mutations. The model explains how the target-bound IDP ensemble adapts to mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence–ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.
Stability of Anthocyanin Content and Antioxidant Capacity Among Local Thai Purple Rice Genotypes in Different Storage Conditions

This study determined whether storage conditions over six months affected grain anthocyanin content and antioxidant capacity of four purple rice genotypes with different initial anthocyanin content. Two forms of grain, paddy and brown rice were stored at three temperatures -25 °C, room temperature (25-30 °C) and 60 °C with three replications. In the two high-anthocyanin genotypes, the anthocyanin continued to decrease until the last month of storage, while the low-anthocyanin genotypes were not affected by storage time. Storage at 60 °C decreased the average anthocyanin content by 42%, compared to the 30% loss for grain stored at either -25 °C or room temperature. Brown rice retained more of its anthocyanin than paddy rice in the high anthocyanin genotypes. Antioxidant capacity substantially declined during storage in all genotypes and the capacity was higher in brown than paddy rice. There was a significant correlation between anthocyanin content and antioxidant capacity in the two high-anthocyanin genotypes, but not in the low-anthocyanin genotypes, indicating the possibility of different anti-oxidative key compounds between the low- and high-anthocyanin genotypes. These results suggest that the anthocyanin content and antioxidant capacity in purple rice genotypes would be most stable when stored at low temperature as brown rice.
Numerical Analysis on Erosion and Optimization of a Blast Furnace Main Trough

The main trough of a blast furnace (BF) is a main passage for hot metal and molten slag transportation from the taphole to the torpedo and the slag handling. Its appropriate working status and controlled erosion ensure a safe, stable, high-efficiency and low-cost continuous production of hot metal. In this work, the tapping process of a main trough of a BF in the east of China was numerically studied with the help of a CFD library written in C++, called OpenFOAM, based on the use of the Finite Volume Method (FVM). The results show that turbulence intensity downstream of the hot metal impact position becomes weaker and the turbulence area becomes larger in the main trough. During the tapping, thermal stress of wall refractory reaches the maximum value of 1.7 × 107 Pa at the 4 m position in the main trough. Furthermore, baffles in the main trough placed between 5.8 m and 6.2 m were found to control and reduce the impact of the turbulence on the refractory life. The metal flowrate upstream of the baffles can be decreased by 6%, and the flow velocity on the upper sidewall and bottom wall decrease by 9% and 7%, respectively, compared with the base model. By using baffles, the minimum fatigue life of the refractory in the main trough increases by 15 tappings compared with the base model, so the period between the maintenance stops can be prolonged by about 2 days.
Increased Sensitivity of Detection of RASSF1A and GSTP1 DNA Fragments in Serum of Prostate Cancer Patients: Optimisation of Diagnostics Using OBBPA-ddPCR

Simple Summary Prostate carcinoma (PCa) incidence rates have continued to increase over the last 3 decades worldwide and PCa is the most common cancer in men in Germany. Classical tumour markers exhibit unsatisfactory sensitivity and specificity, leading to unnecessary prostate biopsies and associated clinical complications. New, minimally invasive biomarkers with high sensitivity and specificity are required for an early diagnosis and a better prognosis. In the present study, we evaluated the performance of a previously developed analytical method to detect trace amounts of aberrant methylated tumour DNA. The optimised method which was developed in this study evaluates DNA methylation changes of RASSF1A and GSTP1 in the blood of PCa patients at different stages compared to benign prostatic hyperplasia patients and healthy individuals. RASSF1A methylation analysis was found to be beneficial as a complementary biomarker for PCa diagnosis in combination with classical PCa markers. Both RASSF1A and GSTP1 exhibited pathological DNA methylation levels in all metastatic PCa patients, which may improve early detection of PCa metastases and therapeutic outcomes. Abstract Identification of aberrant DNA methylation is a promising tool in prostate cancer (PCa) diagnosis and treatment. In this study, we evaluated a two-step method named optimised bias-based preamplification followed by digital PCR (OBBPA-dPCR). The method was used to identify promoter hypermethylation of 2 tumour suppressor genes RASSF1A and GSTP1 in the circulating cell-free DNA (cfDNA) from serum samples of PCa patients (n = 75), benign prostatic hyperplasia (BPH, n = 58), and healthy individuals (controls, n = 155). The PCa cohort was further subdivided into subgroups comprising (I) patients with Gleason Scores (GS) ≤ 7 (n = 55), (II) GS ≥ 8 (n = 10), and (III) patients with metastatic PCa diagnosis (n = 10). We found that RASSF1A methylation levels were significantly increased in all 3 PCa subgroups compared to the controls and BPH cohorts (p < 0.01 for all comparisons). Fractional abundances of methylated GSTP1 DNA fragments were significantly increased in subgroup III of metastatic PCa patients (p < 0.001). RASSF1A methylation analysis was found to be beneficial as a complementary biomarker where further diagnostic validation is most crucial. In combination with free PSA, RASSF1A methylation status helps to identify PCa patients with GS ≥ 8 and grey-zone total PSA values between 2–10 ng/mL. In our study, PCR biases between 80–90% were sufficient to detect minute amounts of tumour DNA with high signal-to-noise ratios as well as high analytical sensitivity and specificity. Both RASSF1A and GSTP1 exhibited strongly increased DNA methylation levels in all metastatic PCa patients. Our data indicates a superior sensitivity of epigenetic biomarker analyses in early detection of PCa metastases that should also help to improve PCa therapy.
Low-Cost Open-Source Device to Measure Maximal Inspiratory and Expiratory Pressures

The measurement of maximal inspiratory (MIP) and maximal expiratory (MEP) pressures is a widely used technique to non-invasively evaluate respiratory muscle strength in clinical practice. The commercial devices that perform this test range from whole body plethysmographs to portable spirometers, both expensive and include a wide range of other respiratory tests. Given that a portable, low-cost, and specific option for MIP and MEP measuring device is not currently available in the market. A high-performance and easy-to-build prototype has been developed and the detailed technical information to easily reproduce it is freely released. A novel device is based on an Arduino microcontroller with a digital display, an integrated pressure transducer, and three-dimensional (3D) printed enclosure (total retail cost €80). The validation of the device was performed by comparison with a laboratory reference setting, and results showed accuracy within ±1%. As the device design is available according to the open-source hardware approach, measuring MIP/MEP can greatly facilitate easily available point-of-care devices for the monitoring of patients and, most important, for making this lung function measurement tool affordable to users in low- and middle-income countries.
Evaluation of Fine and Ultrafine Particles Proportion in Airborne Dust in an Industrial Area

The health impacts of suspended particulate matter (SPM) are significantly associated with size—the smaller the aerosol particles, the stronger the biological effect. Quantitative evaluation of fine and ultrafine particles (FP and UFP) is, therefore, an integral part of ongoing epidemiological studies. The mass concentrations of SPM fractions (especially PM2.5, PM1.0, PM0.25) were measured in an industrial area using cascade personal samplers and a gravimetric method, and their mass ratio was determined. The results of PM2.5, PM1.0 were also compared with the reference measurement at stationary stations. The mean ratios PM2.5/SPM, PM1.0/SPM, and PM1.0/PM2.5 were 0.76, 0.65, and 0.86, respectively. Surprisingly, a mass dominance of UFP with an aerodynamic diameter <0.25 μm (PM0.25) was found with mean ratios of 0.43, 0.57, 0.67 in SPM, PM2.5 and PM1.0. The method used showed satisfactory agreement in comparison with reference measurements. The respirable fraction may consist predominantly of UFP. Despite the measures currently being taken to improve air quality, the most biologically efficient UFP can escape and remain in the air. UFP are currently determined primarily as particle number as opposed to the mass concentration used for conventional fractions. This complicates their mutual comparison and determination of individual fraction ratios.
A rapid method to visualize human mitochondrial DNA replication through rotary shadowing and transmission electron microscopy

Abstract We report a rapid experimental procedure based on high-density in vivo psoralen inter-strand DNA cross-linking coupled to spreading of naked purified DNA, positive staining, low-angle rotary shadowing, and transmission electron microscopy (TEM) that allows quick visualization of the dynamic of heavy strand (HS) and light strand (LS) human mitochondrial DNA replication. Replication maps built on linearized mitochondrial genomes and optimized rotary shadowing conditions enable clear visualization of the progression of the mitochondrial DNA synthesis and visualization of replication intermediates carrying long single-strand DNA stretches. One variant of this technique, called denaturing spreading, allowed the inspection of the fine chromatin structure of the mitochondrial genome and was applied to visualize the in vivo three-strand DNA structure of the human mitochondrial D-loop intermediate with unprecedented clarity.