Miracle-dz/UniFAR-FTUs huggingface dataset:
Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management

One in every four deaths is due to cancer in Europe. In view of its increasing incidence, cancer became the leading cause of death and disease burden in Denmark, France, the Netherlands, and the UK. Without essential improvements in cancer prevention, an additional 775,000 cases of annual incidence have been prognosed until 2040. Between 1995 and 2018, the direct costs of cancer doubled from EUR 52 billion to EUR 103 billion in Europe, and per capita health spending on cancer increased by 86% from EUR 105 to EUR 195 in general, whereby Austria, Germany, Switzerland, Benelux, and France spend the most on cancer care compared to other European countries. In view of the consequent severe socio-economic burden on society, the paradigm change from a reactive to a predictive, preventive, and personalized medical approach in the overall cancer management is essential. Concepts of predictive, preventive, and personalized medicine (3PM) demonstrate a great potential to revise the above presented trends and to implement cost-effective healthcare that benefits the patient and society as a whole. At any stage, application of early and predictive diagnostics, targeted prevention, and personalization of medical services are basic pillars making 3PM particularly attractive for the patients as well as ethical and cost-effective healthcare. Optimal 3PM approach requires novel instruments such as well-designed liquid biopsy application. This review article highlights current achievements and details liquid biopsy approaches specifically in cancer management. 3PM-relevant expert recommendations are provided.
High expression of LEF1 correlates with poor prognosis in solid tumors, but not blood tumors: a meta-analysis

Abstract Background: Previously published studies have indicated that lymphoid enhancer-binding factor 1 (LEF1) expression could be recognized as a valuable biomarker to evaluate clinical outcome for various types of malignant cancer, but the results remained controversial. Therefore, we conducted this meta-analysis to pool the published estimates and discuss the relationship of LEF1 expression with cancer prognosis. Methods: Five electronic databases Pubmed, Web of Science, Embase, CNKI, and Wanfang were systematically searched for eligible literatures. Hazard ratios (HRs) and 95% confidence intervals (CIs) from the included studies were combined to estimate the effect of LEF1 expression on cancer patients’ survival. Results: Eleven original studies met the criteria and were enrolled for analysis. The results indicated that compared with patients in low LEF1 expression group, patients in high LEF1 expression group tended to have shorter overall survival (HR = 1.74, 95% CI: 1.06–2.86, P=0.029), especially for patients with solid tumors (HR = 2.39, 95% CI: 1.86–3.08, P=0.000). Conclusions: Individual evidence about the prognostic value of LEF1 expression in human cancers was limited. Our meta-analysis supported the suggestion that elevated LEF1 expression could function as a promising biomarker to predict the clinical outcomes for malignant cancers, especially solid tumors. More high-quality clinical studies are warranted to highlight the prognostic value of LEF1 expression in human cancers.
Lumbosacral spinal compression device with the use of a cushion back support in supine MRI

Background We hypothesized that axial-loaded magnetic resonance imaging (MRI), modified with the use of a cushion placed behind the lower back (i.e. BS-MRI method), would simulate the standing position more accurately than an axial-loaded MRI without a cushion back support (BS). Purpose To determine whether the BS-MRI method demonstrated similar morphologies on intervertebral disc (IVD), dural sac, and spinal curvature as those detected on 90° standing MRIs in individuals with suspected spinal stenosis. Material and Methods Twenty-five subjects underwent a BS-MRI, as well as axial-loaded and standing MRI studies. Outcome measures were four radiographic parameters of the lumbar spine: IVD height (DH); dural sac cross-sectional area (DCSA); and spinal curvature (i.e. lumbar lordosis [LL] and L1-L3-L5 angle [LA]). Results Major differences (>5%) between standing MRI and BS-MRI methods were observed in DCSA, DH, and LL. Major differences between standing and axial loaded MRIs were observed only in DCSA and LA. Although BS-MRIs demonstrate an image of the lumbar spine curvature (i.e. LA) which is closer to that when standing than axial-loaded MRIs, it is likely to overestimate both narrowing of dural sac and extent of LL. Conclusion Using a compression device with a BS to simulate weight-bearing on the lumbar spine is not recommended due to: (i) overestimation of the narrowing of the dural sac and extent of LL; and (ii) underestimation of loss of disc height. Supine axial-loading produced DCSA and DH which were strongly correlated with those detected with standing MRIs. Exceptions were that LL and LA were underestimated.
The Effect of LINC01296 Expression in Patients with Cancer: A Systematic Review and Meta-Analysis

Background: Recently has been suggested that LINC01296 has an important role in tumor-promoting in different malignancies. We performed first meta-analysis to assess the association between the LINC01296 expression and clinicopathological criteria and the survival of patients with cancers. Methods: Relevant articles Identified by PubMed, EMBASE, Web of Science, and Scopus searching between December 2000 and 28 December 2018. Binomial data were evaluated by the odds ratio (OR) as the rapid statistic. The association between overall survival (OS) and the LINC01296 expression was evaluated using pooling the hazard ratio (HR) with its corresponding 95% confidence interval (CI). Results: Finally, 9 studies with 720 patients with cancer were included. The expression of LINC01296 showed a significant positive association with TNM stage (OR = 2.67, 95% CI = 1.83-3.88), tumor stage (OR= 2.22, 95% CI= 1.34-3.66) and lymph node metastasis (OR = 3.07, 95% CI = 2.23-4.21). A shorter OS was significantly associated with the expression of LINC01296 (HR = 3.95, 95% CI = 2.65-5.25) and lymph node metastasis (HR = 2.39, 95% CI =1.16-3.63). The OS did not show significant association with gender (HR = 0.83, 95% CI = -0.63-2.30) and tumor stage (HR= 2.66, 95% CI= -0.22-5.54). Conclusion: In conclusion, the results of this meta-analysis suggest that the expression of LINC01296 might be considered as a potential biomarker in patients with cancer.
An automatic electronic instrument for accurate measurements of food volume and density

Abstract Objective: Accurate measurements of food volume and density are often required as ‘gold standards’ for calibration of image-based dietary assessment and food database development. Currently, there is no specialised laboratory instrument for these measurements. We present the design of a new volume of density (VD) meter to bridge this technological gap. Design: Our design consists of a turntable, a load sensor, a set of cameras and lights installed on an arc-shaped stationary support, and a microcomputer. It acquires an array of food images, reconstructs a 3D volumetric model, weighs the food and calculates both food volume and density, all in an automatic process controlled by the microcomputer. To adapt to the complex shapes of foods, a new food surface model, derived from the electric field of charged particles, is developed for 3D point cloud reconstruction of either convex or concave food surfaces. Results: We conducted two experiments to evaluate the VD meter. The first experiment utilised computer-synthesised 3D objects with prescribed convex and concave surfaces of known volumes to investigate different food surface types. The second experiment was based on actual foods with different shapes, colours and textures. Our results indicated that, for synthesised objects, the measurement error of the electric field-based method was <1 %, significantly lower compared with traditional methods. For real-world foods, the measurement error depended on the types of food volumes (detailed discussion included). The largest error was approximately 5 %. Conclusion: The VD meter provides a new electronic instrument to support advanced research in nutrition science.
Impact of Early Pandemic Stage Mutations on Molecular Dynamics of SARS-CoV-2 Mpro

A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations. The results showed that SARS-CoV-2 Mpro essentially behaves in a similar manner to its SAR-CoV homolog. However, we report the following new findings from the variants: (1) Residues GLY15, VAL157, and PRO184 have mutated more than once in SARS CoV-2; (2) the D48E variant has lead to a novel “TSEEMLN”” loop at the binding pocket; (3) inactive apo Mpro does not show signs of dissociation in 100 ns MD; (4) a non-canonical pose for PHE140 widens the substrate binding surface; (5) dual allosteric pockets coinciding with various stabilizing and functional components of the substrate binding pocket were found to display correlated compaction dynamics; (6) high betweenness centrality values for residues 17 and 128 in all Mpro samples suggest their high importance in dimer stability—one such consequence has been observed for the M17I mutation whereby one of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between the rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modeling, dynamic residue network (DRN), relevant conformation retrieval from 1-D kernel density estimates from reaction coordinates to other existing approaches of structural analysis, and data visualization within the coronaviral Mpro is also novel and is applicable to other coronaviral proteins.
Anatomic accuracy of airway training manikins compared with humans *

Airway simulators, or training manikins, are frequently used in research studies for device development and training purposes. This study was designed to determine the anatomic accuracy of the most frequently used low‐fidelity airway training manikins. Computerised tomography scans and ruler measurements were taken of the SynDaver®, Laerdal® and AirSim® manikins. These measurements were compared with human computerised tomography (CT) scans (n = 33) from patients at the University of Michigan Medical Center or previously published values. Manikin measurements were scored as a percentile among the distribution of the same measurements in the human population and 10 out of 27 manikin measurements (nine measurements each in three manikins) were outside of two standard deviations from the mean in the participants. All three manikins were visually identifiable as outliers when plotting the first two dimensions from multidimensional scaling. In particular, the airway space between the epiglottis and posterior pharyngeal wall, through which airway devices must pass, was too large in all three manikins. SynDaver, Laerdal and AirSim manikins do not have anatomically correct static dimensions in relation to humans and these inaccuracies may lead to imprecise airway device development, negatively affect training and cause over‐confidence in users.
Efeito da radiação ultravioleta-C no controle de Monilinia fructicola

A radiação UV-C vem sendo utilizada como método alternativo no controle de doenças na pós-colheita de frutos. A podridão parda é uma das principais doenças que acomete pêssegos desde o início do desenvolvimento até a senescência. Neste trabalho, avaliou-se o efeito da radiação UV-C na indução de resistência à podridão parda de pêssegos cv. Chimarrita, em frutos com e sem ferimentos. As variáveis avaliadas foram a severidade da doença, o teor de compostos fenólicos e a capacidade antioxidante. A aplicação da radiação UV-C, tanto como controle preventivo como curativo, não protegeu o pêssego contra a infecção do patógeno, mesmo em frutos sem ferimento. Entretanto, atrasou em um dia o aparecimento de lesões nos frutos não feridos, o que pode ser interessante economicamente para a cadeia produtiva do pêssego. Ao avaliar o teor de compostos fenólicos totais e a capacidade antioxidante, verificou-se que frutos submetidos à radiação UV-C tiveram incrementos nessas propriedades. Tal fato indica que esse tratamento físico (UV-C) estimula o metabolismo secundário, ao menos da síntese de compostos fenólicos, mas não é suficiente para gerar resistência à podridão.
Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway

The thioredoxin (Trx) system plays critical roles in regulating intracellular redox levels and defending organisms against oxidative stress. Recent studies indicated that Trx reductase (TrxR) was overexpressed in various types of human cancer cells indicating that the Trx-TrxR system may be a potential target for anti-cancer drug development. This study investigated the synergistic effect of auranofin, a TrxR-specific inhibitor, on sulforaphane-mediated apoptotic cell death using Hep3B cells. The results showed that sulforaphane significantly enhanced auranofin-induced apoptosis by inhibiting TrxR activity and cell proliferation compared to either single treatment. The synergistic effect of sulforaphane and auranofin on apoptosis was evidenced by an increased annexin-V-positive cells and Sub-G1 cells. The induction of apoptosis by the combined treatment caused the loss of mitochondrial membrane potential (ΔΨm) and upregulation of Bax. In addition, the proteolytic activities of caspases (-3, -8, and -9) and the degradation of poly (ADP-ribose) polymerase, a substrate protein of activated caspase-3, were also higher in the combined treatment. Moreover, combined treatment induced excessive generation of reactive oxygen species (ROS). However, treatment with N-acetyl-L-cysteine, a ROS scavenger, reduced combined treatment-induced ROS production and apoptosis. Thereby, these results deduce that ROS played a pivotal role in apoptosis induced by auranofin and sulforaphane. Furthermore, apoptosis induced by auranofin and sulforaphane was significantly increased through inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. Taken together, the present study demonstrated that down-regulation of TrxR activity contributed to the synergistic effect of auranofin and sulforaphane on apoptosis through ROS production and inhibition of PI3K/Akt signaling pathway.
RNAi mediated gene knockdown in sucking and chewing insect pests.

RNA interference (RNAi) describes the ability of double-stranded RNA (dsRNA) to inhibit homologous gene expression at the RNA level. The specificity is sequence-based and depends on the sequence of one strand of the dsRNA corresponding to part or all of a specific gene transcript. In general, RNAi is a post-transcriptional control mechanism involving degradation of a target mRNA by dicers, mediated through the production of small interfering RNAs or short interfering RNAs (siRNAs). No effective Bt toxins are known against sap-sucking homopteran pests such as aphids, leafhoppers etc. With this view in mind, in the current study, RNAi has been applied to block different proteins biosynthesis by sucking insect pests. To achieve the objectives, clones were selected and transcribed to dsRNA. The transcribed dsRNAs were digested with RNase III to prepare siRNAs. Fifty micro liter volumes of test samples containing either control reagent or siRNA in varying quantities were mixed with the insect diet (1ml and 1g for sucking and chewing pests). Five different concentrations, 40, 20, 10, 5, 1 μg/ml of siRNA from a gene were applied to find out the concentration required to kill 50% of insects. The current investigation has explored the utility of RNAi as a tool for specific and strong silencing of various genes in adult sucking pest and larval chewing pest to examine their potential as candidates target genes for pest management. This report says observations of gene knockdown in sucking pests using siRNAs synthesized from different genes through RNAi technology for the first time. The same siRNA treatment resulted in specific gene silencing (not significant) and consequently brought very less mortality percentage. The present results suggest that feeding of siRNAs through an artificial diet can be exploited for the screening of siRNAs for insect pests control and functional genomic studies in both sucking and chewing insect pests.
Synthesis of Di- and Triacrylamides with Tertiary Amine Cores and Their Evaluation as Monomers in Dental Adhesive Interfaces

PURPOSE/AIM In an attempt to increase the service life of dental adhesive interfaces, more hydrolytically and enzymatically-stable methacrylate alternatives, such as methacrylamides, have been proposed. The aim of this study was to investigate polymerization behavior, as well as mechanical and biological properties of experimental adhesives containing multi-functional acrylamides. MATERIALS AND METHODS Multi-functional acrylamides (N,N-Bis[(3-methylaminoacryl)propyl]methylamine - BMAAPMA, Tris[(2-methylaminoacryl)ethyl]amine - TMAAEA, N,N'-bis(acrylamido) 1,4-diazepane - BAADA, N,N-Diethyl-1,3-bis(acrylamido)propane - DEBAAP) or HEMA (2-Hydroxyethyl methacrylate - control) were added at 40 wt% to UDMA. 0.2 wt% DMPA and 0.4 wt% DPI-PF6 were used as initiators. Polymerization kinetics was followed in real-time in near-IR during photoactivation (320-500 nm, at 630 mW/cm2). Water sorption/solubility and flexural strength/modulus were measured according to ISO 4049. 1H NMR was used to assess monomer degradation kinetics. MTT assay was used to assess cytotoxicity against OD-21 and DPSC cells. Biofilm formation and adhesion were assessed by Luciferase Assay and Impingement technique, respectively. Solvated adhesives (40 vol% ethanol) were used to test interfacial adhesion strength. The results were analyzed by ANOVA/Tukey's test (α = 0.05). RESULTS In general, the pure methacrylate mixture had higher rate of polymerization (Rpmax), degree of conversion (DC) at Rpmax, and final DC than the acrylamides. Flexural properties after water storage decreased between 11 and 65%, more markedly for acrylamides. Interfacial bond strength was greater and more stable long-term for the newly synthesized acrylamide formulations (less than 4% reduction at 6 months) compared to the methacrylate experimental control (42% reduction at 6 months). HEMA degraded by almost 90%, while the acrylamides showed no degradation in acidic conditions. Cytotoxicity and biofilm formation, in general, were similar for all groups. CONCLUSIONS Despite demonstrating high water sorption, the acrylamide-containing materials had similar mechanical and biological properties and enhanced interfacial bond strength stability compared to the methacrylate control.
Elucidation of Melanogenesis Cascade for Identifying Pathophysiology and Therapeutic Approach of Pigmentary Disorders and Melanoma

Melanogenesis is the biological and biochemical process of melanin and melanosome biosynthesis. Melanin is formed by enzymic reactions of tyrosinase family proteins that convert tyrosine to form brown-black eumelanin and yellow-red pheomelanin within melanosomal compartments in melanocytes, following the cascades of events interacting with a series of autocrine and paracrine signals. Fully melanized melanosomes are delivered to keratinocytes of the skin and hair. The symbiotic relation of a melanocyte and an associated pool of keratinocytes is called epidermal melanin unit (EMU). Microphthalmia-associated transcription factor (MITF) plays a vital role in melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes for promoting melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis. Diseases involving alterations of EMU show various forms of pigmentation phenotypes. This review introduces four major topics of melanogenesis cascade that include (1) melanocyte development and differentiation, (2) melanogenesis and intracellular trafficking for melanosome biosynthesis, (3) melanin pigmentation and pigment-type switching, and (4) development of a novel therapeutic approach for malignant melanoma by elucidation of melanogenesis cascade.
Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.