Miracle-dz/UniFAR-FTUs huggingface dataset:
Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening

The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages —hepatocytes and cholangiocytes—and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
Cerebellar Dysfunction in Adults with Prader Willi Syndrome

Severe hypotonia during infancy is a hallmark feature of Prader Willi syndrome (PWS). Despite its transient expression, moto development is delayed and deficiencies in motor coordination are present at older ages, with no clear pathophysiological mechanism yet identified. The diverse motor coordination symptoms present in adult PWS patients could be, in part, the result of a common alteration(s) in basic motor control systems. We aimed to examine the motor system in PWS using functional MRI (fMRI) during motor challenge. Twenty-three adults with PWS and 22 matched healthy subjects participated in the study. fMRI testing involved three hand motor tasks of different complexity. Additional behavioral measurements of motor function were obtained by evaluating hand grip strength, functional mobility, and balance. Whole brain activation maps were compared between groups and correlated with behavioral measurements. Performance of the motor tasks in PWS engaged the neural elements typically involved in motor processing. While our data showed no group differences in the simplest task, increasing task demands evoked significantly weaker activation in patients in the cerebellum. Significant interaction between group and correlation pattern with measures of motor function were also observed. Our study provides novel insights into the neural substrates of motor control in PWS by demonstrating reduced cerebellar activation during movement coordination.
Social factors influence the course and prognosis of malignat diseases.

BACKGROUND A statement of the dia-gnosis of malignant disease fundamentally changes the identity of a man. A healthy person changes to a patient. A lot of studies analyzed the influence of marital status on the disease development. PURPOSE We present an analysis of interpersonal relationships in connection with oncological diseases. The majority of the authors consider living in a couple as a positive prognostic factor. On the other hand, malignant disease at a younger age increases the risk of divorce or breakup.
Potential Assessment of UGT2B17 Inhibition by Salicylic Acid in Human Supersomes In Vitro

Glucuronidation is a Phase 2 metabolic pathway responsible for the metabolism and excretion of testosterone to a conjugate testosterone glucuronide. Bioavailability and the rate of anabolic steroid testosterone metabolism can be affected upon UGT glucuronidation enzyme alteration. However, there is a lack of information about the in vitro potential assessment of UGT2B17 inhibition by salicylic acid. The purpose of this study is to investigate if UGT2B17 enzyme activity is inhibited by salicylic acid. A UGT2B17 assay was developed and validated by HPLC using a C18 reversed phase column (SUPELCO 25 cm × 4.6 mm, 5 μm) at 246 nm using a gradient elution mobile phase system: (A) phosphate buffer (0.01 M) at pH = 3.8, (B) HPLC grade acetonitrile and (C) HPLC grade methanol. The UGT2B17 metabolite (testosterone glucuronide) was quantified using human UGT2B17 supersomes by a validated HPLC method. The type of inhibition was determined by Lineweaver–Burk plots. These were constructed from the in vitro inhibition of salicylic acid at different concentration levels. The UGT2B17 assay showed good linearity (R2 > 0.99), acceptable recovery and accuracy (80–120%), good reproducibility and acceptable inter and intra-assay precision (<15%), low detection (6.42 and 2.76 μM) and quantitation limit values (19.46 and 8.38 μM) for testosterone and testosterone glucuronide respectively, according to ICH guidelines. Testosterone and testosterone glucuronide were found to be stable up to 72 h in normal laboratory conditions. Our investigational study showed that salicylic acid uncompetitively inhibited UGT2B17 enzyme activity. Thus, drugs that are substrates for the UGT2B17 enzyme have negligible potential effect of causing interaction with salicylic acid in humans.
Rodent models of hypertension

Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive‐pregnancy disorders, providing an important resource for researchers.
Ruthenium Complexes as Promising Candidates against Lung Cancer

Lung cancer is one of the most common malignancies with the highest mortality rate and the second-highest incidence rate after breast cancer, posing a serious threat to human health. The accidental discovery of the antitumor properties of cisplatin in the early 1960s aroused a growing interest in metal-based compounds for cancer treatment. However, the clinical application of cisplatin is limited by serious side effects and drug resistance. Therefore, other transition metal complexes have been developed for the treatment of different malignant cancers. Among them, Ru(II/III)-based complexes have emerged as promising anticancer drug candidates due to their potential anticancer properties and selective cytotoxic activity. In this review, we summarized the latest developments of Ru(II/III) complexes against lung cancer, focusing mainly on the mechanisms of their biological activities, including induction of apoptosis, necroptosis, autophagy, cell cycle arrest, inhibition of cell proliferation, and invasion and metastasis of lung cancer cells.
Development and validation of an HPLC-MS/MS method to simultaneously quantify alectinib, crizotinib, erlotinib, gefitinib and osimertinib in human plasma samples, using one assay run.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify alectinib, crizotinib, erlotinib and gefitinib. This assay can be combined with our method for osimertinib, allowing quantification of the most used ALK- and EGFR- tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer with a single-assay setup. Chromatographic separation was performed on a HyPURITY® C18 analytical column using an elution gradient of ammonium acetate in water and in methanol, both acidified with formic acid 0,1%. Detection and quantification were performed by a triple quad mass spectrometer with an electrospray ionization interface. This method led to robust results, as the selectivity, carry-over, precision and accuracy met all pre-specified requirements. The assay was validated over a linear range of 100 - 2000 ng/mL for alectinib and erlotinib and 50 - 1000 ng/mL for crizotinib and gefitinib. Alectinib, crizotinib, erlotinib and gefitinib were all stable for at least 4 hours in whole blood (at room temperature (RT) and at 4°C) and for at least one month in EDTA-plasma when stored at -80°C, while osimertinib proved to be unstable at RT. Although high-performance liquid chromatography was used, the run time was short and comparable with other methods using ultra-high performance liquid chromatography.
TopicBERT: A Topic-Enhanced Neural Language Model Fine-Tuned for Sentiment Classification

Sentiment classification is a form of data analytics where people’s feelings and attitudes toward a topic are mined from data. This tantalizing power to “predict the zeitgeist” means that sentiment classification has long attracted interest, but with mixed results. However, the recent development of the BERT framework and its pretrained neural language models is seeing new-found success for sentiment classification. BERT models are trained to capture word-level information via mask language modeling and sentence-level contexts via next sentence prediction tasks. Out of the box, they are adequate models for some natural language processing tasks. However, most models are further fine-tuned with domain-specific information to increase accuracy and usefulness. Motivated by the idea that a further fine-tuning step would improve the performance for downstream sentiment classification tasks, we developed TopicBERT—a BERT model fine-tuned to recognize topics at the corpus level in addition to the word and sentence levels. TopicBERT comprises two variants: TopicBERT-ATP (aspect topic prediction), which captures topic information via an auxiliary training task, and TopicBERT-TA, where topic representation is directly injected into a topic augmentation layer for sentiment classification. With TopicBERT-ATP, the topics are predetermined by an LDA mechanism and collapsed Gibbs sampling. With TopicBERT-TA, the topics can change dynamically during the training. Experimental results show that both approaches deliver the state-of-the-art performance in two different domains with SemEval 2014 Task 4. However, in a test of methods, direct augmentation outperforms further training. Comprehensive analyses in the form of ablation, parameter, and complexity studies accompany the results.
Comparison of the Toxicity of Pristine Graphene and Graphene Oxide, Using Four Biological Models

There are numerous applications of graphene in biomedicine and they can be classified into several main areas: delivery systems, sensors, tissue engineering and biological agents. The growing biomedical field of applications of graphene and its derivates raises questions regarding their toxicity. We will demonstrate an analysis of the toxicity of two forms of graphene using four various biological models: zebrafish (Danio rerio) embryo, duckweed (Lemna minor), human HS-5 cells and bacteria (Staphylococcus aureus). The toxicity of pristine graphene (PG) and graphene oxide (GO) was tested at concentrations of 5, 10, 20, 50 and 100 µg/mL. Higher toxicity was noted after administration of high doses of PG and GO in all tested biological models. Hydrophilic GO shows greater toxicity to biological models living in the entire volume of the culture medium (zebrafish, duckweed, S. aureus). PG showed the highest toxicity to adherent cells growing on the bottom of the culture plates—human HS-5 cells. The differences in toxicity between the tested graphene materials result from their physicochemical properties and the model used. Dose-dependent toxicity has been demonstrated with both forms of graphene.
Super-Toughened Fumed-Silica-Reinforced Thiol-Epoxy Composites Containing Epoxide-Terminated Polydimethylsiloxanes

In response to the demand for high-performance materials, epoxy thermosetting and its composites are widely used in various industries. However, their poor toughness, resulting from the high crosslinking density of the epoxy network, must be improved to expand their application to the manufacturing of flexible products. In this study, ductile epoxy thermosetting was produced using thiol compounds with functionalities of 2 and 3 as curing agents. The mechanical properties of the epoxy were further enhanced by incorporating fumed silica into it. To increase the filler dispersion, epoxide-terminated polydimethylsiloxane was synthesized and used as a composite component. Thanks to the polysiloxane–silica interaction, the nanosilica was uniformly dispersed in the epoxy composites, and their mechanical properties improved with increasing fumed silica content up to 5 phr (parts per hundred parts of epoxy resin). The toughness and impact strength of the composite containing 5 phr nanosilica were 5.17 (±0.13) MJ/m3 and 69.8 (±1.3) KJ/m2, respectively.
Assessing Fracture Toughness and Impact Strength of PMMA Reinforced with Nano-Particles and Fibre as Advanced Denture Base Materials

Statement of Problem: Polymethyl methacrylate (PMMA) denture resins commonly fracture as a result of the denture being dropped or when in use due to heavy occlusal forces. Purpose: To investigate the effects of E-glass fibre, ZrO2 and TiO2 nanoparticles at different concentrations on the fracture toughness and impact strength of PMMA denture base. Materials and Methods: To evaluate fracture toughness (dimensions: 40 × 8 × 4 mm3; n = 10/group) and impact strength (dimensions: 80 × 10 × 4 mm3; n = 12/group), 286 rectangular tested specimens were prepared and divided into four groups. Group C consisted of the PMMA specimens without any filler (control group), while the specimens in the remaining three groups varied according to the concentration of three filler materials by weight of PMMA resin: 1.5%, 3%, 5%, and 7%. Three-point bending and Charpy impact tests were conducted to measure the fracture toughness and impact strength respectively. Scanning Electron Microscope (SEM) was utilised to examine the fractured surfaces of the specimens after the fracture toughness test. One-way analysis of variance (ANOVA) followed by Tukey post-hoc tests were employed to analyse the results at a p ≤ 0.05 significance level. Results: Fracture toughness of groups with 1.5 and 3 wt. % ZrO2, 1.5 wt. % TiO2, and all E-glass fibre concentrations were significantly higher (p < 0.05) than the control group. The samples reinforced with 3 wt. % ZrO2 exhibited the highest fracture toughness. Those reinforced with a 3 wt. %, 5 wt. %, and 7 wt. % of E-glass fibres had a significantly (p < 0.05) higher impact strength than the specimens in the control group. The heat-cured PMMA modified with either ZrO2 or TiO2 nanoparticles did not exhibit a statistically significant difference in impact strength (p > 0.05) in comparison to the control group. Conclusions: 1.5 wt. %, 3 wt. % of ZrO2; 1.5 wt. % ratios of TiO2; and 1.5 wt. %, 3 wt. %, 5 wt. %, and 7 wt. % of E-glass fibre can effectively enhance the fracture toughness of PMMA. The inclusion of E-glass fibres does significantly improve impact strength, while ZrO2 or TiO2 nanoparticles did not.
Electrochemical Degradation of Tetracycline Using a Ti/Ta2O5-IrO2 Anode: Performance, Kinetics, and Degradation Mechanism

Tetracycline (TC) is widely used in production and in life. The high volume of its use and the difficulty of its disposal have become the most important causes of environmental pollution. A suitable method needs to be found to solve this problem. In this study, the Ti/Ta2O5-IrO2 electrode was characterized for its surface morphology and crystal composition. The electrochemical catalytic ability of the Ti/Ta2O5-IrO2 electrode was investigated using LSV and CV tests. The electrochemical degradation of tetracycline (TC) in water with a Ti/Ta2O5-IrO2 anode was investigated. The main influence factors, such as current density (2.5–10 mA/cm2), electrode spacing (20–40 mm), initial TC concentration (20–80 mg/L) and initial solution pH (4.74–9.48) were analyzed in detail and their influences on reaction kinetics was summed up. The removal rate increased along with the increasing current density, decreasing initial TC concentration and decreasing of electrode distance under the experimental conditions. The optimum pH was 4.74. UV–vis, total organic carbon (TOC) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses were used to reveal the mechanism of TC degradation. Nine main intermediates were identified, and the degradation pathways were proposed. A new insight has been postulated for the safe and efficient degradation of TC using the Ti/Ta2O5-IrO2 electrode.
Hyperlipidemia‐induced metabolic changes in regulatory T cells result in altered function

Regulatory T cells (Tregs) play a critical role in maintaining self‐tolerance and controlling inflammation. However, physiologically relevant conditions that alter Treg function and drive disease pathogenesis are poorly understood and few have been defined. We have previously shown that induction of hyperlipidemia in mice results in changes in Tregs that reduce their function. Here, we set out to examine mechanisms by which hyperlipidemia alters Tregs. Using live‐cell metabolic assays, we observed that induction of hyperlipidemia increases metabolism in Tregs but not conventional T cells. Increased metabolism resulted from preferential activation of the serine/threonine kinase Akt2 (PKB‐β). Expression of a constitutively activated form of Akt2 in CD4 T cells was sufficient to increase glycolysis in Tregs and drive changes in Treg subsets. Induction of hyperlipidemia did not alter Treg metabolism in mice lacking Akt2. Activation of Akt2 was sufficient to drive the production of inflammatory cytokines by Tregs. We suggest that hyperlipidemia alters Treg function through effects on metabolism via Akt2 activation thereby promoting plasticity and decreased function of FoxP3+ T cells.
Copresence of High-Risk Human Papillomaviruses and Epstein–Barr Virus in Colorectal Cancer: A Tissue Microarray and Molecular Study from Lebanon

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Human papillomaviruses (HPVs) and Epstein–Barr virus (EBV) have been reported to be present in different types of human cancers, including CRCs, where they can play a key role in the onset and/or progression of these cancers. Thus, we herein explored the prevalence of high-risk HPVs and EBV in a cohort of 94 CRC tissue samples and 13 colorectal normal tissues from the Lebanese population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We found that high-risk HPVs are present in 64%, while EBV is present in 29% of our CRC samples. Additionally, our data showed that high-risk HPV types (16, 18, 35, 58, 51, 45, 52, 31, and 33) are the most frequent in CRC in the Lebanese cohort, respectively. Our data point out that HPVs and EBV are copresent in 28% of the samples. Thus, this study clearly suggests that high-risk HPVs and EBV are present/copresent in CRCs, where they could play an important role in colorectal carcinogenesis. Nevertheless, further investigations using a larger cohort are needed to elucidate the possible cooperation between these oncoviruses in the development of CRC.
Fatty Acid Synthesis in Glial Cells of the CNS

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer’s disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases.
A Prospective Cohort Study of Stability in Preferred Place of Death Among Patients With Stage IV Cancer in Singapore.

BACKGROUND Advance care planning (ACP) involves documentation of patients' preferred place of death (PoD). This assumes that patients' preferred PoD will not change over time; yet, evidence for this is inconclusive. We aimed to assess the extent and correlates of change in patients' preferred PoD over time. MATERIALS AND METHODS Using data from a cohort study of patients with advanced cancer in Singapore, we analyzed preferred PoD (home vs institution including hospital, hospice, and nursing home vs unclear) among 466 patients every 6 months for a period of 2 years. At each time point, we assessed the proportion of patients who changed their preferred PoD from the previous time point. Using a multinomial logistic regression model, we assessed patient factors (demographics, understanding of disease stage, ACP, recent hospitalization, quality of life, symptom burden, psychologic distress, financial difficulty, prognosis) associated with change in their preferred PoD. RESULTS More than 25% of patients changed their preferred PoD every 6 months, with no clear trend in change toward home or institution. Patients psychologically distressed at the time of the survey had increased likelihood of changing their preferred PoD to home (relative risk ratio [RRR], 1.02; 95% CI, 1.00-1.05) and to an institution (RRR, 1.06; 95% CI, 1.02-1.10) relative to no change in preference. Patients hospitalized in the past 6 months were more likely to change their preferred PoD to home (RRR, 1.56; 95% CI, 1.07-2.29) and less likely to change to an institution (RRR, 0.50; 95% CI, 0.28-0.88) relative to no change in preference. CONCLUSIONS The present study provides evidence of instability in the preferred PoD of patients with advanced cancer. ACP documents need to be updated regularly to ensure they accurately reflect patients' current preference.
Bulbine natalensis (currently Bulbine latifolia) and select bulbine knipholones modulate the activity of AhR, CYP1A2, CYP2B6, and P-gp

Abstract Bulbine natalensis, an emerging medicinal herb on the global market with androgenic properties, is often formulated in dietary supplements that promote perceived sexual enhancement. However, to date, comprehensive safety studies of B. natalensis are lacking, particularly those related to its herb-drug interaction potential. The purpose of this study was to assess the inductive and inhibitory effects of extracts and pure compounds of B. natalensis on human cytochrome P-450 isozymes in vitro. Our findings demonstrated that both water and methanolic extracts of B. natalensis as well as knipholone, bulbine-knipholone, and 6′-O-methylknipholone dose-dependently increased mRNA expression encoded by CYP2B6, CYP1A2, and ABCB1 genes. Functional analyses showed that water (60 to 2.20 µg/mL) and methanolic (30 to 3.75 µg/mL) extracts and knipholones (10 to 0.33 µM) increased CYP2B6 and CYP1A2 activity in a dose-dependent manner. Additionally, water extract (60 µg/mL), methanolic extract (30 µg/mL), and knipholone (10 µM) caused activation of the aryl hydrocarbon receptor up to 11.1 ± 0.7, 8.9 ± 0.6, and 7.1 ± 2.0-fold, respectively. Furthermore, inhibition studies revealed that methanolic extract attenuated the activity of metabolically active CYP1A2 (IC50, 22.6 ± 0.4 µg/mL) and CYP2B6 (IC50, 34.2 ± 6.6 µg/mL) proteins, whereas water extracts had no inhibitory effect on either isoform. These findings suggest that chronic consumption of B. natalensis may affect normal homeostasis of select CYPs with subsequent risks for HDIs when concomitantly ingested with conventional medications that are substrates of CYP2B6 and CYP1A2. However, more in-depth translational studies are required to validate our current findings and their clinical relevance.