Miracle-dz/UniFAR-FTUs huggingface dataset:
Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor–immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.
Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far?

Chronic kidney disease (CKD) in children is a major concern of medical care and public health as it is related to high morbidity and mortality due to progression to end-stage kidney disease (ESKD). It is essential to identify patients with a risk of developing CKD to implement therapeutic interventions. Unfortunately, conventional markers of CKD, such as serum creatinine, glomerular filtration rate (GFR) and proteinuria, have many limitations in serving as an early and specific diagnostic tool for this condition. Despite the above, they are still the most frequently utilized as we do not have better. Studies from the last decade identified multiple CKD blood and urine protein biomarkers but mostly assessed the adult population. This article outlines some recent achievements and new perspectives in finding a set of protein biomarkers that might improve our ability to prognose CKD progression in children, monitor the response to treatment, or even become a potential therapeutic target.
Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.
Dietary Supplementation with Puerarin Improves Intestinal Function in Piglets Challenged with Escherichia coli K88

Simple Summary The aim of this study was to investigate the effect of puerarin supplementation on the growth performance and intestinal function of piglets challenged with enterotoxigenic Escherichia coli (ETEC) K88, which provided a theoretical basis for its practical application as a new feed additive. Dietary supplementation with 5 mg/kg puerarin alleviated intestinal injury and improved the intestinal function of piglets challenged with ETEC K88 by increasing the number of Bifidobacterium in the colon and Lactobacillus in the jejunum, cecum and colon; decreasing the number of Escherichia coli in the jejunum and cecum; reducing the hydrogen peroxide content in the jejunum and myeloperoxidase activity in the jejunum and ileum; and increasing the activities of catalase and superoxide dismutase in the jejunum and ileum. These results provide important insights into the development of an effective treatment for ETEC K88 infection and other enteric diseases. Abstract The objective of this study was to investigate the effect of puerarin supplementation on the growth performance and intestinal function of piglets challenged with enterotoxigenic Escherichia coli (ETEC) K88. Twenty-four ternary crossbred piglets were randomly assigned to three treatment groups: control group, ETEC group (challenged with ETEC K88 on day 8), and ETEC + Puerarin group (supplemented with 5 mg/kg puerarin and challenged with ETEC K88 on day 8). All piglets were orally administered D-xylose (0.1 g/kg body weight) on day 10, and blood samples were collected after 1 h. Subsequently, piglets were killed and intestinal samples were collected for further analysis. The results showed that puerarin supplementation significantly decreased the adverse effects of ETEC K88-challenged piglets; significantly improved growth performance; increased the number of Bifidobacterium in the colon and Lactobacillus in the jejunum, cecum and colon; decreased the number of Escherichia coli in the jejunum and cecum; reduced the hydrogen peroxide content in the jejunum and myeloperoxidase activity in the jejunum and ileum; and increased the activities of catalase and superoxide dismutase in the jejunum and ileum. In addition, puerarin supplementation alleviated ETEC K88-induced intestinal injury in piglets, significantly downregulated the mRNA level of Interleukin-1β and upregulated the mRNA levels of intercellular cell adhesion molecule-1, myxovirus resistance protein 1, myxovirus resistance protein 2, and guanylate-binding protein-1 in the small intestine of piglets. In conclusion, dietary supplementation with puerarin could attenuate ETEC K88-induced intestinal injury by increasing the antioxidant and anti-inflammatory capacity and the number of beneficial intestinal bacteria in piglets.
Peripheral and Central Impact of Methionine Source and Level on Growth Performance, Circulating Methionine Levels and Metabolism in Broiler Chickens

Simple Summary As it is the first limiting amino acid, the use of DL-methionine in poultry diet formulation is critical for poultry growth, yet its mode of action is not fully defined. In this study, we conducted two peripheral and central feeding trials to determine the effect of DL-methionine and its analog HMTBa on growth performance, plasma metabolites, and the gene expression of feeding-related hypothalamic neuropeptides in broilers raised to market age (35 d). The study shows for the first time that both sources of methionine share some pathways, but each one has a unique pathway. Abstract The present study was designed to evaluate the effects of DL-methionine (DL-Met) 2-hydroxy-4-(methylthio) butanoic acid (HMTBa), or S-(5′-Adenosyl)-L-methionine chloride (SAM), using feeding trial and central administration, on live performance, plasma metabolites, and the expression of feeding-related hypothalamic neuropeptides in broilers raised to a market age (35 d). Final average body weight (BW) and feed conversion ratio (FCR) from the feeding trial exceeded the performance measurements published by the primary breeder. At d35, the MTBHa group had better BW and lower feed intake, which resulted in a better FCR than the DL-Met group at 87 TSAA to lysine. At the molecular levels, the expression of hypothalamic neuropeptide (NPY) and monocarboxylate transporter (MCT) 2 did not differ between all treated groups; however, the mRNA abundances of hypothalamic MCT1 and orexin (ORX) were significantly upregulated in DL-Met- treated groups compared to the control. The ICV administration of SAM significantly reduced feed intake at all tested periods (from 30 to 180 min post injection) compared to the aCSF-treated group (control). The central administration of HMTBa increased feed intake, which reached a significant level only 60 min post administration, compared to the control group. ICV administration of DL-Met slightly increased feed intake compared to the control group, but the difference was not statistically discernable. Quantitative real-time PCR analysis showed that the hypothalamic expression of NPY, cocaine- and amphetamine-regulated transcript, MCT1, and MCT2 was significantly upregulated in the ICV-HMTBa group compared to the aCSF birds. The hypothalamic expression of the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPKα1), D-amino acid oxidase, and hydroxyacid oxidase was significantly upregulated in DL-Met compared to the control group. The mRNA abundances of ORX were significantly increased in the hypothalamus of both DL-Met and HMTBa groups compared to the aCSF birds; however, mTOR gene expression was significantly downregulated in the SAM compared to the control group. Taken together, these data show, for the first time, that DL-Met and HMTBa have a common downstream (ORX) pathway, but also a differential central pathway, typically NPY-MCT for HMTBa and mTOR-AMPK for methionine.
CD207 Expression Level is a New Prognostic Marker for Condyloma Acuminatum

Background Condyloma cuminata (CA) is a sexually transmitted disease caused by human papillomavirus (HPV) infection, which is prone to recurrence and difficult to cure in the short term. CD207 is a C-type lectin receptor that is specifically expressed on the surface of Langerhans cells (LCs) and is considered as an LC-specific immunohistochemical marker. The main purpose of this study is to explore the correlation between the expression of CD207 in CA skin lesions and the duration of CA disease course and frequency of recurrence, in order to provide new prognostic markers for CA to clinicians. Materials and Methods A total of 40 male patients with CA and their skin lesions were collected, as well as 40 healthy male penile tissue samples. The skin lesions of CA were clinically and histologically confirmed by acetic acid test. The expression of CD207 in epidermal tissues was detected using immunohistochemistry. The difference in the number of CD207 positive cells between CA skin lesions and healthy skin controls was compared, and the association between the number of CD207 positive cells in CA skin lesions and the duration of disease course and the frequency of recurrence was determined through Spearman correlation analysis. Conclusion In CA skin lesions, CD207 positive cells were found to have morphological abnormalities and the number of cells was significantly reduced compared to healthy skin, suggesting that there may be antigen presentation dysfunction in CA skin lesions, which may be the reason for the prolonged and unresolved condition of the disease. The fewer CD207 positive cells in CA skin lesions, the longer the disease course and the more frequent the recurrence, therefore, the expression level of CD207 can be used as a new prognostic marker for predicting the outcome of CA.
In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals

Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for drug development and frequently exert less toxicity than synthetic drugs. Bioinformatics can accelerate and simplify the highly complex, time-consuming, and expensive drug development process. Here, we analyzed 375 phytochemicals using virtual screenings, molecular docking, and in silico toxicity predictions. Based on these in silico studies, six candidate compounds were further investigated in vitro. Resazurin assays were performed to determine the growth-inhibitory effects towards wild-type CCRF-CEM leukemia cells and their multidrug-resistant, P-glycoprotein (P-gp)-overexpressing subline, CEM/ADR5000. Flow cytometry was used to measure the potential to measure P-gp-mediated doxorubicin transport. Bidwillon A, neobavaisoflavone, coptisine, and z-guggulsterone all showed growth-inhibitory effects and moderate P-gp inhibition, whereas miltirone and chamazulene strongly inhibited tumor cell growth and strongly increased intracellular doxorubicin uptake. Bidwillon A and miltirone were selected for molecular docking to wildtype and mutated P-gp forms in closed and open conformations. The P-gp homology models harbored clinically relevant mutations, i.e., six single missense mutations (F336Y, A718C, Q725A, F728A, M949C, Y953C), three double mutations (Y310A-F728A; F343C-V982C; Y953A-F978A), or one quadruple mutation (Y307C-F728A-Y953A-F978A). The mutants did not show major differences in binding energies compared to wildtypes. Closed P-gp forms generally showed higher binding affinities than open ones. Closed conformations might stabilize the binding, thereby leading to higher binding affinities, while open conformations may favor the release of compounds into the extracellular space. In conclusion, this study described the capability of selected phytochemicals to overcome multidrug resistance.
Guideline Implementation for Improved Asthma Management and Treatment Adherence in Children in Jordan

Asthma imposes a significant social burden on children, their families, and society at large. As a chronic health condition, effective management could greatly benefit from consistent adherence to guidelines. Despite this, minimal effort has been exerted to examine the impact of asthma management guidelines and adherence to treatment on children with asthma and the mothers caring for them. This study was designed to evaluate the influence of asthma management guidelines on the knowledge and treatment adherence among children with asthma and their mothers. A quasi-experimental design was utilized, and the study was conducted at two large hospitals in Jordan: Princess Rahma Hospital and King Hussein Medical Center. A purposive sample of children aged 6–12 years (n = 100) who were accompanied by their mothers (n = 100) were recruited for this study. Data were collected using a structured questionnaire and an observation checklist before and after the implementation of guidelines. Statistical analyses were performed using SPSS. The results revealed a statistically significant improvement in knowledge related to asthma among children and their mothers (p < 0.001). Additionally, a statistically significant difference was observed in the children’s adherence to their treatment regimen before and after the implementation of asthma management guidelines (p < 0.001). Moreover, the improvements in knowledge and practice related to asthma were sustained in the follow-up assessments. In conclusion, the guidelines had a beneficial effect on the children’s adherence to their treatment regimen both before and after their implementation. Thus, asthma patients should adhere to conventional guidelines at various health services to manage their condition effectively.
Robust flatness-based tracking control for brushless direct current motor drives

The trajectory tracking problem for nonlinear brushless direct current drive is solved by combined robust and flatness state feedback control. The drive's nonlinear model is shown to have the flatness property. The proposed controller consists of two parts, linear and nonlinear. Linear matrix inequalities (LMI) optimization is used to design the linear part which achieves robust stability against system uncertainties, desired swiftness, and guaranteed cost performance. System uncertainty due to changes in the drive's parameters is represented with a norm-bounded structure. The nonlinear control part solves the motion planning problem through flatness which avoids integrating the differential equations of the dynamics. The main advantages of this technique are that the LMI algorithm includes an optimal part to preclude high control efforts, and the control burden is heavily placed on the linear part to achieve flatness properties. In some systems, in which flatness cannot be achieved, adding robust linear control can overcome or alleviate this problem.
Preoperative Quality of Life and Mental Health Can Predict Postoperative Outcomes and Quality of Life after Colorectal Cancer Surgery

Background and Objectives: It remains unclear which domains of preoperative health-related quality of life (HRQOL) and mental health are predictive of postoperative clinical and patient-reported outcomes in colorectal cancer (CRC) patients. Materials and Methods: A prospective cohort of 78 CRC patients undergoing elective curative surgery was recruited. The EORTC QLQ-C30 and HADS questionnaires were administered preoperatively and one month after surgery. Results: Preoperative cognitive functioning scores (95% CI 0.131–1.158, p = 0.015) and low anterior resection (95% CI 14.861–63.260, p = 0.002) independently predicted poorer 1-month postoperative global QOL. When postoperative complications were represented using the comprehensive complication index (CCI), poorer preoperative physical function scores were associated with higher CCI scores (B = −0.277, p = 0.014). Preoperative social function score (OR = 0.925, 95% CI 0.87 to 0.99; p = 0.019) was an independent predictor for 30-day readmission, while physical functioning score (OR = −0.620, 95% CI −1.073–−0.167, p = 0.008) was inversely related to the length of hospitalization. The overall regressions for 1-month postoperative global QOL (R2: 0.546, F: 1.961, p = 0.023) and 30-day readmission (R2: 0.322, χ2: 13.129, p < 0.001) were statistically significant. Conclusions: Various QLQ-C30 domains were found to be predictive of postoperative outcomes, including complications, readmission, and length of hospitalization. Preoperative cognitive dysfunction and low AR were independent predictors of poorer postoperative global QOL. Future research should seek to examine the efficacy of targeting specific baseline QOL domains in improving clinical as well as patient-reported outcomes after CRC surgery.
AlGaN/GaN high-electron-mobility transistor technology for high-voltage and low-on-resistance operation

In this paper, we give an overview of the recent progress in GaN-based high-electron-mobility transistors (HEMTs) developed for mainstream acceptance in the power electronics field. The comprehensive investigation of AlGaN/GaN HEMTs fabricated on a free-standing semi-insulating GaN substrate reveals that an extracted effective lateral breakdown field of approximately 1 MV/cm is likely limited by the premature device breakdown originating from the insufficient structural and electrical quality of GaN buffer layers and/or the GaN substrate itself. The effective lateral breakdown field is increased to 2 MV/cm by using a highly resistive GaN substrate achieved by heavy Fe doping. Various issues relevant to current collapse are also discussed in the latter half of this paper, where a more pronounced reduction in current collapse is achieved by combining two different schemes (i.e., a prepassivation oxygen plasma treatment and a field plate structure) for intensifying the mitigating effect against current collapse. Finally, a novel approach to suppress current collapse is presented by introducing a three-dimensional field plate (3DFP) in AlGaN/GaN HEMTs, and its possibility of realizing true collapse-free operation is described.
Greater resting frontal alpha asymmetry associated with higher emotional expressive flexibility

ABSTRACT Emotional expressive flexibility (EEF) is an important social ability that has prompted scholars to examine its benefits to human mental health. However, the neural underpinnings of individual differences in the EEF remain unclear. In neuroscience, frontal alpha asymmetry (FAA) is regarded as a sensitive indicator of certain emotional modalities and affective styles. To the best of our knowledge, no study has linked FAA with EEF to examine whether FAA could be a potential neural indicator of EEF. In the present study, 47 participants (M age = 22.38 years, 55.3% women) underwent a resting electroencephalogram and completed the flexible regulation of emotional expression scale (FREE). The results revealed that after controlling for gender, resting FAA scores positively predicted EEF, with relative left frontal activity associated with higher EEF. Additionally, this prediction was reflected in both the enhancement and suppression dimensions of EEF. Furthermore, individuals with relative left frontal activity reported greater enhancement and EEF than individuals with relative right frontal activity. The present study indicated that FAA may be a neural marker of EEF. In the future, more empirical studies are needed to provide causal evidence that the improvement in FAA can enhance EEF.
Causality assessment of adverse drug reaction: A narrative review to find the most exhaustive and easy-to-use tool in post-authorization settings.

BACKGROUND The core motive of pharmacovigilance is the detection and prevention of adverse drug reactions (ADRs), to improve the risk-benefit balance of the drug. However, the causality assessment of ADRs remains a major challenge among clinicians, and none of the available tools of causality assessment used for assessing ADRs have been universally accepted. OBJECTIVE To provide an up-to-date overview of the different causality assessment tools. METHODS We conducted electronic searches in MEDLINE, EMBASE, and the Cochrane database. The eligibility of each tool was screened by three reviewers. Each eligible tool was then scrutinized for its domains (the reported specific set of questions/areas used for calculating the likelihood of cause-and-effect relation of an ADR) to discover the most comprehensive tool. Finally, we subjectively assessed the tool's ease-of-use in a Canadian, Indian, Hungarian, and Brazilian clinical context. RESULTS Twenty-one eligible causality assessment tools were retrieved. Naranjo's tool and De Boer's tool appeared the most comprehensive among all the tools, covering 10 domains each. Regarding "ease-of-use" in a clinical setting, we judged that many tools were hard to implement in a clinical context because of their complexity and/or lengthiness. Naranjo's tool, Jones's tool, Danan and Benichou's tool, and Hsu and Stoll's tool appeared to be the easiest to implement into various clinical contexts. CONCLUSION Among the many tools identified, 1981 Naranjo's scale remains the most comprehensive and easy to use for performing causality assessment of ADRs. Upcoming analysis should compare the performance of each ADR tool in clinical settings.