Miracle-dz/UniFAR-FTUs huggingface dataset:
Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
Antibiotic Resistance, spa Typing and Clonal Analysis of Methicillin-Resistant Staphylococcus aureus (MRSA) Isolates from Blood of Patients Hospitalized in the Czech Republic

Staphylococcus aureus is one of the major causes of bloodstream infections. The aim of our study was to characterize methicillin-resistant Staphylococcus aureus (MRSA) isolates from blood of patients hospitalized in the Czech Republic between 2016 and 2018. All MRSA strains were tested for antibiotic susceptibility, analyzed by spa typing and clustered using a Based Upon Repeat Pattern (BURP) algorithm. The representative isolates of the four most common spa types and representative isolates of all spa clonal complexes were further typed by multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec (SCCmec) typing. The majority of MRSA strains were resistant to ciprofloxacin (94%), erythromycin (95.5%) and clindamycin (95.6%). Among the 618 strains analyzed, 52 different spa types were detected. BURP analysis divided them into six different clusters. The most common spa types were t003, t586, t014 and t002, all belonging to the CC5 (clonal complex). CC5 was the most abundant MLST CC of our study, comprising of 91.7% (n = 565) of spa-typeable isolates. Other CCs present in our study were CC398, CC22, CC8, CC45 and CC97. To our knowledge, this is the biggest nationwide study aimed at typing MRSA blood isolates from the Czech Republic.
Laparoscopic Liver Resection Should Be a Standard Procedure for Hepatocellular Carcinoma with Low or Intermediate Difficulty

Background: To investigate the feasibility of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC), we compared the outcome between LLR and conventional open liver resection (OLR) in patient groups with different IWATE criteria difficulty scores (DS). Methods: We retrospectively reviewed 607 primary HCC patients (LLR: 81, OLR: 526) who underwent liver resection in Linkou Chang Gung Memorial hospital from 2012 to 2019. By using 1:1 propensity score-matched (PSM) analysis, their baseline characteristics and the DS stratified by the IWATE criteria were matched between the LLR and OLR. Their perioperative and oncologic outcomes were compared. Results: After 1:1 PSM, 146 patients (73 in LLR, 73 in OLR) were analyzed. Among them, 13, 41, 13 and 6 patients were classified as low, intermediate, advanced and expert DS group, respectively. Compared to OLR, the LLR had shorter hospital stay (9.4 vs. 11.5 days, p = 0.071), less occurrence of surgical complications (16.4% vs. 30.1%, p = 0.049), lower rate of hepatic inflow control (42.5% vs. 65.8%, p = 0.005), and longer time of inflow control (70 vs. 51 min, p = 0.022). The disease-free survival (DFS) and overall survivals were comparable between the two groups. While stratified by the DS groups, the LLR tended to have lower complication rate and shorter hospital stay than OLR. The DFS of LLR in the intermediate DS group was superior to that of the OLR (p = 0.020). In the advanced and expert DS groups, there were no significant differences regarding outcomes between the two groups. Conclusion: We have demonstrated that with sufficient experience and technique, LLR for HCC is feasible and the perioperative outcome is favorable. Based on the current study, we suggest LLR should be a standard procedure for HCC with low or intermediate difficulty. It can provide satisfactory postoperative recovery and comparable oncological outcomes. Further larger scale prospective studies are warranted to validate our findings.
Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
Differences in Intestinal Barrier Development between Intrauterine Growth Restricted and Normal Birth Weight Piglets

Simple Summary Animals with intrauterine growth restriction (IUGR) are defined as neonates born at term but with low birth weight and a characteristic shape of the head. A number of structural and functional modifications in the IUGR intestine affecting its digestive and absorptive function and impairing intestinal barrier function have been reported in the past. Far less is known about the immune system in the gut of IUGR pigs. Therefore, the aim of the present study was to evaluate the structures of the immune system of the gut mucosa in IUGR neonates. We found that the immune deficiency in the gut mucosa that results from restricted intrauterine development occurs at postnatal day (PD) 7, but it disappears thereafter within a week. However, all examined IUGR piglets had an increased number of intraepithelial leukocytes in the gut mucosa on PD 14. We have shown that the immune system of the gut of IUGR piglets is able to quickly compensate for the immunological deficiency postnatally and hardly shows any morphological disabilities in later life. Abstract Intrauterine growth restricted (IUGR) piglets are born at term but have low birth mass and a characteristic shape of the head. Impaired general condition, especially in intestinal function, leads to an increase in the occurrence of diarrhoea and high mortality in the first days of life. So far, the mechanical and immunological gut barrier functions in IUGR are poorly understood. The aim of this study was to microscopically evaluate the early postnatal changes in the gut mucosa occurring in IUGR piglets. Whole-tissue small intestine samples were collected from littermate pairs (IUGR and normal) on postnatal day (PD) 7, 14 and 180 and analysed by light microscopy. We found that in the IUGR piglets, the percentage of intraepithelial leukocytes was reduced in the duodenum on PD 7, but it increased in the proximal and middle jejunum both on PD 7 and PD 14, which suggested the development of an inflammatory process. The number of goblet cells was also reduced on PD 14. The average size of the Peyer’s patches in the distal jejunum and ileum showed significant reduction on PD 7 as compared to normal pigs; however, on PD 14, it returned to normal. On PD 180, we did not find any differences in the measured parameters between the IUGR and the normal pigs. In conclusion, we found that in one-week-old IUGR pig neonates, the gut barrier and the immune system structures display signs of retarded development but recover within the second postnatal week of life.
Full-Genome Sequences and Phylogenetic Analysis of Archived Danish European Bat Lyssavirus 1 (EBLV-1) Emphasize a Higher Genetic Resolution and Spatial Segregation for Sublineage 1a

European bat lyssavirus type 1 (EBLV-1) is the causative agent for almost all reported rabies cases found in European bats. In recent years, increasing numbers of available EBLV-1 full genomes and their phylogenetic analyses helped to further elucidate the distribution and genetic characteristics of EBLV-1 and its two subtypes, namely EBLV-1a and EBLV-1b. Nonetheless, the absence of full-genome sequences from regions with known detections of EBLV-1 still limit the understanding of the phylogeographic relations between viruses from different European regions. In this study, a set of 21 archived Danish EBLV-1 samples from the years 1985 to 2009 was processed for the acquisition of full-genome sequences using a high-throughput sequencing approach. Subsequent phylogenetic analysis encompassing all available EBLV-1 full genomes from databases revealed the Danish sequences belong to the EBLV-1a subtype and further highlighted the distinct, close phylogenetic relationship of Danish, Dutch and German isolates in this region. In addition, the formation of five putative groups nearly exclusively formed by Danish isolates and the overall increased resolution of the EBLV-1a branch indicate a higher genetic diversity and spatial segregation for this sublineage than was previously known. These results emphasize the importance of phylogenetic analyses of full-genome sequences of lyssaviruses for genetic geography.
A Model-Informed Drug Development (MIDD) Approach for a Low Dose of Empagliflozin in Patients with Type 1 Diabetes

In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data.
An Improved Boundary-Aware U-Net for Ore Image Semantic Segmentation

Particle size is the most important index to reflect the crushing quality of ores, and the accuracy of particle size statistics directly affects the subsequent operation of mines. Accurate ore image segmentation is an important prerequisite to ensure the reliability of particle size statistics. However, given the diversity of the size and shape of ores, the influence of dust and light, the complex texture and shadows on the ore surface, and especially the adhesion between ores, it is difficult to segment ore images accurately, and under-segmentation can be a serious problem. The construction of a large, labeled dataset for complex and unclear conveyor belt ore images is also difficult. In response to these challenges, we propose a novel, multi-task learning network based on U-Net for ore image segmentation. To solve the problem of limited available training datasets and to improve the feature extraction ability of the model, an improved encoder based on Resnet18 is proposed. Different from the original U-Net, our model decoder includes a boundary subnetwork for boundary detection and a mask subnetwork for mask segmentation, and information of the two subnetworks is fused in a boundary mask fusion block (BMFB). The experimental results showed that the pixel accuracy, Intersection over Union (IOU) for the ore mask (IOU_M), IOU for the ore boundary (IOU_B), and error of the average statistical ore particle size (ASE) rate of our proposed model on the testing dataset were 92.07%, 86.95%, 52.32%, and 20.38%, respectively. Compared to the benchmark U-Net, the improvements were 0.65%, 1.01%, 5.78%, and 12.11% (down), respectively.
Association between Periodontal Disease and Systemic Inflammatory Conditions Using Electronic Health Records: A Pilot Study

Aims: To investigate the association between periodontal disease and systemic inflammatory conditions and examine the link between medical conditions and the extent of missing teeth in a large population. Methods: In this retrospective study, a total of 4890 randomly selected patients who had attended the University of Minnesota dental clinics were analyzed. Severity of periodontal disease was determined based on the percentage of bone loss, evaluated through the examination of a full-mouth intraoral series of radiographs. The number of missing teeth was calculated from the examined radiographs, while ten systemic inflammatory conditions were extracted from patients’ self-reported medical histories. Results: Moderate bone loss was observed in 730 (14.9%) and severe in 323 (6.6%) patients of the total population, while the mean number of missing teeth was 3.54 ± 3.93. The prevalence of systemic conditions and tobacco use were gender-dependent (p < 0.05). Regression analysis showed that hypertension, arthritis, asthma, diabetes and HIV were associated significantly with the severity of bone loss, while diabetes and lupus with the extent of missing teeth. Conclusions: The findings reported in our study add to this body of knowledge, strengthening the association between periodontal disease with systemic inflammatory conditions.
Role of D-Mannose in the Prevention of Recurrent Uncomplicated Cystitis: State of the Art and Future Perspectives

Background: Urinary tract infections (UTI) are highly frequent in women, with a significant impact on healthcare resources. Although antibiotics still represent the standard treatment to manage recurrent UTI (rUTI), D-mannose, an inert monosaccharide that is metabolized and excreted in urine and acts by inhibiting bacterial adhesion to the urothelium, represents a promising nonantibiotic prevention strategy. The aim of this narrative review is to critically analyze clinical studies reporting data concerning the efficacy and safety of D-mannose in the management of rUTIs. Methods: A non-systematic literature search, using the Pubmed, EMBASE, Scopus, Web of science, Cochrane Central Register of Controlled Trials, and Cochrane Central Database of Systematic Reviews databases, was performed for relevant articles published between January 2010 and January 2021. The following Medical Subjects Heading were used: “female/woman”, “urinary tract infection”, and “D-mannose”. Only clinical studies, systematic reviews, and meta-analyses reporting efficacy or safety data on D-mannose versus placebo or other competitors were selected for the present review. Evidence was limited to human data. The selected studies were organized in two categories according to the presence or not of a competitor to D-mannose. Results: After exclusion of non-pertinent studies/articles, 13 studies were analyzed. In detail, six were randomized controlled trials (RCTs), one a randomized cross-over trial, five prospective cohort studies, and one a retrospective analysis. Seven studies compared D-mannose to placebo or others drugs/dietary supplements. Six studies evaluated the efficacy of D-mannose comparing follow-up data with the baseline. D-mannose is well tolerated, with few reported adverse events (diarrhea was reported in about 8% of patients receiving 2 g of D-mannose for at least 6 months). Most of the studies also showed D-mannose can play a role in the prevention or rUTI or urodynamics-associated UTI and can overlap antibiotic treatments in some cases. The possibility to combine D-mannose with polyphenols or Lactobacillus seems another important option for UTI prophylaxis. However, the quality of the collected studies was very low, generating, consequently, a weak grade of recommendations as suggested by international guidelines. Data on D-mannose dose, frequency, and duration of treatment are still lacking. Conclusion: D-mannose alone or in combination with several dietary supplements or Lactobacillus has a potential role in the non antimicrobial prophylaxis or recurrent UTI in women. Despite its frequent prescription in real-life practice, we believe that further well-designed studies are urgently needed to definitively support the role of D-mannose in the management of recurrent UTIs in women.
Screening of Lactic Acid Bacteria for the Bio-Control of Botrytis cinerea and the Potential of Lactiplantibacillus plantarum for Eco-Friendly Preservation of Fresh-Cut Kiwifruit

Botrytis cinerea, responsible for grey mold, represents the first biological cause of fruit and vegetable spoilage phenomena in post-harvest. Kiwifruit is a climacteric fruit particularly prone to this mold infestation during storage. Lactic acid bacteria (LAB) are food-grade bacteria that can synthesize several metabolites with antimicrobial activity and are, therefore, suggested as promising and eco-friendly resources for the bio-control of molds on fruits and vegetables. In this work, we propose the screening of a collection of 300 LAB previously isolated from traditional sourdoughs for their ability to counteract in vitro the growth of Botrytis cinerea CECT 20973. Only 2% of tested LAB strains belonging to Lactiplantibacillus plantarum species, exerted a strong antagonism against B. cinerea. The cell-free supernatants were partially characterized and results clearly indicated that high levels of lactic acid contributed to the antagonistic activity. PAN01 and UFG 121 cell-free supernatants were investigated as potential bio-control agents in a preliminary in vivo assay using freshly cut kiwifruits as a food model. The application of cell-free supernatants allowed to delay the growth of B. cinerea on artificially contaminated kiwifruits until two weeks. The antagonistic activity was greatly affected by the storage temperature (25 °C and 4 °C) selected for the processed fruits, suggesting the importance to include microbial-based solution in a broader framework of hurdle technologies.
Treatment of Rice Stubble with Pleurotus ostreatus and Urea Improves the Growth Performance in Slow-Growing Goats

Simple Summary Fungi treatment is well established as a promising approach to upgrade the nutritional value of lignocellulosic biomass. This potency of fungi treatment is, however, primarily based on in vitro experiments, and extrapolation to practice is currently hindered, owing to a dearth of studies addressing the practical relevance of fungal treatment of high-fiber feed, such as rice straw and rice stubble. These potential biomasses are rife in Southeast Asian countries, coinciding with increasing rice production; however, it remains a big challenge to utilize rice stubble as a potential feed for ruminants. Similar to rice straw, rice stubble is traditionally eliminated through controlled burning, which is harmful to the environment. The aim of this study was to convert rice stubble into a new animal feed capable of increasing environmental friendliness. Using urea, it is well known to modify the lignification or silicification of lignocellulosic biomass. However, it remains scanty in combination with fungi treatment. Therefore, we treated rice stubble with either urea or oyster fungus (Pleurotus ostreatus) or a combination of these two treatments and offered these treated rice stubbles to slow-growing goats with the objective to study their effect on feed intake, digestibility, and fermentation end-products. Abstract The objective of this study was to evaluate the efficacy of the fungal treatment (Pleurotus ostreatus) of urea-treated rice stubble on growth performance in slow-growing goats. Eighteen crossbred Thai-native x Anglo-Nubian male goats (average body weight: 20.4 ± 2.0 kg) were randomly assigned to three experimental total mixed rations containing 35% rice stubble (RS) that were either untreated (URS), urea treated (UTRS), or treated with urea and fungi (UFTRS). URS and UTRS were cultivated and harvested from an aseptically fungal spawn, incubated at 25–30 °C for 25 days. Indicators of growth performance were monitored, and feces were collected quantitatively to assess nutrient digestibility, during a 12-week feeding trial. All goats remained healthy throughout the experiment. The goats fed UFTRS had a lower feed conversion ratio (kg feed/kg growth) compared to goats fed URS or UTRS. Compared to URS, dietary UFTRS increased the nutrient digestibility of slow-growing goats, such as organic matter (OM) (+8.5%), crude protein (CP) (+5.5%), neutral detergent fiber (NDF) (+39.2%), and acid detergent fiber (ADF) (+27.4%). Likewise, dietary UFTRS tended to increase rumen ammonia concentrations, but rumen pH and volatile fatty acids were not affected by UFTRS. In conclusion, the present study indicates that the fungal treatment of RS is an effective tool to improve the growth performance of slow-growing goats.
Colonic Stenting in the Emergency Setting

Nowadays, colorectal cancer (CRC) is the third most frequent cancer, and about a third of patients with CRC presents themselves with symptoms of large bowel obstruction. Historically, surgical resection was the treatment of choice for colonic obstruction, but this kind of approach is burdened by a high risk of postoperative morbidity and mortality. In recent times, the use of a colonic stent has been proposed to overcome the obstruction and transform an emergency surgical case into an elective one to avoid emergency surgery complications. Endoscopic stenting is the first-line treatment option in the palliative management of colonic obstruction, and there is sufficient scientific evidence to support this approach. However, endoscopic stent used as a bridge to surgery is not yet widely adopted because the concern was raised about the long-term survival and cancer safety of this approach. The recent scientific evidence has shown that this approach improves the short-term outcomes, such as postoperative complications and the stoma rate, without differences in long-term outcomes compared to emergency surgery. Therefore, the European Society for Gastrointestinal Endoscopy in 2020 has reconsidered stenting as a bridge to surgery as a valid alternative to emergency surgery.