bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD271 activation prevents low to high-risk progression of cutaneous squamous cell carcinoma and improves therapy outcomes
Authors: Quadri Marika , Tiso Natascia , Musmeci Francesco , Morasso Maria I. , Brooks Stephen R. , Bonetti Luca Reggiani , Panini Rossana , Lotti Roberta , Marconi Alessandra , Pincelli Carlo , Palazzo Elisabetta 
Published: July 2023

Abstract
Background
Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer, showing a rapid increasing incidence worldwide. Although most cSCC can be cured by surgery, a sizeable number of cases are diagnosed at advanced stages, with local invasion and distant metastatic lesions. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk) form a complex network regulating epidermal homeostasis. Recently, several works suggested a significant implication of NT receptors in cancer. However, CD271 functions in epithelial tumors are controversial and its precise role in cSCC is still to be defined.

Methods
Spheroids from cSCC patients with low-risk (In situ or Well-Differentiated cSCC) or high-risk tumors (Moderately/Poorly Differentiated cSCC), were established to explore histological features, proliferation, invasion abilities, and molecular pathways modulated in response to CD271 overexpression or activation in vitro. The effect of CD271 activities on the response to therapeutics was also investigated. The impact on the metastatic process and inflammation was explored in vivo and in vitro, by using zebrafish xenograft and 2D/3D models.

Results
Our data proved that CD271 is upregulated in Well-Differentiated tumors as compared to the more aggressive Moderately/Poorly Differentiated cSCC, both in vivo and in vitro. We demonstrated that CD271 activities reduce proliferation and malignancy marker expression in patient-derived cSCC spheroids at each tumor grade, by increasing neoplastic cell differentiation. CD271 overexpression significantly increases cSCC spheroid mass density, while it reduces their weight and diameter, and promotes a major fold-enrichment in differentiation and keratinization genes. Moreover, both CD271 overexpression and activation decrease cSCC cell invasiveness in vitro. A significant inhibition of the metastatic process by CD271 was observed in a newly established zebrafish cSCC model. We found that the recruitment of leucocytes by CD271-overexpressing cells directly correlates with tumor killing and this finding was further highlighted by monocyte infiltration in a THP-1-SCC13 3D model. Finally, CD271 activity synergizes with Trk receptor inhibition, by reducing spheroid viability, and significantly improves the outcome of photodynamic therapy (PTD) or chemotherapy in spheroids and zebrafish.

Conclusion
Our study provides evidence that CD271 could prevent the switch between low to high-risk cSCC tumors. Because CD271 contributes to maintaining active differentiative paths and favors the response to therapies, it might be a promising target for future pharmaceutical development.
ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden
Authors: Sharo Andrew G. , Zou Yangyun , Adhikari Aashish N. , Brenner Steven E. 
Published: July 2023

Abstract
Background
Curated databases of genetic variants assist clinicians and researchers in interpreting genetic variation. Yet, these databases contain some misclassified variants. It is unclear whether variant misclassification is abating as these databases rapidly grow and implement new guidelines.

Methods
Using archives of ClinVar and HGMD, we investigated how variant misclassification has changed over 6 years, across different ancestry groups. We considered inborn errors of metabolism (IEMs) screened in newborns as a model system because these disorders are often highly penetrant with neonatal phenotypes. We used samples from the 1000 Genomes Project (1KGP) to identify individuals with genotypes that were classified by the databases as pathogenic. Due to the rarity of IEMs, nearly all such classified pathogenic genotypes indicate likely variant misclassification in ClinVar or HGMD.

Results
While the false-positive rates of both ClinVar and HGMD have improved over time, HGMD variants currently imply two orders of magnitude more affected individuals in 1KGP than ClinVar variants. We observed that African ancestry individuals have a significantly increased chance of being incorrectly indicated to be affected by a screened IEM when HGMD variants are used. However, this bias affecting genomes of African ancestry was no longer significant once common variants were removed in accordance with recent variant classification guidelines. We discovered that ClinVar variants classified as Pathogenic or Likely Pathogenic are reclassified sixfold more often than DM or DM? variants in HGMD, which has likely resulted in ClinVar’s lower false-positive rate.

Conclusions
Considering misclassified variants that have since been reclassified reveals our increasing understanding of rare genetic variation. We found that variant classification guidelines and allele frequency databases comprising genetically diverse samples are important factors in reclassification. We also discovered that ClinVar variants common in European and South Asian individuals were more likely to be reclassified to a lower confidence category, perhaps due to an increased chance of these variants being classified by multiple submitters. We discuss features for variant classification databases that would support their continued improvement.
Synthesis and preclinical evaluation of a novel fluorine-18 labeled small-molecule PET radiotracer for imaging of CXCR3 receptor in mouse models of atherosclerosis
Authors: Alluri Santosh R. , Higashi Yusuke , Berendzen Ashley , Grisanti Laurel A. , Watkinson Lisa D. , Singh Kamlendra , Hoffman Timothy J. , Carmack Terry , Devanny Elizabeth A. , Tanner Miles , Kil Kun-Eek 
Published: July 2023

Abstract
Background
CXCR3 is a chemokine receptor and is expressed in innate and adaptive immune cells. It promotes the recruitment of T-lymphocytes and other immune cells to the inflammatory site in response to the binding of cognate chemokines. Upregulation of CXCR3 and its chemokines has been found during atherosclerotic lesion formation. Therefore, detection of CXCR3 by positron emission tomography (PET) radiotracer can be a useful tool for detecting the development of atherosclerosis in a noninvasive manner. Herein, we report the synthesis, radiosynthesis, and characterization of a novel fluorine-18 (F-18, 18F) labeled small-molecule radiotracer for the imaging of the CXCR3 receptor in mouse models of atherosclerosis.

Results
The reference standard 1 and its precursor 9 were synthesized over 5 steps from starting materials in good to moderate yields. The measured Ki values of CXCR3A and CXCR3B were 0.81 ± 0.02 nM and 0.31 ± 0.02 nM, respectively. [18F]1 was prepared by a two-step radiosynthesis with a decay-corrected radiochemical yield of 13 ± 2%, radiochemical purity > 99%, and specific activity of 44.4 ± 3.7 GBq/µmol at the end of synthesis (n = 6). The baseline studies showed that [18F]1 displayed high uptake in the atherosclerotic aorta and brown adipose tissue in Apolipoprotein E (ApoE) knockout (KO) mice fed with a high-fat diet over 12 weeks. The uptake of [18F]1 in these regions was reduced significantly in self-blocking studies, demonstrating CXCR3 binding specificity. Contrary to this, no significant differences in uptake of [18F]1 in the abdominal aorta of C57BL/6 control mice fed with a normal diet were observed in both baseline and blocking studies, indicating increased CXCR3 expression in atherosclerotic lesions. Immunohistochemistry studies demonstrated that [18F]1-positive regions were correlated with CXCR3 expression, but some atherosclerotic plaques with significant size were not detected by [18F]1, and their CXCR3 expressions were minimal.

Conclusion
[18F]1 was synthesized with good radiochemical yield and high radiochemical purity. In PET imaging studies, [18F]1 displayed CXCR3-specific uptake in the atherosclerotic aorta in ApoE KO mice. [18F]1 visualized CXCR3 expression in different regions in mice aligned with the tissue histology studies. Taken together, [18F]1 is a potential PET radiotracer for imaging CXCR3 in atherosclerosis.
Anthelmintic activity of European fern extracts against Haemonchus contortus
Authors: Pavičić Antonio , Zajíčková Markéta , Šadibolová Michaela , Svobodová Gabriela , Matoušková Petra , Szotáková Barbora , Langhansová Lenka , Maršík Petr , Skálová Lenka 
Published: July 2023

AbstractMost drugs used in the treatment of helminthiasis in humans and animals have lost their efficacy due to the development of drug-resistance in helminths. Moreover, since anthelmintics, like many pharmaceuticals, are now recognized as hazardous contaminants of the environment, returning to medicinal plants and their products represents an environmentally friendly way to treat helminthiasis. The goal of the present study was to test the anthelminthic activity of methanol extracts of eight selected European ferns from the genera Dryopteris, Athyrium and Blechnum against the nematode Haemonchus contortus, a widespread parasite of small ruminants. Eggs and adults of H. contortus drug-susceptible strain ISE and drug-resistant strain WR were isolated from experimentally infected sheep. The efficacy of fern extracts was assayed using egg hatch test and adults viability test based on ATP-level measurement. Among the ferns tested, only Dryopteris aemula extract (0.2 mg/mL) inhibited eggs hatching by 25% in comparison to control. Athyrium distentifolium, Dryopteris aemula and Dryopteris cambrensis were effective against H. contortus adults. In concentration 0.1 mg/mL, A. distentifolium, D. aemula, D. cambrensis significantly decreased the viability of females from ISE and WR strains to 36.2%, 51.9%, 32.9% and to 35.3%, 27.0%, 23.3%, respectively in comparison to untreated controls. None of the extracts exhibited toxicity in precise cut slices from ovine liver. Polyphenol’s analysis identified quercetin, kaempferol, luteolin, 3-hydroxybenzoic acid, caffeic acid, coumaric acid and protocatechuic acid as the major components of these anthelmintically active ferns.
Multi-headed deep learning-based estimator for correlated-SIRV Pareto type II distributed clutter
Authors: Kerbaa Taha Hocine , Mezache Amar , Gini Fulvio , Greco Maria S. 
Published: July 2023

AbstractThis paper deals with the problem of estimating the parameters of heavy-tailed sea clutter in high-resolution radar, when the clutter is modeled by the correlated Pareto type II distribution. Existing estimators based on the maximum likelihood (ML) approach, integer-order moments (IOM) approach, fractional-order moments (FOM), and log-moments (log-MoM) have shown to be sensitive to changes in data correlation. In this work, we resort to a deep learning (DL) approach based on a multi-headed architecture to overcome this problem. Offline training of the artificial neural networks (ANN) is carried out by using several combinations of the clutter parameters, with different correlation degrees. To assess the performance of the proposed estimator, we resort to Monte Carlo simulation, and we observed that it has superior performance over existing approaches in terms of estimation mean square error (MSE) and robustness to changes of the clutter correlation coefficient.
A systematic literature review of economic evaluation studies of interventions impacting antimicrobial resistance
Authors: Painter Chris , Faradiba Dian , Chavarina Kinanti Khansa , Sari Ella Nanda , Teerawattananon Yot , Aluzaite Kristina , Ananthakrishnan Aparna 
Published: July 2023

Abstract
Background
Antimicrobial resistance (AMR) is accelerated by widespread and inappropriate use of antimicrobials. Many countries, including those in low- and middle- income contexts, have started implementing interventions to tackle AMR. However, for many interventions there is little or no economic evidence with respect to their cost-effectiveness. To help better understand the scale of this evidence gap, we conducted a systematic literature review to provide a comprehensive summary on the value for money of different interventions affecting AMR.

Methods
A systematic literature review was conducted of economic evaluations on interventions addressing AMR. a narrative synthesis of findings was produced. Systematic searches for relevant studies were performed across relevant databases and grey literature sources such as unpublished studies, reports, and other relevant documents. All identified economic evaluation studies were included provided that they reported an economic outcome and stated that the analysed intervention aimed to affect AMR or antimicrobial use in the abstract. Studies that reported clinical endpoints alone were excluded. Selection for final inclusion and data extraction was performed by two independent reviewers. A quality assessment of the evidence used in the included studies was also conducted.

Results
28,597 articles were screened and 35 articles were identified that satisfied the inclusion criteria. The review attempted to answer the following questions: (1) What interventions to address AMR have been the subject of an economic evaluation? (2) In what types of setting (e.g. high-income, low-income, regions etc.) have these economic evaluations been focused? (3) Which interventions have been estimated to be cost-effective, and has this result been replicated in other settings/contexts? (4) What economic evaluation methods or techniques have been used to evaluate these interventions? (5) What kind and quality of data has been used in conducting economic evaluations for these interventions?

Discussion
The review is one of the first of its kind, and the most recent, to systematically review the literature on the cost-effectiveness of AMR interventions. This review addresses an important evidence gap in the economics of AMR and can assist AMR researchers’ understanding of the state of the economic evaluation literature, and therefore inform future research.
Systematic review registration PROSPERO (CRD42020190310).
Dietary bile acid supplementation in weaned piglets with intrauterine growth retardation improves colonic microbiota, metabolic activity, and epithelial function
Authors: Liu Yang , Azad Md. Abul Kalam , Ding Sujuan , Zhu Qian , Blachier Francois , Yu Zugong , Gao Haijun , Kong Xiangfeng 
Published: July 2023

Abstract
Background
Intrauterine growth retardation (IUGR) is one of the major constraints in animal production. Our previous study showed that piglets with IUGR are associated with abnormal bile acid (BA) metabolism. This study explored whether dietary BA supplementation could improve growth performance and colonic development, function, microbiota, and metabolites in the normal birth weight (NBW) and IUGR piglets. A total of 48 weaned piglets (24 IUGR and 24 NBW) were allocated to four groups (12 piglets per group): (i) NBW group, (ii) NBW + BA group, (iii) IUGR group, and (iv) IUGR + BA group. Samples were collected after 28 days of feeding.

Results
The results showed that dietary BA supplementation increased the length and weight of the colon and colon weight to body weight ratio, while decreased the plasma diamine oxidase (DAO) concentration in the NBW piglets (P < 0.05). Dietary BA supplementation to IUGR piglets decreased (P < 0.05) the plasma concentrations of D-lactate and endotoxin and colonic DAO and endotoxin, suggesting a beneficial effect on epithelial integrity. Moreover, dietary BA supplementation to NBW and IUGR piglets increased Firmicutes abundance and decreased Bacteroidetes abundance (P < 0.05), whereas Lactobacillus was the dominant genus in the colon. Metabolome analysis revealed 65 and 51 differential metabolites in the colon of piglets fed a diet with/without BA, respectively, which was associated with the colonic function of IUGR piglets. Furthermore, dietary BA supplementation to IUGR piglets upregulated the expressions of CAT, GPX, SOD, Nrf1, IL-2, and IFN-γ in colonic mucosa (P < 0.05).

Conclusions
Collectively, dietary BA supplementation could improve the colonic function of IUGR piglets, which was associated with increasing proportions of potentially beneficial bacteria and metabolites. Furthermore, BA shows a promising application prospect in improving the intestinal ecosystem and health of animals.
BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells
Authors: Zhong Jiamin , Tian Luyao , Gou Yannian , Zhao Piao , Dong Xiangyu , Guo Meichun , Zhao Guozhi , Li Aohua , Hao Ailing , He Tong-Chuan , Fan Jiaming 
Published: July 2023

AbstractBackgroundExcessive hepatic glycogen accumulation benefits tumorigenesis and cancer cell survival. We previously reported that BMP4 has the strongest ability to promote glycogenesis among the 14 BMPs in hepatocytes and augmented hepatocellular carcinoma (HCC) cell survival under hypoxia and hypoglycemia conditions by promoting the glycolysis pathway. However, the mechanism underlying BMP4’s effect on glycogenesis in HCC remains elusive.MethodsThe expression of BMP4 and SLC2A1 were acquired by analyzing the TCGA-LIHC dataset, as well as by immunohistochemical analysis of the 40 pairs of human HCC samples and para-tumor tissues. Gene expressions were detected by qPCR, immunoflurorescence staining, and Western blotting. Overexpression and silencing of BMP4 were accomplished through adenoviruses Ad-B4 and Ad-siB4 infection. Hepatic glycogen was detected by PAS staining. SLC2A1 (GLUT1) function was blocked by the inhibitor BAY-876. ChIP assay was used to determine the binding of SMADs to the promoter region of SLC2A1 in HCC cells. Lastly, the in vivo effect of BMP4-regulated SLC2A1 on HCC tumor growth was assessed in a xenograft model of HCC.ResultsThe elevated expression of BMP4 in HCC tumor tissues was highly correlated with hepatic glycogen accumulation in clinical samples. SLC2A1 was highly expressed in HCC tumor tissue and correlated with clinical stage and prognosis. Exogenous BMP4 augmented glycogen accumulation and upregulated the expression of glycogen synthesis-related genes in Huh7 and HepG2 cells, both of which were effectively blunted by SLC2A1inhibitor BAY-876. In mechanism, BMP4 activated SMAD5 to regulate the promoter of SLC2A1to enhance its expression. The in vivo xenograft experiments revealed that BMP4 promoted glycogen accumulation and tumor growth, which were effectively diminished by BAY-876.ConclusionThese results demonstrate that BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in HCC cells, which may be exploited as novel therapeutic targets for HCC treatment.
Hydroxylases involved in terpenoid biosynthesis: a review
Authors: Zhang Zihan , Wu Qing-Yang , Ge Yue , Huang Zheng-Yu , Hong Ran , Li Aitao , Xu Jian-He , Yu Hui-Lei 
Published: July 2023

AbstractTerpenoids are pervasive in nature and display an immense structural diversity. As the largest category of plant secondary metabolites, terpenoids have important socioeconomic value in the fields of pharmaceuticals, spices, and food manufacturing. The biosynthesis of terpenoid skeletons has made great progress, but the subsequent modifications of the terpenoid framework are poorly understood, especially for the functionalization of inert carbon skeleton usually catalyzed by hydroxylases. Hydroxylase is a class of enzymes that plays an important role in the modification of terpenoid backbone. This review article outlines the research progress in the identification, molecular modification, and functional expression of this class of enzymes in the past decade, which are profitable for the discovery, engineering, and application of more hydroxylases involved in the plant secondary metabolism.
Graphical Abstract
Diagnostic accuracy of a rapid nucleic acid test for group A streptococcal pharyngitis using saliva samples: protocol for a prospective multicenter study in primary care
Authors: Touitou Robert , Bidet Philippe , Dubois Constance , Partouche Henri , Bonacorsi Stéphane , Jung Camille , Cohen Robert , Levy Corinne , Cohen Jérémie F. 
Published: July 2023

Abstract
Background
Group A streptococcus is found in 20–40% of cases of childhood pharyngitis; the remaining cases are viral. Streptococcal pharyngitis (“strep throat”) is usually treated with antibiotics, while these are not indicated in viral cases. Most guidelines recommend relying on a diagnostic test confirming the presence of group A streptococcus before prescribing antibiotics. Conventional first-line tests are rapid antigen detection tests based on throat swabs. Recently, rapid nucleic acid tests were developed; they allow the detection of elements of the genome of group A streptococcus. We hypothesize that these rapid nucleic acid tests are sensitive enough to be performed on saliva samples instead of throat swabs, which could be more convenient in practice.

Methods
This is a multicenter, prospective diagnostic accuracy study evaluating the performance of a rapid nucleic acid test for group A streptococcus (Abbott ID NOW STREP A2) in saliva, compared with a conventional pharyngeal rapid antigen detection test (EXACTO PRO STREPTATEST, lateral flow assay, comparator test), with a composite reference standard of throat culture and group A streptococcus PCR in children with pharyngitis in primary care (i.e., 27 primary care pediatricians or general practitioners). To ensure group A streptococcus is not missed, the salivary rapid nucleic acid test requires a minimally acceptable value of sensitivity (primary outcome) set at 80%. Assuming 35% of participants will have group A streptococcus, we will recruit 800 consecutive children with pharyngitis. Secondary outcomes will include difference in sensitivity between the pharyngeal rapid antigen detection test and the salivary rapid nucleic acid test; variability in sensitivity and specificity of the salivary rapid nucleic acid test with the level of McIsaac score; time to obtain the result of the salivary rapid nucleic acid test; patient, physician, and parents satisfaction; and barriers and facilitators to using rapid tests for group A streptococcus in primary care.

Ethics and dissemination
Approved by the Institutional Review Board “Comité de protection des personnes Ile de France I” (no. 2022-A00085-38). Results will be presented at international meetings and disseminated in peer-reviewed journals.

Trial registration number
ClinicalTrials.gov: NCT05521568.