bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Leishmania major infection on the gut microbiome of resistant and susceptible mice
Authors: Mrázek Jakub , Mrázková Lucie , Mekadim Chahrazed , Jarošíková Taťána , Krayem Imtissal , Sohrabi Yahya , Demant Peter , Lipoldová Marie 
Published: January 2024

Abstract
Cutaneous leishmaniasis, a parasitic disease caused by Leishmania major, is a widely frequent form in humans. To explore the importance of the host gut microbiota and to investigate its changes during L. major infection, two different groups of mouse models were assessed. The microbiome of two parts of the host gut—ileum and colon—from infected and non-infected mice were characterised by sequencing of 16S rDNA using an Ion Torrent PGM platform. Microbiome analysis was performed to reveal changes related to the susceptibility and the genetics of mice strains in two different gut compartments and to compare the results between infected and non-infected mice. The results showed that Leishmania infection affects mainly the ileum microbiota, whereas the colon bacterial community was more stable. Different biomarkers were determined in the gut microbiota of infected resistant mice and infected susceptible mice using LEfSe analysis. Lactobacillaceae was associated with resistance in the colon microbiota of all resistant mice strains infected with L. major. Genes related to xenobiotic biodegradation and metabolism and amino acid metabolism were primarily enriched in the small intestine microbiome of resistant strains, while genes associated with carbohydrate metabolism and glycan biosynthesis and metabolism were most abundant in the gut microbiome of the infected susceptible mice. These results should improve our understanding of host-parasite interaction and provide important insights into the effect of leishmaniasis on the gut microbiota. Also, this study highlights the role of host genetic variation in shaping the diversity and composition of the gut microbiome.

Key points
• Leishmaniasis may affect mainly the ileum microbiota while colon microbiota was more stable.
• Biomarkers related with resistance or susceptibility were determined in the gut microbiota of mice.
• Several pathways were predicted to be upregulated in the gut microbiota of resistant or susceptible mice.

Graphical Abstract
Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3
Authors: Eichholz Thomas , Heubach Florian , Arendt Anne-Marie , Seitz Christian , Brecht Ines B. , Ebinger Martin , Flaadt Tim , Süsskind Daniela , Richter Lisa , Hülsenbeck Isabel , Zerweck Leonie , Göricke Sophia , Paulsen Frank , Dombrowski Frank , Flotho Christian , Schönberger Stefan , Ketteler Petra , Schulte Johannes , Lang Peter 
Published: January 2024

Abstract
Background
GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors.

Methods
The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed.

Results
We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated.

Conclusion
Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.
Phellinus linteus activates Treg cells via FAK to promote M2 macrophage polarization in hepatocellular carcinoma
Authors: Chen Feihua , Gong Mouchun , Weng Dengcheng , Jin Zhaoqing , Han Guofeng , Yang Ziqiang , Han Junjun , Wang Jianjiang 
Published: January 2024

AbstractHepatocellular carcinoma (HCC) is the most prevalent malignant tumor worldwide. Within HCC's tumor microenvironment, focal adhesion kinase (FAK) plays a critical role. Regulatory T cells (Treg) modulate the polarization of tumor-associated macrophages , but the relationship between FAK, Treg cells, and macrophages remains underexplored. Phellinus linteus (PL) shows promise as a treatment for HCC due to its pharmacological effects. This study aimed to explore the relationship between FAK and Treg-macrophages and to assess whether PL could exert a protective effect through the FAK process in HCC. Initially, C57BL/6-FAK−/− tumor-bearing mice were utilized to demonstrate that FAK stimulates HCC tumor development. High dosages (200 μM) of FAK and the FAK activator ZINC40099027 led to an increase in Treg (CD4+CD25+) cells, a decrease in M1 macrophages (F4/80+CD16/32+, IL-12, IL-2, iNOS), and an increase in M2 macrophages (F4/80+CD206+, IL-4, IL-10, Arg1, TGF-β1). Additionally, FAK was found to encourage cell proliferation, migration, invasion, and epithelial-mesenchymal transition while inhibiting apoptosis in HepG2 and SMMC7721 cells. These effects were mediated by the PI3K/AKT1/Janus Kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase (p38 MAPK)/Jun N-terminal Kinase (JNK) signaling pathways. Furthermore, PL exhibited a potent antitumor effect in vivo in a dose-dependent manner, reducing FAK, Treg cells, and M2 macrophages, while increasing M1 macrophages. This effect was achieved through the inhibition of the PI3K/AKT/JAK/STAT3, and p38/JNK pathways. Overall, our findings suggest that FAK promotes HCC via Treg cells that polarize macrophages toward the M2 type through specific signaling pathways. PL, acting through FAK, could be a protective therapy against HCC.
Compatible Spanning Circuits and Forbidden Induced Subgraphs
Authors: Guo Zhiwei , Brause Christoph , Geißer Maximilian , Schiermeyer Ingo 
Published: January 2024

AbstractA compatible spanning circuit in an edge-colored graph G (not necessarily properly) is defined as a closed trail containing all vertices of G in which any two consecutively traversed edges have distinct colors. The existence of extremal compatible spanning circuits (i.e., compatible Hamilton cycles and compatible Euler tours) has been studied extensively. Recently, sufficient conditions for the existence of compatible spanning circuits visiting each vertex at least a specified number of times in specific edge-colored graphs satisfying certain degree conditions have been established. In this paper, we continue the research on sufficient conditions for the existence of such compatible s-panning circuits. We consider edge-colored graphs containing no certain forbidden induced subgraphs. As applications, we also consider the existence of such compatible spanning circuits in edge-colored graphs G with κ(G) ≥ α(G), κ(G) ≥ α(G) − 1 and κ (G) ≥ α(G), respectively. In this context, κ(G), α(G) and κ (G) denote the connectivity, the independence number and the edge connectivity of a graph G, respectively.
Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden
Authors: Bentivenga Giuseppe Mario , Mammana Angela , Baiardi Simone , Rossi Marcello , Ticca Alice , Magliocchetti Franco , Mastrangelo Andrea , Poleggi Anna , Ladogana Anna , Capellari Sabina , Parchi Piero 
Published: January 2024

AbstractThe development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein (αSyn) in cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance in early pathological stages or low Lewy body (LB) pathology load has only been assessed in small cohorts. Moreover, the relationship between SAA kinetic parameters, the number of αSyn brain seeds and the LB pathology burden assessed by immunohistochemistry has never been systematically investigated. We tested 269 antemortem CSF samples and 138 serially diluted brain homogenates from patients with and without neuropathological evidence of LBD in different stages by the αSyn Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. Moreover, we looked for LB pathology by αSyn immunohistochemistry in a consecutive series of 604 Creutzfeldt–Jakob disease (CJD)-affected brains. αSyn CSF RT-QuIC showed 100% sensitivity in detecting LBD in limbic and neocortical stages. The assay sensitivity was significantly lower in patients in early stages (37.5% in Braak 1 and 2, 73.3% in Braak 3) or with focal pathology (50% in amygdala-predominant). The average number of CSF RT-QuIC positive replicates significantly correlated with LBD stage. Brain homogenate RT-QuIC showed higher sensitivity than immunohistochemistry for the detection of misfolded αSyn. In the latter, the kinetic parameter lag phase (time to reach the positive threshold) strongly correlated with the αSyn seed concentration in serial dilution experiments. Finally, incidental LBD prevalence was 8% in the CJD cohort. The present results indicate that (a) CSF RT-QuIC has high specificity and sufficient sensitivity to detect all patients with LB pathology at Braak stages > 3 and most of those at stage 3; (b) brain deposition of misfolded αSyn precedes the formation of LB and Lewy neurites; (c) αSyn SAA provides “quantitative” information regarding the LB pathology burden, with the lag phase and the number of positive replicates being the most promising variables to be used in the clinical setting.
Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2
Authors: Kleefeld Felix , Horvath Rita , Pinal-Fernandez Iago , Mammen Andrew L. , Casal-Dominguez Maria , Hathazi Denisa , Melchert Sarah , Hahn Katrin , Sickmann Albert , Muselmann-Genschow Claudia , Hentschel Andreas , Preuße Corinna , Roos Andreas , Schoser Benedikt , Stenzel Werner 
Published: January 2024

AbstractMyotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.
Efficacy of CDK4/6 inhibitors combined with endocrine therapy in HR+/HER2− breast cancer: an umbrella review
Authors: Pu Dongqing , Xu Debo , Wu Yue , Chen Hanhan , Shi Guangxi , Feng Dandan , Zhang Mengdi , Liu Zhiyong , Li Jingwei 
Published: January 2024

Abstract
Background
The use of Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors has profoundly changed the challenge of endocrine therapy (ET) resistance in hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, there is currently no comprehensive evaluation of the evidence for the efficacy of CDK4/6 inhibitors. We conducted an umbrella review to explore the impact of CDK4/6 inhibitor combined with ET on breast cancer by summarizing and assessing the meta-analysis (MA) and systematic review (SR) evidence.

Methods
Cochrane, PubMed, Embase, and Web of Science databases were searched from inception to August 1st, 2022. Eligible studies were assessed for methodological quality, report quality, and evidence quality using the AMSTAR-2 scale, PRISMA 2020, and GRADE grading systems, respectively. We summarized all efficacy outcomes of CDK4/6 inhibitors for breast cancer and reported them in narrative form.

Results
Our study included 24 MAs and SRs. The strongest evidence demonstrated that CDK4/6 inhibitor combined with ET significantly improved progression-free survival (PFS), overall survival (OS) in advanced breast cancer (ABC). A large body of moderate to high evidence showed a significant association between combination therapy and objective response rate (ORR), and clinical benefit response (CBR) benefit in ABC. Low evidence suggested some degree of benefit from combination therapy in second progression-free survival (PFS2) and time to subsequent chemotherapy (TTC) outcomes in ABC and invasive disease-free survival (IDFS) outcomes in early breast cancer.

Conclusions
Based on current evidence, CDK4/6 inhibitors combined with ET have great confidence in improving PFS, OS, ORR, and CBR outcomes in patients with ABC, which provides more rational and valid evidence-based medicine for CDK4/6 inhibitor promotion and clinical decision support.
Derivation and validation of a nomogram based on clinical characteristics to diagnose endometriosis associated ovarian cancer preoperatively
Authors: Xu Ting , Nie Xianglin , Zhang Lin , Meng Huangyang , Jiang Yi , Wan Yicong , Cheng Wenjun 
Published: January 2024

Abstract
Purpose
The preoperative diagnosis of endometriosis associated ovarian cancer (EAOC) remains challenging for lack of effective diagnostic biomarker. We aimed to study clinical characteristics and develop a nomogram for diagnosing EAOC before surgery.

Methods
A total of 87 patients with EAOC and 348 patients with ovarian endometrioma (OEM) were enrolled in our study. Least absolute shrinkage and selection operator (LASSO) regression and Logistic regression were utilized to select variables and construct the prediction model. The performance of the model was assessed using receiver operating characteristic (ROC) analyses and calibration plots, while decision curve analyses (DCAs) were conducted to assess clinical value. Bootstrap resampling was used to evaluated the stability of the model in the derivation set.

Results
The EAOC patients were older compared to the OEM patients (46.41 ± 9.62 vs. 36.49 ± 8.09 year, P < 0.001) and proportion of postmenopausal women was higher in EAOC group than in the OEM group (34.5 vs. 1.5%, P < 0.001). Our prediction model, which included age at diagnosis, tumor size, cancer antigen (CA) 19–9 and risk of ovarian malignancy algorithm (ROMA), demonstrated an area under the curve (AUC) of 0.858 (95% confidence interval (CI): 0.795–0.920) in the derivation set (N = 304) and an AUC of 0.870 (95% CI: 0.779–0.961) in the validation set (N = 131). The model fitted both the derivation (Hosmer–Lemeshow test (HL) chi-square = 12.600, P = 0.247) and the validation (HL chi-square = 8.210, P = 0.608) sets well.

Conclusion
Compared to patients with OEM, those with EAOC exhibited distinct clinical characteristics. Our four-variable prediction model demonstrated excellent performance in both the derivation and validation sets, suggesting its potential to assist with preoperative diagnosis of EAOC.
Ultrasound-based deep learning radiomics nomogram for risk stratification of testicular masses: a two-center study
Authors: Fang Fuxiang , Sun Yan , Huang Hualin , Huang Yueting , Luo Xing , Yao Wei , Wei Liyan , Xie Guiwu , Wu Yongxian , Lu Zheng , Zhao Jiawen , Li Chengyang 
Published: January 2024

Abstract
Objective
To develop an ultrasound-driven clinical deep learning radiomics (CDLR) model for stratifying the risk of testicular masses, aiming to guide individualized treatment and minimize unnecessary procedures.

Methods
We retrospectively analyzed 275 patients with confirmed testicular lesions (January 2018 to April 2023) from two hospitals, split into training (158 cases), validation (68 cases), and external test cohorts (49 cases). Radiomics and deep learning (DL) features were extracted from preoperative ultrasound images. Following feature selection, we utilized logistic regression (LR) to establish a deep learning radiomics (DLR) model and subsequently derived its signature. Clinical data underwent univariate and multivariate LR analyses, forming the "clinic signature." By integrating the DLR and clinic signatures using multivariable LR, we formulated the CDLR nomogram for testicular mass risk stratification. The model’s efficacy was gauged using the area under the receiver operating characteristic curve (AUC), while its clinical utility was appraised with decision curve analysis(DCA). Additionally, we compared these models with two radiologists' assessments (5–8 years of practice).

Results
The CDLR nomogram showcased exceptional precision in distinguishing testicular tumors from non-tumorous lesions, registering AUCs of 0.909 (internal validation) and 0.835 (external validation). It also excelled in discerning malignant from benign testicular masses, posting AUCs of 0.851 (internal validation) and 0.834 (external validation). Notably, CDLR surpassed the clinical model, standalone DLR, and the evaluations of the two radiologists.

Conclusion
The CDLR nomogram offers a reliable tool for differentiating risks associated with testicular masses. It augments radiological diagnoses, facilitates personalized treatment approaches, and curtails unwarranted medical procedures.
Localization of nitric oxide–producing hemocytes in Aedes and Culex mosquitoes infected with bacteria
Authors: Bergmann Stella , Graf Emily , Hoffmann Pascal , Becker Stefanie C. , Stern Michael 
Published: January 2024

AbstractMosquitoes are significant vectors of various pathogens. Unlike vertebrates, insects rely solely on innate immunity. Hemocytes play a crucial role in the cellular part of the innate immune system. The gaseous radical nitric oxide (NO) produced by hemocytes acts against pathogens and also functions as a versatile transmitter in both the immune and nervous systems, utilizing cyclic guanosine monophosphate (cGMP) as a second messenger. This study conducted a parallel comparison of NO synthase (NOS) expression and NO production in hemocytes during Escherichia coli K12 infection in four vector species: Aedes aegypti, Aedes albopictus, Culex pipiens molestus, and Culex pipiens quinquefasciatus. Increased NOS expression by NADPH diaphorase (NADPHd) staining and NO production by immunofluorescence against the by-product L-citrulline were observed in infected mosquito hemocytes distributed throughout the abdomens. NADPHd activity and citrulline labeling were particularly found in periostial hemocytes near the heart, but also on the ventral nerve chord (VNC). Pericardial cells of Ae. aegypti and Cx. p. molestus showed increased citrulline immunofluorescence, suggesting their involvement in the immune response. Oenocytes displayed strong NADPHd and citrulline labeling independent of infection status. This comparative study, consistent with findings in other species, suggests a widespread phenomenon of NO’s role in hemocyte responses during E. coli infection. Found differences within and between genera highlight the importance of species-specific investigations.
AI and data-driven media analysis of TV content for optimised digital content marketing
Authors: Nixon Lyndon , Apostolidis Konstantinos , Apostolidis Evlampios , Galanopoulos Damianos , Mezaris Vasileios , Philipp Basil , Bocyte Rasa 
Published: January 2024

AbstractTo optimise digital content marketing for broadcasters, the Horizon 2020 funded ReTV project developed an end-to-end process termed “Trans-Vector Publishing” and made it accessible through a Web-based tool termed “Content Wizard”. This paper presents this tool with a focus on each of the innovations in data and AI-driven media analysis to address each key step in the digital content marketing workflow: topic selection, content search and video summarisation. First, we use predictive analytics over online data to identify topics the target audience will give the most attention to at a future time. Second, we use neural networks and embeddings to find the video asset closest in content to the identified topic. Third, we use a GAN to create an optimally summarised form of that video for publication, e.g. on social networks. The result is a new and innovative digital content marketing workflow which meets the needs of media organisations in this age of interactive online media where content is transient, malleable and ubiquitous.
Familiar but also radical? The moderating role of regional clusters for family firms in the emergence of radical innovation
Authors: Grashof Nils 
Published: January 2024

AbstractFamily firms are widely acknowledged to be the most predominant form of organization and hold a great relevance in most economies. Nevertheless, despite their popularity, research has thus far yielded inconsistent findings with regard to their innovative performance. This paper aims to address this research gap by focussing on a specific form of innovation: radical innovation. It seeks to determine the propensity of family firms to generate such innovations. Furthermore, by considering the heterogeneity between regions and firms, this paper also investigates the potential moderating effects of being located in a regional cluster and firm size. Based on various data sources, it is empirically shown that family firms are on average less capable of producing radical innovation than non-family firms. However, the corresponding regional context matters in this regard. By being located within regional clusters, family firms can reap the benefits of localization externalities, leading to produce more radical innovations than being located outside regional clusters.