bluuebunny/crossref_metadata_2025_split huggingface dataset:
Numerical evaluation of internal femur osteosynthesis based on a biomechanical model of the loading in the proximal equine hindlimb
Authors: Lang Jan J. , Li Xinhao , Micheler Carina M. , Wilhelm Nikolas J. , Seidl Fritz , Schwaiger Benedikt J. , Barnewitz Dirk , von Eisenhart-Rothe Ruediger , Grosse Christian U. , Burgkart Rainer 
Published: May 2024

SummaryFemoral fractures are often considered lethal for adult horses because femur osteosynthesis is still a surgical challenge. For equine femur osteosynthesis, primary stability is essential, but the detailed physiological forces occurring in the hindlimb are largely unknown. The objective of this study was to create a numerical testing environment to evaluate equine femur osteosynthesis based on physiological conditions. The study was designed as a finite element analysis (FEA) of the femur using a musculoskeletal model of the loading situation in stance. Relevant forces were determined in the musculoskeletal model via optimization. The treatment of four different fracture types with an intramedullary nail was investigated in FEA with loading conditions derived from the model. The analyzed diaphyseal fracture types were a transverse (TR) fracture, two oblique fractures in different orientations (OB-ML: medial-lateral and OB-AP: anterior-posterior) and a ”gap” fracture (GAP) without contact between the fragments. For the native femur, the most relevant areas of increased stress were located distally to the femoral head and proximally to the caudal side of the condyles. For all fracture types, the highest stresses in the implant material were present in the fracture-adjacent screws. Maximum compressive (-348 MPa) and tensile stress (197 MPa) were found for the GAP fracture, but material strength was not exceeded. The mathematical model was able to predict a load distribution in the femur of the standing horse and was used to assess the performance of internal fixation devices via FEA. The analyzed intramedullary nail and screws showed sufficient stability for all fracture types.
DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy
Authors: Su Po-Lan , Chakravarthy Karthik , Furuya Naoki , Brownstein Jeremy , Yu Jianhua , Long Meixiao , Carbone David , Li Zihai , He Kai 
Published: May 2024

AbstractDLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab’s clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs β-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.
METTL14 regulates CD8+T-cell activation and immune responses to anti‐PD‐1 therapy in lung cancer
Authors: Sun Chongqi , Wang Jian , Li Huixing , Liu Luyao , Lin Yu , Zhang Ling , Zu Xianglong , Zhu Yizhi , Shu Yongqian , Shen Dong , Wang Qiong , Liu Yiqian 
Published: May 2024

Abstract
Background
N6-methyladenosine (m6A) modification plays an important role in lung cancer. However, methyltransferase-like 14 (METTL14), which serves as the main component of the m6A complex, has been less reported to be involved in the immune microenvironment of lung cancer. This study aimed to analyze the relationship between METTL14 and the immune checkpoint inhibitor programmed death receptor 1 (PD-1) in lung cancer.

Methods
CCK-8, colony formation, transwell, wound healing, and flow cytometry assays were performed to explore the role of METTL14 in lung cancer progression in vitro. Furthermore, syngeneic model mice were treated with sh-METTL14 andan anti-PD-1 antibody to observe the effect of METTL14 on immunotherapy. Flow cytometry and immunohistochemical (IHC) staining were used to detect CD8 expression. RIP and MeRIP were performed to assess the relationship between METTL14 and HSD17B6. LLC cells and activated mouse PBMCs were cocultured in vitro to mimic immune cell infiltration in the tumor microenvironment. ELISA was used to detect IFN-γ and TNF-α levels.

Results
The online database GEPIA showed that high METTL14 expression indicated a poor prognosis in patients with lung cancer. In vitro assays suggested that METTL14 knockdown suppressed lung cancer progression. In vivo assays revealed that METTL14 knockdown inhibited tumor growth and enhanced the response to PD-1 immunotherapy. Furthermore, METTL14 knockdown enhanced CD8+T-cell activation and infiltration. More importantly, METTL14 knockdown increased the stability of HSD17B6 mRNA by reducing its m6A methylation. In addition, HSD17B6 overexpression promoted the activation of CD8+ T cells.

Conclusion
The disruption of METTL14 contributed to CD8+T-cell activation and the immunotherapy response to PD-1 via m6A modification of HSD17B6, thereby suppressing lung cancer progression.
Helicobacter pylori disrupts gastric mucosal homeostasis by stimulating macrophages to secrete CCL3
Authors: Wei Yan-Fei , Li Xue , Zhao Meng-Ran , Liu Si , Min Li , Zhu Sheng-Tao , Zhang Shu-Tian , Xie Si-An 
Published: May 2024

Abstract
Background
Helicobacter pylori (H. pylori) is the predominant etiological agent of gastritis and disrupts the integrity of the gastric mucosal barrier through various pathogenic mechanisms. After H. pylori invades the gastric mucosa, it interacts with immune cells in the lamina propria. Macrophages are central players in the inflammatory response, and H. pylori stimulates them to secrete a variety of inflammatory factors, leading to the chronic damage of the gastric mucosa. Therefore, the study aims to explore the mechanism of gastric mucosal injury caused by inflammatory factors secreted by macrophages, which may provide a new mechanism for the development of H. pylori-related gastritis.

Methods
The expression and secretion of CCL3 from H. pylori infected macrophages were detected by RT-qPCR, Western blot and ELISA. The effect of H. pylori-infected macrophage culture medium and CCL3 on gastric epithelial cells tight junctions were analyzed by Western blot, immunofluorescence and transepithelial electrical resistance. EdU and apoptotic flow cytometry assays were used to detect cell proliferation and apoptosis levels. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were used to study CCL3 transcription factors. Finally, gastric mucosal tissue inflammation and CCL3 expression were analyzed by hematoxylin and eosin staining and immunohistochemistry.

Results
After H. pylori infection, CCL3 expressed and secreted from macrophages were increased. H. pylori-infected macrophage culture medium and CCL3 disrupted gastric epithelial cells tight junctions, while CCL3 neutralizing antibody and receptor inhibitor of CCL3 improved the disruption of tight junctions between cells. In addition, H. pylori-infected macrophage culture medium and CCL3 recombinant proteins stimulated P38 phosphorylation, and P38 phosphorylation inhibitor improved the disruption of tight junctions between cells. Besides, it was identified that STAT1 was a transcription factor of CCL3 and H. pylori stimulated macrophage to secret CCL3 through the JAK1-STAT1 pathway. Finally, after mice were injected with murine CCL3 recombinant protein, the gastric mucosal injury and inflammation were aggravated, and the phosphorylation level of P38 was increased.

Conclusions
In summary, our findings demonstrate that H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 pathway. Subsequently, CCL3 damages gastric epithelial tight junctions through the phosphorylation of P38. This may be a novel mechanism of gastric mucosal injury in H. pylori-associated gastritis.
Exploring the changing association between parental and adolescent fruit and vegetable intakes, from age 10 to 30 years
Authors: Braune Tanya , Adams Jean , Winpenny Eleanor M. 
Published: May 2024

Abstract
Background
Adolescence is a pivotal developmental stage, where escalating rates of overweight and obesity have raised concerns about diet quality and its association with adverse health outcomes. Parents are known to have considerable influence on childhood diet, but how this influence changes as adolescents mature is unknown. This study investigates the association between parental fruit and vegetable (FV) intake and adolescent FV consumption, exploring how this changes across adolescence and when adolescents leave home.

Methods
Adolescents aged 10–30 years (n = 12,805) from the UK Household Longitudinal Study (UKHLS), and their parents, reported FV intakes every 2 years. Multilevel linear regression models were fitted to assess associations between parental and adolescent FV intakes, investigating interactions with age and living arrangement, and adjusting for sociodemographic covariates.

Results
Parental FV intake was positively associated with adolescent FV intake (β = 0.20 [95%CI:0.19,0.22] portions/day), with the strength of this association lowest during early adolescence (10–14 years) and peaking at 17–18 years (β = 0.30 [95%CI: 0.27,0.33] portions/day). When adolescents no longer lived in the parental home, the association of parental FV intake with adolescent FV consumption decreased, but a positive association was maintained up to age 30 years.

Conclusions
Our findings emphasise the enduring effect of parental FV consumption on adolescent FV consumption, highlighting the potential for interventions to promote increased FV intake, acknowledging the lasting influence of parental diet, even beyond the confines of the parental home.
Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation
Authors: Xiao Bijing , Li Guanjun , Gulizeba Haimiti , Liu Hong , Sima Xiaoxian , Zhou Ting , Huang Yan 
Published: May 2024

Abstract
Introduction
Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear.

Methods
Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan–Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed.

Results
Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis.

Conclusion
Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.
Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial
Authors: van Dijk Bastiaan T. , Bergstra Sytske Anne , van den Berg J. Merlijn , Schonenberg-Meinema Dieneke , van Suijlekom-Smit Lisette W.A. , van Rossum Marion A.J. , Koopman-Keemink Yvonne , ten Cate Rebecca , Allaart Cornelia F. , Brinkman Daniëlle M.C. , Hissink Muller Petra C.E. 
Published: May 2024

Abstract
Background
Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial.

Methods
92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week.

Results
32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4–10), median 10 months (7–16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6–9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group.

Conclusions
Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety.

Trial registration
Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585.
Monocytes release cystatin F dimer to associate with Aβ and aggravate amyloid pathology and cognitive deficits in Alzheimer’s disease
Authors: Li Qiang , Li Bing , Liu Li , Wang Kang-Ji , Liu Ming-Yue , Deng Yu , Li Ze , Zhao Wei-Dong , Wu Li-Yong , Chen Yu-Hua , Zhang Ke 
Published: May 2024

Abstract
Background
Understanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear.

Methods
Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology.

Results
Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice.

Conclusions
Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.
Third molar eruption in dental panoramic radiographs as a feature for forensic age assessment – new reference data from a German population
Authors: Timme Maximilian , Viktorov Jan , Steffens Laurin , Streeter Adam , Karch André , Schmeling Andreas 
Published: May 2024

AbstractForensic age assessment in the living can provide legal certainty when an individual’s chronological age is unknown or when age-related information is questionable. An established method involves assessing the eruption of mandibular third molars through dental panoramic radiographs (PAN). In age assessment procedures, the respective findings are compared to reference data. The objective of this study was to generate new reference data in line with the required standards for mandibular third molar eruption within a German population. For this purpose, 605 PANs from 302 females and 303 males aged 15.04 to 25.99 years were examined. The PANs were acquired between 2013 and 2020, and the development of the mandibular third molars was rated independently by two experienced examiners using the Olze et al. staging scale from 2012. In case of disagreement in the assigned ratings, a consensus was reached through arbitration. While the mean, median and minimum ages were observed to increase with each stage of mandibular third molar eruption according to the Olze method, there was considerable overlap in the distribution of age between the stages. The minimum age for stage D, which corresponds to complete tooth eruption, was 16.1 years for females and 17.1 years for males. Thus, the completion of mandibular third molar eruption was found in both sexes before reaching the age of 18. In all individuals who had at least one tooth with completed eruption and who were younger than 17.4 years of age (n = 10), mineralization of the teeth in question was not complete. Based on our findings, the feature of assessing mandibular third molar eruption in PAN cannot be relied upon for determining age of majority.
Pressure injury treatment by intermittent electrical stimulation (PROTECT-2): protocol for a multicenter randomized clinical trial
Authors: Donaldson Chase , de Abreu Marcelo Gama , Mascha Edward J. , Rowbottom James , Harvester Eric , Khanna Ashish , Sura Tanmay , Sessler Daniel I. , Patarroyo Fabio Rodriguez , Gulluoglu Alper , Zajic Paul , Chauhan Utkarsh , Essber Hani , Kurz Andrea 
Published: May 2024

Abstract
Background
Pressure ulcers account for a substantial fraction of hospital-acquired pathology, with consequent morbidity and economic cost. Treatments are largely focused on preventing further injury, whereas interventions that facilitate healing remain limited. Intermittent electrical stimulation (IES) increases local blood flow and redistributes pressure from muscle-bone interfaces, thus potentially reducing ulcer progression and facilitating healing.

Methods
The Pressure Injury Treatment by Intermittent Electrical Stimulation (PROTECT-2) trial will be a parallel-arm multicenter randomized trial to test the hypothesis that IES combined with routine care reduces sacral and ischial pressure injury over time compared to routine care alone. We plan to enroll 548 patients across various centers. Hospitalized patients with stage 1 or stage 2 sacral or ischial pressure injuries will be randomized to IES and routine care or routine care alone. Wound stage will be followed until death, discharge, or the development of an exclusion criteria for up to 3 months. The primary endpoint will be pressure injury score measured over time.

Discussion
Sacral and ischial pressure injuries present a burden to hospitalized patients with both clinical and economic consequences. The PROTECT-2 trial will evaluate whether IES is an effective intervention and thus reduces progression of stage 1 and stage 2 sacral and ischial pressure injuries.

Trial registration
ClinicalTrials.gov NCT05085288 Registered October 20, 2021.