bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still’s disease
Authors: Jia Jinchao , Wang Mengyan , Ma Yuning , Meng Jianfen , Zhu Dehao , Chen Xia , Shi Hui , Sun Yue , Liu Honglei , Cheng Xiaobing , Su Yutong , Ye Junna , Chi Huihui , Liu Tingting , Zhou Zhuochao , Wang Fan , Chen Longfang , Yi Da , Xiao Yu , Yang Chengde , Teng Jialin , Hu Qiongyi 
Published: December 2023

Abstract
Background
Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14brightCD16 −), intermediate monocytes (IMs, CD14brightCD16 +), and non-classical monocytes (NCMs, CD14dimCD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified.

Methods
We performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation.

Results
Higher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1β, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment.

Conclusions
Our results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target.
Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke
Authors: Henrich Luise , Kiessling Iva , Steimer Matti , Frase Sibylle , Kaiser Sandra , Schallner Nils 
Published: December 2023

Abstract
Background
The heme oxygenase-1 (HO-1) enzyme pathway is of crucial importance in the removal of toxic blood components and regulation of neuroinflammation following hemorrhagic stroke. Although a circadian pattern dependency in the incidence and severity of hemorrhagic stroke exists, it is unknown whether the activity of the HO-1 system in the context of hemorrhagic injury also exhibits circadian dependency. We hypothesized that the circadian regulation of microglial HO-1 would determine the extent of neuroinflammation and neuronal injury in a murine model of subarachnoid hemorrhage (SAH).

Methods
In vitro expression patterns of HO-1 and circadian rhythm genes were analyzed in the microglial BV-2 cell line and primary microglia (PMG) using Western blot and qPCR. PMG isolated from Hmox1fl/fl and LyzM-Cre-Hmox1fl/fl mice were used to evaluate the role of microglial HO-1. We further investigated the in vivo relevance in a murine subarachnoid hemorrhage (SAH) model using Hmox1fl/fl and LyzM-Cre-Hmox1fl/fl mice with myeloid cell HO-1 deficiency, inducing SAH at different zeitgeber (ZT) times and analyzing the expression of HO-1 and the circadian control gene Period-2 (Per-2), respectively. Furthermore, we measured the inflammatory cytokine Monocyte Chemoattractant Protein-1 (MCP-1) in the cerebrospinal fluid of SAH patients in correlation with clinical outcome.

Results
HO-1 baseline expression and response to CO with blood exposure depended on ZT. In vitro expression of circadian control genes was de-synchronized in LyzM-Cre-Hmox1fl/fl PMG and did not respond to exogenous CO exposure. We found that circadian rhythm plays a crucial role in brain damage after SAH. At ZT2, we observed less phagocytic function, more vasospasm and increased microglial activation. CO reduced mortality at ZT12 in HO-1 deficient mice and reduced the difference between ZT2 and ZT12 in the inflammatory response. Induction of MCP-1 in the CSF from SAH patients was time-dependent and correlated with the expression of circadian control genes, SAH severity, functional impairment and delirium.

Conclusions
Our data point towards a crucial role for the HO-1 enzyme system and circadian control in neuronal injury after a hemorrhagic stroke.
Potential therapeutic effects of milk-derived exosomes on intestinal diseases
Authors: Cui Zhifu , Amevor Felix Kwame , Zhao Xingtao , Mou Chunyan , Pang Jiaman , Peng Xie , Liu Anfang , Lan Xi , Liu Lingbin 
Published: December 2023

AbstractExosomes are extracellular vesicles with the diameter of 30 ~ 150 nm, and are widely involved in intercellular communication, disease diagnosis and drug delivery carriers for targeted disease therapy. Therapeutic application of exosomes as drug carriers is limited due to the lack of sources and methods for obtaining adequate exosomes. Milk contains abundant exosomes, several studies have shown that milk-derived exosomes play crucial roles in preventing and treating intestinal diseases. In this review, we summarized the biogenesis, secretion and structure, current novel methods used for the extraction and identification of exosomes, as well as discussed the role of milk-derived exosomes in treating intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, colorectal cancer, and intestinal ischemia and reperfusion injury by regulating intestinal immune homeostasis, restoring gut microbiota composition and improving intestinal structure and integrity, alleviating conditions such as oxidative stress, cell apoptosis and inflammation, and reducing mitochondrial reactive oxygen species (ROS) and lysosome accumulation in both humans and animals. In addition, we discussed future prospects for the standardization of milk exosome production platform to obtain higher concentration and purity, and complete exosomes derived from milk. Several in vivo clinical studies are needed to establish milk-derived exosomes as an effective and efficient drug delivery system, and promote its application in the treatment of various diseases in both humans and animals.
Highly hydrophilic and dispersed TiO2 nano-system with enhanced photocatalytic antibacterial activities and accelerated tissue regeneration under visible light
Authors: Lu Boyao , Zhang Jie , Zhu Guixin , Liu Tiqian , Chen Jinwei , Liang Xing 
Published: December 2023

AbstractTitanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.
A novel polymer enabled by polymerized small molecule strategy for tumor photothermal and photodynamic therapy
Authors: Xie Xin , Wang Ke , Zeng Jie , Xu Miao-Yan , Qu Xin-Hui , Xiang Zheng-Bin , Tou Fang-Fang , Huang Shaorong , Han Xiao-Jian 
Published: December 2023

AbstractPhotothermal therapy (PTT) and photodynamic therapy (PDT) are effective method for tumor treatment. However, the limited variety and quantity of photothermal agents (PTAs) and photosensitizer (PSs) are still major challenges. Moreover, the cell apoptosis mechanism induced by PDT and PTT is still elusive. A fused-ring small molecule acceptor–donor acceptor′ donor–acceptor (A-DA′D-A) type of Y5 (Scheme 1) has a narrow band-gap and strong light absorption. Herein, we used Y5 to polymerize with thiophene unit to obtain polymer PYT based on polymerized small molecule strategy, and PYT nanoparticles (PYT NPs) was prepared via one-step nanoprecipitation strategy with DSPE-PEG2000. PYT NPs had excellent biocompatibility, good photostability, high photothermal conversion efficiency (67%) and reactive oxygen species (ROS) production capacity under 808 nm laser irradiation (PYT NPs + NIR). In vitro and in vivo experiments revealed that PYT NPs + NIR had the ability to completely ablate tumor cells. It was demonstrated that cell apoptosis induced by PYT NPs + NIR was closely related to mitochondrial damage. This study provides valuable guidance for constructing high-performance organic PTAs and PSs for tumor treatment.
Health expenditure: how much is spent on health and care worker remuneration? An analysis of 33 low- and middle-income African countries
Authors: Toure Hapsatou , Aranguren Garcia Maria , Bustamante Izquierdo Juana Paola , Coulibaly Seydou , Nganda Benjamin , Zurn Pascal 
Published: December 2023

Abstract
Objectives
To assess the amount spent on health and care workforce (HCW) remuneration in the African countries, its importance as a proportion of country expenditure on health, and government involvement as a funding source.

Methods
Calculations are based on country-produced disaggregated health accounts data from 33 low- and middle-income African countries, disaggregated wherever possible by income and subregional economic group.

Results
Per capita expenditure HCW remuneration averaged US$ 38, or 29% of country health expenditure, mainly coming from domestic public sources (three-fifths). Comparable were the contributions from domestic private sources and external aid, measured at around one-fifth each—23% and 17%, respectively. Spending on HCW remuneration was uneven across the 33 countries, spanning from US$ 3 per capita in Burundi to US$ 295 in South Africa. West African countries, particularly members of the West African Economic and Monetary Union (WAEMU), were lower spenders than countries in the Southern African Development Community (SADC), both in terms of the share of country health expenditure and in terms of government efforts/participation. By income group, HCW remuneration accounted for a quarter of country health expenditure in low-income countries, compared to a third in middle-income countries. Furthermore, an average 55% of government health expenditure is spent on HCW remuneration, across all countries. It was not possible to assess the impact of fragile and vulnerable countries, nor could we draw statistics by type of health occupation.

Conclusions
The results clearly show that the remuneration of the health and care workforce is an important part of government health spending, with half (55%) of government health spending on average devoted to it. Comparing HCW expenditure components allows for identifying stable sources, volatile sources, and their effects on HCW investments over time. Such stocktaking is important, so that countries, WHO, and other relevant agencies can inform necessary policy changes.
Patient-derived scaffolds representing breast cancer microenvironments influence chemotherapy responses in adapted cancer cells consistent with clinical features
Authors: Leiva Maria Carmen , Gustafsson Anna , Garre Elena , Ståhlberg Anders , Kovács Anikó , Helou Khalil , Landberg Göran 
Published: December 2023

Abstract
Background
The tumor microenvironment clearly influences cancer progressing properties but less is known about how individual cancer microenvironments potentially moderate cancer treatment effects. By cultivating and treating cancer cell lines in patient-derived scaffolds (PDS), the impact of specific characteristics of individual cancer microenvironments can be incorporated in human-like growth modelling and cancer drug treatment testing.

Methods
PDSs from 78 biobanked primary breast cancer samples with known patient outcomes, were prepared and repopulated with donor breast cancer cell lines, followed by treatment with 5-fluorouracil or doxorubicin after cellular adaption to the various microenvironments. Cancer cell responses to the treatments were monitored by RNA-analyses, highlighting changes in gene sets representative for crucial tumor biological processes such as proliferation, cancer stem cell features, differentiation and epithelial-to-mesenchymal transition.

Results
The chemotherapy treatments induced distinct gene expression patterns in adapted cancer cells with clusters of similar treatment responses depending on the patient-derived cancer microenvironment used as growth substrate. The doxorubicin treatment displayed a favorable gene signature among surviving cancer cells with low proliferation (MKI67) and pluripotency features (NANOG, POU5F1), in comparison to 5-fluorouracil showing low proliferation but increased pluripotency. Specific gene changes monitored post-treatment were also significantly correlated with clinical data, including histological grade (NANOG), lymph node metastasis (SLUG) and disease-free patient survival (CD44).

Conclusions
This laboratory-based treatment study using patient-derived scaffolds repopulated with cancer cell lines, clearly illustrates that the human cancer microenvironment influences chemotherapy responses. The differences in treatment responses defined by scaffold-cultures have potential prognostic and treatment predictive values.
Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment
Authors: Dehoorne Jo L. , Groth Helena , Carlé Emma , De Schrijver Ilse , Sys Celine , Delbeke Patricia , Kreps Elke O. , Renson Thomas , Bonroy Carolien 
Published: December 2023

Abstract
Background
Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.

Methods
A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab.

Results
Adalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9–33.0) compared to partial or non-responders 9,2 μg/mL (range 0–13.6) (p = 0,004). Receiver–operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561–0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%).

Conclusions
A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.
Lung infection or inflammation-a puzzling case of MDA-5 associated juvenile dermatomyositis
Authors: Vuppala Anusha , Sondhi Manush , Umer Sarwat 
Published: December 2023

Abstract
Background
Juvenile dermatomyositis (JDM) is an uncommon inflammatory myopathy predominantly affecting children under 18 years of age. Diagnosis relies on identifying specific clinical features, such as muscle weakness, skin rash, elevated muscle enzymes, and MRI and muscle biopsy findings. Autoantibodies associated with inflammatory myopathy offer valuable prognostic insights and can indicate the risk of internal organ involvement, though they are relatively rare in childhood myopathies. JDM can progress to interstitial lung disease (ILD) if associated with MDA5 antibodies, and immunosuppressive therapy constitutes the primary treatment approach.

Case presentation
We present a unique case of JDM complicated by disseminated histoplasmosis in a 12-year-old African American male cross-country runner with no prior medical history. He presented with unintentional weight loss and a rash on his hands, genitals, and fingertips, which persisted despite previous treatments. Diagnosis of JDM was confirmed through clinical and laboratory evaluations. Over time, the patient developed recurrent fevers, thrombocytopenia, and signs of ILD, leading to the identification of disseminated histoplasmosis as a complicating factor. Appropriate antifungal treatment resolved the infectious condition, while continued immunosuppression aided in managing JDM and ILD.

Conclusions
Juvenile dermatomyositis (JDM) remains a rare and intricate autoimmune disorder affecting young individuals. The presence of MDA5 antibodies in JDM patients can lead to severe complications like ILD, necessitating vigilant monitoring. Management includes immunosuppressive therapy, with glucocorticoids and mycophenolate mofetil proving effective, particularly in Clinically Amyopathic Dermatomyositis (CADM) cases. In cases of refractory disease, intravenous immunoglobulin (IVIG) plays a crucial role, offering a safe and beneficial adjunct to treatment. We emphasize the importance of recognizing atypical presentations of JDM, as it can lead to delays in diagnosis and treatment. Our case highlights the complexities of managing dual lung pathology, where a secondary infection exacerbated lung nodules and thrombocytopenia, while ILD was a consequence of atypical myopathy. Combining antifungal treatment with immunosuppression effectively managed both conditions and follow-up evaluations demonstrated improvement in ILD. Awareness of potential fungal infections in immunosuppressed JDM patients is crucial for successful treatment and patient outcomes.
Finite element mechanical analysis of ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery
Authors: Li Wenzheng , Han Junjian , Xin Qingyun , Liu Qitao , Feng Chao , Liu Yichan , Zhang Dengjun 
Published: December 2023

Abstract
Background
Unilateral bilateral endoscopic spine surgery (UBE) is often performed to treat lumbar spinal stenosis and disc herniation. It has become a prominent method in endoscopic spine surgery because of its very low learning curve and broader operative field of vision. Currently, the ipsilateral approach and contralateral approach have been established for disc herniation in the foraminal area, intervertebral foramen region, or pedicle region. The contralateral method offers many benefits over the ipsilateral approach, including less bone labour during microsurgical decompression and the preservation of facet joints. However, because it uses the interlaminar window approach, it inevitably involves osteotomy of the patient’s superior and inferior articular processes, which may result in corresponding deterioration in the spine’s biomechanical stability and subsequent adjacent facet joint diseases caused by facet joint degeneration postoperatively.

Objective
As a result, the purpose of this work is to use a finite element model to evaluate how the ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery affect spinal stability while treating identical intervertebral disc herniation.

Study design
In this study, a three-dimensional lumbar-sacral spine model was built and verified. Osteotomies were conducted for armpit-type lumbar disc herniation (LDH), periradicular-type LDH, and shoulder-type LDH. Postoperative lumbar spine models of the ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery were developed. The von Mises stress on the endplate, shear force on the annulus fibrosus, pressure inside the intervertebral disc, and range of motion (ROM) of the L3 segment were all determined. The results of our well-validated model showed that osteotomy done in the ipsilateral approach deteriorated most biomechanical metrics.

Results
In the majority of loading conditions, the contralateral approach caused the intervertebral disc’s biomechanical properties to increase, and the ipsilateral approach caused the intervertebral disc’s biomechanical properties to increase sharply more than the contralateral approach.

Conclusion
The contralateral approach, which is now extensively employed in unilateral bilateral endoscopic spine surgery, may be regarded as an ideal surgical alternative for treating lumbar disc herniation without producing iatrogenic instability. This approach has a low facet joint reduction rate, minimum soft tissue injury, and precisely identifies the midline of the central spinal canal during the retraction of the thecal sac and nerve roots.