bluuebunny/crossref_metadata_2025_split huggingface dataset:
The structure of blood–tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases
Authors: Ye Ling-yun , Sun Li-xiang , Zhong Xiu-hua , Chen Xue-song , Hu Song , Xu Rong-rong , Zeng Xiao-ning , Xie Wei-ping , Kong Hui 
Published: October 2021

Abstract
Background
Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood–brain barrier (BBB) is frequently impaired, forming blood–tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors.

Methods
Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS).

Results
Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases.

Conclusions
Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.
Elevated expression of MKRN3 in squamous cell carcinoma of the head and neck and its clinical significance
Authors: Zhang Shuiting , Liu Chao , Li Guo , Liu Yong , Wang Xingwei , Qiu Yuanzheng 
Published: October 2021

Abstract
Background
Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported.

Methods
The Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quantify the MKRN3 mRNA expression levels in SCCHN; immunohistochemical staining or immunoblotting analyses were performed to detect MKRN3 protein expression. Kaplan–Meier plotter was used to assess the prognostic values of MKRN3 in terms of overall survival and disease-free survival. The expression differences based on various clinicopathological features were evaluated using subgroup analysis and forest map analysis. The regulatory mechanism of MKRN3 was further investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Subsequently, STRING was used to perform a co-expression and enrichment analysis for MKRN3. Homologous modeling, molecular docking, and western blot analyses were performed to investigate the relationship between MKRN3 and its potential target gene P53.

Results
MKRN3 was ectopically expressed between cancerous and noncancerous SCCHN tissues, and its expression level was tightly associated with high T classifications as well as advanced clinical stages. qPCR analysis revealed that MKRN3 was upregulated in the SCCHN cell line. Moreover, Kaplan–Meier and Cox regression analyses indicated that SCCHN patients with high MKRN3 expression had poorer prognosis and that MKRN3 was a potential prognostic marker for SCCHN. Using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we determined that MKRN3 may be involved in the regulation of synthesis and metabolism and cell growth, death and motility, as well as cancer pathways associated with SCCHN progression. Mechanism investigation further revealed that P53, a potential target of MKRN3, may be involved in the SCCHN tumorigenesis mediated by MKRN3.

Conclusions
We performed a comprehensive evaluation of the clinical significance of MKRN3 and explored its underlying mechanisms. We concluded that MKRN3 represents a valuable predictive biomarker and potential therapeutic target in SCCHN.
An urban-to-rural continuum of malaria risk: new analytic approaches characterize patterns in Malawi
Authors: Larson Peter S. , Eisenberg Joseph N. S. , Berrocal Veronica J. , Mathanga Don P. , Wilson Mark L. 
Published: October 2021

Abstract
Background
The urban–rural designation has been an important risk factor in infectious disease epidemiology. Many studies rely on a politically determined dichotomization of rural versus urban spaces, which fails to capture the complex mosaic of infrastructural, social and environmental factors driving risk. Such evaluation is especially important for Plasmodium transmission and malaria disease. To improve targeting of anti-malarial interventions, a continuous composite measure of urbanicity using spatially-referenced data was developed to evaluate household-level malaria risk from a house-to-house survey of children in Malawi.

Methods
Children from 7564 households from eight districts throughout Malawi were tested for presence of Plasmodium parasites through finger-prick blood sampling and slide microscopy. A survey questionnaire was administered and latitude and longitude coordinates were recorded for each household. Distances from households to features associated with high and low levels of development (health facilities, roads, rivers, lakes) and population density were used to produce a principal component analysis (PCA)-based composite measure for all centroid locations of a fine geo-spatial grid covering Malawi. Regression methods were used to test associations of the urbanicity measure against Plasmodium infection status and to predict parasitaemia risk for all locations in Malawi.

Results
Infection probability declined with increasing urbanicity. The new urbanicity metric was more predictive than either a governmentally defined rural/urban dichotomous variable or a population density variable. One reason for this was that 23% of cells within politically defined rural areas exhibited lower risk, more like those normally associated with “urban” locations.

Conclusions
In addition to increasing predictive power, the new continuous urbanicity metric provided a clearer mechanistic understanding than the dichotomous urban/rural designations. Such designations often ignore urban-like, low-risk pockets within traditionally rural areas, as were found in Malawi, along with rural-like, potentially high-risk environments within urban areas. This method of characterizing urbanicity can be applied to other infectious disease processes in rapidly urbanizing contexts.
Prevalence of malaria in an area receiving seasonal malaria chemoprevention in Niger
Authors: Coldiron Matthew E. , Assao Bachir , Guindo Ousmane , Sayinzoga-Makombe Nathan , Koscalova Alena , Sterk Esther , Quere Michel , Ciglenecki Iza , Mumina Ann , Atti Salifou , Langendorf Céline , Grais Rebecca F. 
Published: October 2021

Abstract
Background
Malaria transmission is highly seasonal in Niger. Despite the introduction of seasonal malaria chemoprevention (SMC) in the Magaria District, malaria incidence remains high, and the epidemiology of malaria in the community is not well-understood.

Methods
Four cross-sectional, household-based malaria prevalence surveys were performed in the Magaria District of Niger between October 2016 and February 2018. Two occurred during the peak malaria season and two during the low malaria season. Individuals in each of three age strata (3–59 months, 5–9 years, and 10 years and above) were sampled in randomly-selected households. Capillary blood was collected by fingerprick, thick and thin blood films were examined. Microscopy was performed at Epicentre, Maradi, Niger, with external quality control. The target sample size was 396 households during the high-season surveys and 266 households during the low-season surveys.

Results
Prevalence of parasitaemia was highest in children aged 5–9 years during all four surveys, ranging between 53.6% (95%CI 48.8–63.6) in February 2018 and 73.2% (66.2–79.2) in September 2017. Prevalence of parasitaemia among children aged 3–59 months ranged between 39.6% (33.2–46.4) in February 2018 and 51.9% (45.1–58.6) in October 2016. Parasite density was highest in children aged 3–59 months during all four surveys, and was higher in high season surveys than in low season surveys among all participants. The prevalence of gametocytaemia in children aged 3–59 months ranged between 9.9% (6.5–14.8) in February 2018 and 19.3% (14.6–25.2) in October 2016. The prevalence of gametocytaemia in children aged 5–9 years ranged between 6.3% (3.5–11.1) in February 2018 and 18.5% (12.7–26.1) in October 2016.

Conclusions
Asymptomatic malaria infection is highly prevalent in this area, even during the season with low incidence of clinical malaria. The high prevalence of parasitaemia in children aged 5–9 years warrants considering their inclusion in SMC programmes in this context.
Instantaneous radiated power of brain activity: application to prepulse inhibition and facilitation for body dysmorphic disorder
Authors: Giannopoulos Anastasios E. , Spantideas Sotirios T. , Capsalis Christos , Papageorgiou Panos , Kapsalis Nikolaos , Kontoangelos Konstantinos , Papageorgiou Charalabos 
Published: October 2021

AbstractBackgroundGlobal measures of neuronal activity embrace the advantage of a univariate, holistic and unique description of brain activity, reducing the spatial dimensions of electroencephalography (EEG) analysis at the cost of lower precision in localizing effects. In this work, the instantaneous radiated power (IRP) is proposed as a new whole-brain descriptor, reflecting the cortical activity from an exclusively electromagnetic perspective. Considering that the brain consists of multiple elementary dipoles, the whole-brain IRP takes into account the radiational contribution of all cortical sources. Unlike conventional EEG analyses that evaluate a large number of scalp or source locations, IRP reflects a whole-brain, event-related measure and forces the analysis to focus on a single time-series, thus efficiently reducing the EEG spatial dimensions and multiple comparisons.ResultsTo apply the developed methodology in real EEG data, two groups (25 controls vs 30 body dysmorphic disorder, BDD, patients) were matched for age and sex and tested in a prepulse inhibition (PPI) and facilitation (PPF) paradigm. Two global brain descriptors were extracted for between-groups and between-conditions comparison purposes, namely the global field power (GFP) and the whole-brain IRP. Results showed that IRP can replicate the expected condition differences (with PPF being greater than PPI responses), exhibiting also reduced levels in BDD compared to control group overall. There were also similar outcomes using GFP and IRP, suggesting consistency between the two measures. Finally, regression analysis showed that the PPI-related IRP (during N100 time-window) is negatively correlated with BDD psychometric scores.ConclusionsInvestigating the brain activity with IRP significantly reduces the data dimensionality, giving insights about global brain synchronization and strength. We conclude that IRP can replicate the existing evidence regarding sensorimotor gating effects, revealing also group electrophysiological alterations. Finally, electrophysiological IRP responses exhibited correlations with BDD psychometrics, potentially useful as supplementary tool in BDD symptomatology.
Project20: interpreter services for pregnant women with social risk factors in England: what works, for whom, in what circumstances, and how?
Authors: Rayment-Jones Hannah , Harris James , Harden Angela , Silverio Sergio A. , Turienzo Cristina Fernandez , Sandall Jane 
Published: October 2021

Abstract
Background
Black and minority ethnic women and those with social risk factors such as deprivation, refugee and asylum seeker status, homelessness, mental health issues and domestic violence are at a disproportionate risk of poor birth outcomes. Language barriers further exacerbate this risk, with women struggling to access, engage with maternity services and communicate concerns to healthcare professionals. To address the language barrier, many UK maternity services offer telephone interpreter services. This study explores whether or not women with social risk factors find these interpreter services acceptable, accessible and safe, and to suggest solutions to address challenges.

Methods
Realist methodology was used to refine previously constructed programme theories about how women with language barriers access and experience interpreter services during their maternity care. Twenty-one longitudinal interviews were undertaken during pregnancy and the postnatal period with eight non-English speaking women and their family members. Interviews were analysed using thematic framework analysis to confirm, refute or refine the programme theories and identify specific contexts, mechanisms and outcomes relating to interpreter services.

Results
Women with language barriers described difficulties accessing maternity services, a lack of choice of interpreter, suspicion around the level of confidentiality interpreter services provide, and questioned how well professional interpreters were able to interpret what they were trying to relay to the healthcare professional during appointments. This resulted in many women preferring to use a known and trusted family member or friend to interpret for them where possible. Their insights provide detailed insight into how poor-quality interpreter services impact on their ability to disclose risk factors and communicate concerns effectively with their healthcare providers. A refined programme theory puts forward mechanisms to improve their experiences and safety such as regulated, high-quality interpreter services throughout their maternity care, in which women have choice, trust and confidence.

Conclusions
The findings of this study contribute to concerns highlighted in previous literature around interpreter services in the wider healthcare arena, particularly around the lack of regulation and access to high-quality interpretation. This is thought to have a significant effect on pregnant women who are living socially complex lives as they are not able to communicate their concerns and access support. This not only impacts on their safety and pregnancy outcomes, but also their wider holistic needs. The refined program theory developed in this study offers insights into the mechanisms of equitable access to appropriate interpreter services for pregnant women with language barriers.
Elevated gamma-glutamyl transferase has a non-linear association with incident non-alcoholic fatty liver disease in the non-obese Chinese population: a secondary retrospective study
Authors: Wu Liling , Zhang Man , Hu Haofei , Wan Qijun 
Published: October 2021

Abstract
Background
Effective and applicable predictors of non-alcoholic fatty liver disease (NAFLD) are needed for the non-obese Chinese population. This study was undertaken to investigate: whether serum gamma-glutamyl transferase (GGT) was associated with incident NAFLD in the non-obese Chinese population.

Methods
This was a retrospective cohort study that enrolled 33,153 initially NAFLD-free individuals who underwent a health examination in Wenzhou Medical Center of Wenzhou People’s Hospital from January 2010 to December 2014.
Serum GGT levels at the time of enrollment were evaluated in 11,906 persons who follow-up. The relationship between GGT levels and incident NAFLD was analyzed using Cox regression and generalized additive models after adjusting for demographic and clinical variables. In addition, Subgroup analysis was conducted, which was explored by Cox proportional hazard models. It was stated that the data had been downloaded from the DATADRYAD website.

Results
Multivariable Cox regression models were used to estimate the hazard ratio (HR) for GGT with incident NAFLD after adjusted demographic and clinical variables (HR, 1.010; 95% CI, 1.007–1.012; P < 0.001). The incident NAFLD in the highest quartile of GGT levels was 3.653 times as high (95% confidence interval, 2.915 to 4.579) as that the lowest quartile. A non-linear relationship was firstly detected between GGT and incidence of NAFLD, which had an inflection point of GGT was 26 U/L. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 1.104 (1.089–1.120) and 1.001 (0.999–1.004), respectively. In subgroup analyses, the hazard ratio for incident NAFLD remained consistent across subgroups.

Conclusions
In conclusion, the GGT level in the non-obese Chinese population was statistically significantly associated with incident NAFLD. The relationship between GGT level and incident NAFLD is non-linear. When GGT level is less than 26 U/L, GGT was strong positively with incident NAFLD.
An intelligent responsive macrophage cell membrane-camouflaged mesoporous silicon nanorod drug delivery system for precise targeted therapy of tumors
Authors: Li Minghua , Gao Xiaolong , Lin Chao , Shen Aijun , Luo Jing , Ji Qiongqiong , Wu Jiaqi , Wang Peijun 
Published: October 2021

AbstractMacrophage cell membrane-camouflaged nanocarriers can effectively reduce immune cell clearance and actively target tumors. In this study, a macrophage cell membrane-camouflaged mesoporous silica nanorod (MSNR)-based antitumor drug carrier equipped with a cationic polymer layer was developed. As drug carriers, these MSNRs were loaded with the thermosensitive phase change material L-menthol (LM), the chemotherapy drug doxorubicin (DOX) and the fluorescent molecule indocyanine green (ICG). The rod-like shape of the MSNRs was shown to enhance the penetration of the drug carriers to tumors. In the weakly acidic tumor microenvironment, the cationic polymer exhibited a proton sponge effect to trigger macrophage cell membrane coating detachment, promoting tumor cell uptake. Following nanocarrier uptake, ICG is heated by near-infrared (NIR) irradiation to make LM undergo a phase transition to release DOX and generate a synergistic effect of thermochemotherapy which kills tumor cells and inhibits tumor growth together with reactive oxygen species (ROS) produced by ICG. Overall, this nanohybrid drug delivery system demonstrates an intelligent cascade response, leads to tissue-cell specific targeting and improves drug release accuracy, thus proving to be an effective cancer therapy.
Graphical Abstract
Targeted theranostic photoactivation on atherosclerosis
Authors: Song Joon Woo , Ahn Jae Won , Lee Min Woo , Kim Hyun Jung , Kang Dong Oh , Kim Ryeong Hyun , Kang Un Gyo , Kim Yeon Hoon , Han Jeongmoo , Park Ye Hee , Nam Hyeong Soo , Yoo Hongki , Park Kyeongsoon , Kim Jin Won 
Published: October 2021

Abstract
Background
Photoactivation targeting macrophages has emerged as a therapeutic strategy for atherosclerosis, but limited targetable ability of photosensitizers to the lesions hinders its applications. Moreover, the molecular mechanistic insight to its phototherapeutic effects on atheroma is still lacking. Herein, we developed a macrophage targetable near-infrared fluorescence (NIRF) emitting phototheranostic agent by conjugating dextran sulfate (DS) to chlorin e6 (Ce6) and estimated its phototherapeutic feasibility in murine atheroma. Also, the phototherapeutic mechanisms of DS-Ce6 on atherosclerosis were investigated.

Results
The phototheranostic agent DS-Ce6 efficiently internalized into the activated macrophages and foam cells via scavenger receptor-A (SR-A) mediated endocytosis. Customized serial optical imaging-guided photoactivation of DS-Ce6 by light illumination reduced both atheroma burden and inflammation in murine models. Immuno-fluorescence and -histochemical analyses revealed that the photoactivation of DS-Ce6 produced a prominent increase in macrophage-associated apoptotic bodies 1 week after laser irradiation and induced autophagy with Mer tyrosine-protein kinase expression as early as day 1, indicative of an enhanced efferocytosis in atheroma.

Conclusion
Imaging-guided DS-Ce6 photoactivation was able to in vivo detect inflammatory activity in atheroma as well as to simultaneously reduce both plaque burden and inflammation by harmonic contribution of apoptosis, autophagy, and lesional efferocytosis. These results suggest that macrophage targetable phototheranostic nanoagents will be a promising theranostic strategy for high-risk atheroma.

Graphical abstract
Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell lung cancer
Authors: Zhang Wei , Gong Chunai , Chen Ziqiang , Li Ming , Li Yuping , Gao Jing 
Published: October 2021

AbstractBackgroundBiomimetic nanotechnology-based RNA interference (RNAi) has been successful in improving theranostic efficacy in malignant tumors. Its integration with hybrid biomimetic membranes made of natural cell membranes fused with liposomal membranes is mutually beneficial and extends their biofunctions. However, limited research has focused on engineering such biomimetics to endow them with unique properties and functions, in particular, those essential for a “smart” drug delivery system, such as a tumor microenvironment (TME)-activated multifunctional biomimetic nanoplatform.ResultsHerein, we utilized an integrated hybrid nanovesicle composed of cancer cell membranes (Cm) and matrix metallopeptidase 9 (MMP-9)-switchable peptide-based charge-reversal liposome membranes (Lipm) to coat lipoic acid-modified polypeptides (LC) co-loaded with phosphoglycerate mutase 1 (PGAM1) siRNA (siPGAM1) and DTX. The nanovesicle presented a negatively charged coating (citraconic anhydride-grafted poly-l-lysine, PC) in the middle layer for pH-triggered charge conversion functionalization. The established chemotherapeutic drug (DTX) co-delivery system CLip-PC@CO-LC nanoparticles (NPs) have a particle size of ~ 193 nm and present the same surface proteins as the Cm. Confocal microscopy and flow cytometry results indicated a greater uptake of MMP-9-treated CLip-PC@CO-LC NPs compared with that of the CLip-PC@CO-LC NPs without MMP-9 pretreatment. The exposure to MMP-9 activated positively charged cell-penetrating peptides on the surface of the hybrid nanovesicles. Moreover, pH triggered membrane disruption, and redox triggered DTX and siRNA release, leading to highly potent target-gene silencing in glycolysis and chemotherapy with enhanced antiproliferation ability. The biodistribution results demonstrated that the CLip-PC@LC-DiR NPs accumulated in the tumor owing to a combination of long blood retention time, homologous targeting ability, and TME-activated characteristics. The CLip-PC@CO-LC NPs led to more effective tumor growth inhibition than the DTX and free siPGAM1 formulations.ConclusionsTME-activated cancer cell membrane-liposome integrated hybrid NPs provide an encouraging nanoplatform that combines RNAi with chemotherapy for precise treatment of non-small cell lung cancer.Graphical abstract