bluuebunny/crossref_metadata_2025_split huggingface dataset:
Golgi phosphoprotein 3 promotes angiogenesis and sorafenib resistance in hepatocellular carcinoma via upregulating exosomal miR-494-3p
Authors: Gao Ying , Yin Zheng , Qi Yunling , Peng Hong , Ma Wenbin , Wang Ruizhi , Li Wen 
Published: January 2022

Abstract
Background
Golgi phosphoprotein 3 (GOLPH3) has been frequently reported as an oncoprotein in a variety of tumors. However, its role in the cancer-associated intercellular signaling communication has not yet been explored. This study aimed at exploring whether GOLPH3 regulates angiogenesis and sorafenib resistance via exosomal mechanisms in hepatocellular carcinoma (HCC).

Methods
In vivo assays were performed to elucidate the function of GOLPH3 in HCC. Exosomes of HCC cells were isolated by differential centrifugation, and then measured and quantified using nanoparticle tracking analysis (NTA), BCA assay, western blot (WB), and transmission electron microscopy (TEM). Differentially expressed miRNAs in exosome were analyzed and verified through small RNA sequencing (sRNA-seq) and reverse-transcription polymerase chain reaction (RT-PCR). In addition, a series of in vitro assays were performed to determine the function of exosomes and miR-494-3p in HCC. The candidate target gene of miR-494-3p was identified by bioinformatics prediction and dual-luciferase reporter assay.

Results
Downregulation of GOLPH3 expression could suppress angiogenesis and enhance sorafenib sensitivity in HCC. Exosomes derived from GOLPH3 overexpression HCC cells promoted the angiogenesis ability of HUVECs and induced sorafenib resistance in HCC cells. A total of 13 differentially expressed miRNAs between negative control and GOLPH3 knockdown group were found in exosomes. However, GOLPH3 was only associated with miR-494-3p expression level in exosomes derived from HCC cells without affecting total cellular miR-494-3p content. Results confirmed that exosomal miR-494-3p promotes angiogenesis of HUVECs and sorafenib resistance in HCC cells through directly targeting PTEN.

Conclusions
HCC cells with high expression levels of GOLPH3 could promote angiogenesis and sorafenib resistance by enhancing exosomal miR-494-3p secretion to recipient HUVECs and HCC cells, respectively.
Decoquinate liposomes: highly effective clearance of Plasmodium parasites causing severe malaria
Authors: Zeng Sumei , Wang Hongxing , Tao Long , Ning Xiaohui , Fan Yinzhou , Zhao Siting , Qin Li , Chen Xiaoping 
Published: January 2022

Abstract
Background
Severe malaria caused by Plasmodium falciparum leads to most malaria-related deaths globally. Decoquinate (DQ) displays strong activity against multistage infection by Plasmodium parasites. However, the development of DQ as an oral dosage form for the treatment of malaria at the blood stage has not been successful. In this study, liposome formulations of DQ were created for intravenous (IV) injection to suppress Plasmodium berghei, a parasite that causes severe malaria in mice.

Methods
DQ liposomes were prepared by conventional ethanol injection method with slight modifications and encapsulation efficiency evaluated by the well-established centrifugation method. Potency of the DQ liposomes against P. falciparum was assessed in vitro using freshly isolated human red blood cells. The efficacy of the DQ liposomes was examined in the mouse model of severe malaria.

Results
The DQ liposomes were around 150 nm in size and had the encapsulation efficiency rates > 95%. The freshly prepared and lyophilized liposomes were stable after storage at − 20 °C for 6 months. The liposomes were shown to have excellent activity against P. falciparum in vitro with DQ IC50 0.91 ± 0.05 nM for 3D7 (chloroquine sensitive strain) and DQ IC50 1.33 ± 0.14 nM for Dd2 (multidrug resistant strain), which were 18- and 14-fold more potent than artemisinin, respectively. Mice did not have any signs of toxicity after receiving high dose of the liposomes (DQ 500 mg/kg per mouse) by IV injection. In the mouse model of severe malaria, the liposomes had impressive efficacy against P. berghei with DQ ED50 of 0.720 mg/kg.

Conclusion
The DQ liposomes prepared in this study were stable for long term storage and safe for IV injection in mammalian animals. The newly created liposome formulations had excellent activity against Plasmodium infection at the blood-stage, which encourages their application in the treatment of severe malaria.
The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin
Authors: Wang Zehao , Yang Lu , Wu Peng , Li Xing , Tang Yuhui , Ou Xueqi , Zhang Yue , Xiao Xiangsheng , Wang Jin , Tang Hailin 
Published: January 2022

Abstract
Background
Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous.

Methods
In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot.

Results
In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5.

Conclusions
Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.
Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery
Authors: Huang Lingling , Yang Jianmiao , Wang Tiantian , Gao Jianqing , Xu Donghang 
Published: January 2022

AbstractA widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs extremely uplift the physicochemical properties, site-specificity, and antitumor activities of therapeutic agents while reducing systemic toxicity. Although great perspectives have been summarized in the progress of prodrug-based nanoplatforms, no attention has been paid to emphasizing the rational design of small-molecule lipidic prodrugs (SLPs). With the aim of outlining the prospect of the SLPs approach, the review will first provide an overview of conjugation strategies that are amenable to SLPs fabrication. Then, the rational design of SLPs in response to the physiological barriers of chemotherapeutic agents is highlighted. Finally, their biomedical applications are also emphasized with special functions, followed by a brief introduction of the promising opportunities and potential challenges of SLPs-based drug delivery systems (DDSs) in clinical application.
Graphical Abstract
Nos2−/− mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis
Authors: Poh Xuan Ying , Hong Jia Mei , Bai Chen , Miow Qing Hao , Thong Pei Min , Wang Yu , Rajarethinam Ravisankar , Ding Cristine S. L. , Ong Catherine W. M. 
Published: January 2022

AbstractBackgroundUnderstanding the pathophysiology of central nervous system tuberculosis (CNS-TB) is hampered by the lack of a good pre-clinical model that mirrors the human CNS-TB infection. We developed a murine CNS-TB model that demonstrates neurobehavioral changes with similar immunopathology with human CNS-TB.MethodsWe injected twoMycobacterium tuberculosis(M.tb) strains, H37Rv and CDC1551, respectively, into two mouse strains, C3HeB/FeJ andNos2−/−mice, either into the third ventricle or intravenous. We compared the neurological symptoms, histopathological changes and levels of adhesion molecules, chemokines, and inflammatory cytokines in the brain induced by the infections through different routes in different strains.ResultsIntra-cerebroventricular infection ofNos2−/−mice withM.tbled to development of neurological signs and more severe brain granulomas compared to C3HeB/FeJ mice. Compared with CDC1551M.tb, H37RvM.tbinfection resulted in a higher neurobehavioral score and earlier mortality. Intra-cerebroventricular infection caused necrotic neutrophil-dominated pyogranulomas in the brain relative to intravenous infection which resulted in disseminated granulomas and mycobacteraemia. Histologically, intra-cerebroventricular infection ofNos2−/−mice withM.tbresembled human CNS-TB brain biopsy specimens. H37Rv intra-cerebroventricular infected mice demonstrated higher brain concentrations of inflammatory cytokines, chemokines and adhesion molecule ICAM-1 than H37Rv intravenous-infected mice.ConclusionsIntra-cerebroventricular infection ofNos2−/−mice with H37Rv creates a murine CNS-TB model that resembled human CNS-TB immunopathology, exhibiting the worst neurobehavioral score with a high and early mortality reflecting disease severity and its associated neurological morbidity. Our murine CNS-TB model serves as a pre-clinical platform to dissect host–pathogen interactions and evaluate therapeutic agents for CNS-TB.
Addressing a silent and neglected scourge in sexual and reproductive health in Sub-Saharan Africa by development of training competencies to improve prevention, diagnosis, and treatment of female genital schistosomiasis (FGS) for health workers
Authors: Jacobson Julie , Pantelias Anastasia , Williamson Megan , Kjetland Eyrun Floerecke , Krentel Alison , Gyapong Margaret , Mbabazi Pamela Sabina , Djirmay Amadou Garba 
Published: January 2022

Abstract
Background
Schistosomiasis is an acute and chronic disease caused by parasitic worms, that can take two main forms: intestinal or urogenital. If left untreated, the urogenital form can lead to female genital schistosomiasis (FGS) in women and girls; frequently resulting in severe reproductive health complications which are often misdiagnosed as sexually-transmitted infections (STIs) or can be confused with cervical cancer. Despite its impact on women’s reproductive health, FGS is typically overlooked in medical training and remains poorly recognized with low awareness both in affected communities and in health professionals. FGS has been described as the one of the most neglected sexual and reproductive health issues in sub-Saharan Africa (Swai in BMC Infect Dis 6:134, 2006; Kukula in PLoS Negl Trop Dis 13:e0007207; Joint United Nations Programme on HIV/AIDS (UNAIDS) 2019). Increased knowledge and awareness of FGS is required to end this neglect, improve women’s reproductive health, and decrease the burden of this preventable and treatable neglected tropical disease.

Methods
We conducted interactive virtual workshops, in collaboration with the World Health Organization (WHO), engaging 64 participants with medical and public health backgrounds from around the world to establish standardized skills (or competencies) for prevention, diagnosis, and treatment of FGS at all levels of the health system. The competencies were drafted in small groups, peer-reviewed, and finalized by participants.

Results
This participatory process led to identification of 27 skills needed for FGS prevention, diagnosis, and management for two categories of health workers; those working in a clinical setting, and those working in a community setting. Among them, ten relate to the diagnosis of FGS including three that involve a pelvic exam and seven that do not. Six constitute the appropriate behaviors required to treat FGS in a clinical setting. Eleven address the community setting, with six relating to the identification of women at risk and five relating to prevention.

Conclusion
Defining the skills necessary for FGS management is a critical step to prepare for proper diagnosis and treatment of women and girls in sub-Saharan Africa by trained health professionals. The suggested competencies can now serve as the foundation to create educative tools and curricula to better train health care workers on the prevention, diagnosis, and management of FGS.
Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles
Authors: Gren Louise , Dierschke Katrin , Mattsson Fredrik , Assarsson Eva , Krais Annette M. , Kåredal Monica , Lovén Karin , Löndahl Jakob , Pagels Joakim , Strandberg Bo , Tunér Martin , Xu Yiyi , Wollmer Per , Albin Maria , Nielsen Jörn , Gudmundsson Anders , Wierzbicka Aneta 
Published: January 2022

AbstractBackgroundDiesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system (‘HVOPM+NOx’ PM1: 93 µg m−3, EC: 54 µg m−3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter (‘HVONOx’ PM1: ~ 1 µg m−3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study.ResultsThe average total respiratory tract deposition of PM1 during HVOPM+NOxwas 27 µg h−1. The estimated deposition fraction of HVO PM1 was 40–50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOxexhaust. Compared to FA, exposure to HVOPM+NOxand HVONOxcaused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA,p < 0.03). Especially, exposure to HVOPM+NOxshowed 40–50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOxexposures (− 18.1, 95% CI: − 27.3 to − 8.8 L min−1,p < 0.001), and for the HVOPM+NOx(− 7.4 (− 15.6 to 0.8) L min−1,p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique).ConclusionShort-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.
Growth pattern trajectories in boys with Duchenne muscular dystrophy
Authors: Stimpson Georgia , Raquq Sarah , Chesshyre Mary , Fewtrell Mary , Ridout Deborah , Sarkozy Anna , Manzur Adnan , Ayyar Gupta Vandana , De Amicis Ramona , Muntoni Francesco , Baranello Giovanni ,   the NorthStar Network, Ambegaonkar Gautam , Alhaswani Zoya , Baxter Alex , Childs Anne-Marie , Chow Gabby , De Goede Christian , Fernandez Miguel , Gibbon Frances , Gowda Vasantha , Guglieri Michela , Hart Tony , Hewawitharana Gemunu , Horrocks Iain , Hughes Imelda , Illingworth Marjorie , Krishnakumar Deepa , Majumdar Anirban , Marini-Bettolo Chiara , Ong Min , Parasuraman Deepak , Ramdas Sithara , Servais Laurent , Skone Kate , Spinty Stefan , Stephens Elma , Straub Volker , Tirupathi Sandya , Thomas Neil , Willis Tracey , White Cathy , Wong Jarod , Wraige Elizabeth , Vijayakumar Kayal , Naismith Karen 
Published: January 2022

Abstract
Objectives
The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5–12 years with Duchenne muscular dystrophy (DMD).

Background
We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003–2020) on one of five regimes: “GC naïve”, “deflazacort daily” (DD), “deflazacort intermittent” (DI), “prednisolone daily” (PD) and “prednisolone intermittent” (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90).

Results
The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI − 0.30, − 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation.

Conclusion
These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.
Development of a novel combined nomogram model integrating deep learning-pathomics, radiomics and immunoscore to predict postoperative outcome of colorectal cancer lung metastasis patients
Authors: Wang Renjie , Dai Weixing , Gong Jing , Huang Mingzhu , Hu Tingdan , Li Hang , Lin Kailin , Tan Cong , Hu Hong , Tong Tong , Cai Guoxiang 
Published: January 2022

AbstractLimited previous studies focused on the death and progression risk stratification of colorectal cancer (CRC) lung metastasis patients. The aim of this study is to construct a nomogram model combing machine learning-pathomics, radiomics features, Immunoscore and clinical factors to predict the postoperative outcome of CRC patients with lung metastasis. In this study, a total of 103 CRC patients having metastases limited to lung and undergoing radical lung resection were identified. Patch-level convolutional neural network training in weakly supervised manner was used to perform whole slides histopathological images survival analysis. Synthetic minority oversampling technique and support vector machine classifier were used to identify radiomics features and build predictive signature. The Immunoscore for each patient was calculated from the density of CD3+ and CD8+ cells at the invasive margin and the center of metastatic tumor which were assessed on consecutive sections of automated digital pathology. Finally, pathomics and radiomics signatures were successfully developed to predict the overall survival (OS) and disease free survival (DFS) of patients. The predicted pathomics and radiomics scores are negatively correlated with Immunoscore and they are three independent prognostic factors for OS and DFS prediction. The combined nomogram showed outstanding performance in predicting OS (AUC = 0.860) and DFS (AUC = 0.875). The calibration curve and decision curve analysis demonstrated the considerable clinical usefulness of the combined nomogram. Taken together, the developed nomogram model consisting of machine learning-pathomics signature, radiomics signature, Immunoscore and clinical features could be reliable in predicting postoperative OS and DFS of colorectal lung metastasis patients.
sPLINK: a hybrid federated tool as a robust alternative to meta-analysis in genome-wide association studies
Authors: Nasirigerdeh Reza , Torkzadehmahani Reihaneh , Matschinske Julian , Frisch Tobias , List Markus , Späth Julian , Weiss Stefan , Völker Uwe , Pitkänen Esa , Heider Dominik , Wenke Nina Kerstin , Kaissis Georgios , Rueckert Daniel , Kacprowski Tim , Baumbach Jan 
Published: January 2022

AbstractMeta-analysis has been established as an effective approach to combining summary statistics of several genome-wide association studies (GWAS). However, the accuracy of meta-analysis can be attenuated in the presence of cross-study heterogeneity. We present sPLINK, a hybrid federated and user-friendly tool, which performs privacy-aware GWAS on distributed datasets while preserving the accuracy of the results. sPLINK is robust against heterogeneous distributions of data across cohorts while meta-analysis considerably loses accuracy in such scenarios. sPLINK achieves practical runtime and acceptable network usage for chi-square and linear/logistic regression tests. sPLINK is available at https://exbio.wzw.tum.de/splink.