bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer
Authors: Wang Yueqin , Wei Jingyao , Feng Luyao , Li Ouwen , Huang Lan , Zhou Shaoxuan , Xu Yingjie , An Ke , Zhang Yu , Chen Ruiying , He Lulu , Wang Qiming , Wang Han , Du Yue , Liu Ruijuan , Huang Chunmin , Zhang Xiaojian , Yang Yun-gui , Kan Quancheng , Tian Xin 
Published: May 2023

Abstract
Background
RNA 5-methylcytosine (m5C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m5C modification in tumor drug resistance remain unclear.

Methods
The correlation between RNA m5C methylation, m5C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m5C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays.

Results
RNA m5C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m5C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m5C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m5C reader Y-box binding protein 1 (YBX1).

Conclusions
Our study reveals a critical function of aberrant RNA m5C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.
Syndemic conditions and quality of life in the PISCIS Cohort of people living with HIV in Catalonia and the Balearic Islands: a cross sectional study
Authors: Mesías-Gazmuri Jocelyn , Folch Cinta , Palacio-Vieira Jorge , Bruguera Andreu , Egea-Cortés Laia , Forero Carlos G. , Hernández Juan , Miró José M. , Navarro Jordi , Riera Melchor , Peraire Joaquim , Alonso-García Lucía , Díaz Yesika , Casabona Jordi , Reyes-Urueña Juliana 
Published: May 2023

Abstract
Background
People living with HIV (PLWH) face structural and psychosocial factors that affect health-related quality of life (HRQoL). We aimed to evaluate how syndemic conditions affected HRQoL in PLWH.

Methods
A cross-sectional survey was conducted among 861 PLWH, to determine whether syndemic conditions (monthly income; sexual satisfaction; depressive symptoms; social role satisfaction; social isolation; cognitive function; nicotine dependence; perception of stigma) have an effect on HRQoL. A linear regression model and measures of Additive Interaction (AI) were used to determine the effects of syndemic conditions on HRQoL, controlling for other risk factors.

Results
Overall, the most frequently observed were stigma perception (56.9%), poor cognitive function (50.6%) and the perception of social isolation (51.6%). The presence of depressive symptoms was the risk factor most associated with worse Physical Health (PH) (B 3.93, 2.71–5.15) and Mental Health (MH) (B 5.08, 3.81–6.34) in linear regression model. Specifically, an interaction was observed between poor cognitive function and poor satisfaction with social role on worse PH and MH (AI 2.08, 0.14–4.02; AI 2.69, 0.15–5.22, respectively); and low income and perception of stigma (AI 2.98, 0.26–5.71), low income and perception of social isolation (AI 2.79, 0.27–5.32), and low income and poor satisfaction with social role (AI 3.45, 0.99–5.91) on MH.

Conclusion
These findings provide evidence that syndemic factors impact HRQoL. HIV prevention programs should screen and address co-occurring health problems to improve patient-centered health care and outcomes.
Evaluation of the EQ-5D-5L, EQ-VAS stand-alone component and Oxford knee score in the Australian knee arthroplasty population utilising minimally important difference, concurrent validity, predictive validity and responsiveness
Authors: Lin D-Yin , Cheok Tim Soon , Kaambwa Billingsley , Samson Anthony J. , Morrison Craig , Chan Teik , Kroon Hidde M. , Jaarsma Ruurd L. 
Published: May 2023

Abstract
Purpose
To evaluate the Oxford Knee Score (OKS), EQ-5D-5L utility index and EQ-5D visual analogue scale (EQ-VAS) for health-related quality of life outcome measurement in patients undergoing elective total knee arthroplasty (TKA) surgery.

Methods
In this prospective multi-centre study, the OKS and EQ-5D-5L index scores were collected preoperatively, six weeks (6w) and six months (6 m) following TKA. The OKS, EQ-VAS and EQ-5D-5L index were evaluated for minimally important difference (MID), concurrent validity, predictive validity (Spearman's Rho of predicted and observed values from a generalised linear regression model (GLM)), responsiveness (effect size (ES) and standard response mean (SRM)). The MID for the individual patient was determined utilising two approaches; distribution-based and anchor-based.

Results
533 patients were analysed. The EQ-5D-5L utility index showed good concurrent validity with the OKS (r = 0.72 preoperatively, 0.65 at 6w and 0.69 at 6 m). Predictive validity for the EQ-5D-5L index was lower than OKS when regressed. Responsiveness was large for all fields at 6w for the EQ-5D-5L and OKS (EQ-5D-5L ES 0.87, SRM 0.84; OKS ES 1.35, SRM 1.05) and 6 m (EQ-5D-5L index ES 1.31, SRM 0.95; OKS ES 1.69, SRM 1.59). The EQ-VAS returned poorer results, at 6w an ES of 0.37 (small) and SRM of 0.36 (small). At 6 m, the EQ-VAS had an ES of 0.59 (moderate) and SRM of 0.47 (small). It, however, had similar predictive validity to the OKS, and better than the EQ-5D-5L index. MID determined using anchor approach, was shown that for OKS at 6 weeks it was 8.84 ± 9.28 and at 6 months 13.37 ± 9.89. For the EQ-5D-5L index at 6 weeks MID was 0.23 ± 0.39, and at 6 months 0.26 ± 0.36.

Conclusions
The EQ-5D-5L index score and the OKS demonstrate good concurrent validity. The EQ-5D-5L index demonstrated lower predictive validity at 6w, and 6 m than the OKS, and both PROMs had adequate responsiveness. The EQ-VAS had poorer responsiveness but better predictive validity than the EQ-5D-5L index.
This article includes MID estimates for the Australian knee arthroplasty population.
Postoperative intermittent pneumatic compression for preventing venous thromboembolism in Chinese lung cancer patients: a randomized clinical trial
Authors: Li Jingyao , Huang Aihong , Han Zhaojie , Zhou Yi , Tang Meng , Wu Wei , Zhang Shixin , Liao Kelong , Xie Yihui , Chen Qiao , Zou Xinliang , Liu Shuai , Gao Shuaixiang , Ren Junlong , Xu Qingyuan , Liu Xi , Liao Yi , Jing Tao , Tan WenFeng , Qiu Yang , Wang Haidong 
Published: May 2023

Abstract
Background
Postoperative lung cancer patients belong to the high-risk group for venous thromboembolism (VTE). The standardized preventive measures for perioperative VTE in lung cancer are not perfect, especially for the prevention and treatment of catheter-related thrombosis (CRT) caused by carried central venous catheters (CVCs) in lung cancer surgery.

Patients and methods
This study included 460 patients with lung cancer undergoing video-assisted thoracic surgery (VATS) in our center from July 2020 to June 2021. Patients were randomized into two groups, and intraoperatively-placed CVCs would be carried to discharge. During hospitalization, the control group was treated with low-molecular-weight heparin (LMWH), and the experimental group with LMWH + intermittent pneumatic compression (IPC). Vascular ultrasound was performed at three time points which included before surgery, before discharge, and one month after discharge. The incidence of VTE between the two groups was studied by the Log-binomial regression model.

Results
CRT occurred in 71.7% of the experimental group and 79.7% of the control group. The multivariate regression showed that the risk of developing CRT in the experimental group was lower than in the control group (Adjusted RR = 0.889 [95%CI0.799–0.989], p = 0.031), with no heterogeneity in subgroups (P for Interaction > 0.05). Moreover, the fibrinogen of patients in the experimental group was lower than control group at follow-up (P = 0.019).

Conclusion
IPC reduced the incidence of CRT during hospitalization in lung cancer patients after surgery.

Trial registration
No. ChiCTR2000034511.
Drivers of retention of the HIV workforce transitioned from PEPFAR support to the Uganda government payroll
Authors: Zakumumpa Henry , Rujumba Joseph , Kyomuhendo Marjorie , Stempler llyse , Amde Woldekidan 
Published: May 2023

Abstract
Background
Health worker (HW) retention in the public health sector in Uganda is an enduring health system constraint. Although previous studies have examined the retention of in-service HWs, there is little research focusing on donor-recruited HWs. The objective of this study was to explore drivers of retention of the HIV workforce transitioned from PEPFAR support to the Uganda government payroll between 2015 and 2017.

Methods
We conducted ten focus group discussions with HWs (n = 87) transitioned from PEPFAR support to the public sector payroll in 10 purposively selected districts across Uganda. In-depth interviews were conducted with national-level stakeholders (n = 17), district health and personnel officers (n = 15) and facility in-charges (n = 22). Data were analyzed by a hybrid approach of inductive and deductive thematic development based on the analytical framework by Schaefer and Moos regarding individual-level and organizational-context drivers.

Results
At the individual level, job security in the public sector was the most compelling driver of health worker retention. Community embeddedness of HWs in the study districts, opportunities for professional development and career growth and the ability to secure salary loans due to ‘permanent and pensionable’ terms of employment and the opportunity to work in ‘home districts’, where they could serve their ‘kinsmen’ were identified as enablers. HWs with prior private sector backgrounds perceived public facilities as offering more desirable challenging professional work. Organizational context enablers identified include perceptions that public facilities had relaxed supervision regimes and more flexible work environments. Work environment barriers to long-term retention include frequent stock-out of essential commodities, heavy workloads, low pay and scarcity of rental accommodation, particularly in rural Northern Uganda. Compared to mid-cadres (such as nurses and midwives), higher calibre cadres, such as physicians, pharmacists and laboratory technologists, expressed a higher affinity for seeking alternative employment in the private sector in the immediate future.

Conclusions
Overall, job security was the most compelling driver of retention in public service for the health workforce transitioned from PEPFAR support to the Uganda government payroll. Monetary and non-monetary policy strategies are needed to enhance the retention of upper cadre HWs, particularly physicians, pharmacists and laboratory technologists in rural districts of Uganda.
The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice
Authors: Li Jia-Mei , Hu Ting , Zhou Xiao-Na , Zhang Ting , Guo Jia-Hui , Wang Min-Yuan , Wu Yi-Lin , Su Wen-Jun , Jiang Chun-Lei 
Published: May 2023

Abstract
Background
Numerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NLRP3 inflammasome in cognitive decline in depression and explore the common neuro-immunological mechanisms of depression and Alzheimer’s disease (AD).

Methods
Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 5 weeks, treatment group was administered with the NLRP3 inhibitor MCC950 (10 mg/kg, i.p.), fluoxetine served as positive control. Then, the mice were assessed for cognitive behaviors and depression-like behaviors, and changes of microglia and neurons in hippocampus and levels of Aβ metabolic pathway and tau protein were measured. To explore the mechanism of NLRP3 activation on neurons, we performed in vitro studies using BV2 microglia and mouse primary neurons. Furthermore, we focused on the role of NLRP3 inflammasome in the function of neurons and the expression of AD pathological indicators.

Results
CUMS induced depressive-like behaviors and cognitive decline in mice, which could be reversed by inhibiting NLRP3 inflammasome. MCC950, a specific NLRP3 inhibitor, alleviated CUMS-induced neuron injury and AD-like pathological changes, including the abnormal expression of Aβ metabolic pathway and the hyper-phosphorylation of tau protein. LPS (1 μg/mL) + ATP (1 mM) treatment activated the expression of NLRP3 inflammasome and IL-1β in vitro. In vitro experiment also proved that inhibiting the expression of NLRP3 inflammasome in microglia can restore the Aβ metabolic pathway to normal, decrease neuronal tau protein phosphorylation and protect neurons.

Conclusions
Inhibition of NLRP3 inflammasome effectively alleviated CUMS-induced depressive-like behaviors and cognitive decline in mice, and inhibited the activation of AD physiological indicators.
Inhibition of lysophosphatidic acid receptor 1 relieves PMN recruitment in CNS via LPA1/TSP1/CXCR2 pathway and alleviates disruption on blood-brain barrier following intracerebral haemorrhage in mice
Authors: Gao Ling , Peng Li , Sherchan Prativa , Tang Hong , Liu Yu , Xiao Jie , Shi Hui , Luo Yujie , Tang Jiping , Zhang John H. , Xia Ying 
Published: May 2023

Abstract
Backgroud
The frequencies of morbidity and impairment associated with spontaneous intracerebral haemorrhage (ICH) are comparatively high. Blood-brain barrier (BBB) integrity was compromised due to subsequent brain injury induced by ICH, which is crucial for a poor prognosis. Polymorphonuclear leukocyte (PMN) strongly modulate the disruption of BBB in the central nervous system (CNS). The lysophosphatidic acid receptor 1 (LPA1) mediated thrombospondin-1 (TSP1) regulation in astrocytes, which induce macrophage inflammatory protein 2(MIP2) secretion. MIP2 enhance PMN recruitment through CXC chemokine type 2 (CXCR2) activation. The purpose of this study was to investigate whether the LPA1-mediated inhibition of PMN recruitment and BBB protection after ICH is regulated by TSP1 and CXCR2 networks.

Methods
ICH induction was performed in CD1 mice using collagenase administration. AM966, a targeted LPA1 antagonist, was orally administered 1 and 12 h following ICH. further identify possible LPA1-mediated BBB protection mechanisms, we intracerebroventricularly (ICV) administered a CXCR2 ligand MIP2, as well as TSP1 CRISPR activation (ACT) with AM966. Consequently, we performed neurobehavioral, brain water content (BWC), Evans blue staining (EBS), immunofluorescence (IF), and western blot (WB) analyses.

Results
After ICH, astrocytes showed signs of LPA1, which peaked after 24 h, while PMN\ displayed evidence of CXCR2. The AM966-mediated LPA1 suppression relieved PMN recruitment, diminished brain oedema, demonstrated extravasation (as evidenced by EBS), protected BBB integrity, and enhanced neurologic activity following ICH. AM966 treatment strongly reduced TSP1, CXCR2, Occludin, and Claudin-5 expressions and PMN recruitment following ICH, and their expressions were restored by MIP2 and TSP1 CRISPR (ACT).

Conclusions
This study shows that LAP1 suppression reduced PMN recruitment after ICH in mice via TSP1/CXCR2 signalling, which minimized BBB disruption and improved the CNS’s neurobehavioral functioning. Hence, LPA1 is a strong candidate for therapy to reduce PMN recruitment and offer protection of BBB integrity after ICH.
Second-generation bone cement-injectable cannulated pedicle screws for osteoporosis: biomechanical and finite element analyses
Authors: Li Congcan , Song Lei , Xiao Jun , Wu Wenwen , Jiang Yifan , Zhou Rui , Dai Fei 
Published: May 2023

Abstract
Background
Biomechanical and finite element analyses were performed to investigate the efficacy of second-generation bone cement-injectable cannulated pedicle screws (CICPS) in osteoporosis.

Methods
This study used the biomechanical test module of polyurethane to simulate osteoporotic cancellous bone. Polymethylmethacrylate (PMMA) bone cement was used to anchor the pedicle screws in the module. The specimens were divided into two groups for the mechanical tests: the experimental group (second-generation CICPS) and control group (first-generation CICPS). Safety was evaluated using maximum shear force, static bending, and dynamic bending tests. Biomechanical stability evaluations included the maximum axial pullout force and rotary torque tests. X-ray imaging and computed tomography were used to evaluate the distribution of bone cement 24 h after PMMA injection, and stress distribution at the screw fracture and screw–cement–bone interface was assessed using finite element analysis.

Results
Mechanical testing revealed that the experimental group (349.8 ± 28.6 N) had a higher maximum axial pullout force than the control group (277.3 ± 8.6 N; P < 0.05). The bending moments of the experimental group (128.5 ± 9.08 N) were comparable to those of the control group (113.4 ± 20.9 N; P > 0.05). The screw-in and spin-out torques of the experimental group were higher than those of the control group (spin-in, 0.793 ± 0.015 vs. 0.577 ± 0.062 N, P < 0.01; spin-out, 0.764 ± 0.027 vs. 0.612 ± 0.049 N, P < 0.01). Bone cement was mainly distributed at the front three-fifths of the screw in both groups, but the distribution was more uniform in the experimental group than in the control group. After pullout, the bone cement was closely connected to the screw, without loosening or fragmentation. In the finite element analysis, stress on the second-generation CICPS was concentrated at the proximal screw outlet, whereas stress on the first-generation CICPS was concentrated at the screw neck, and the screw–bone cement–bone interface stress of the experimental group was smaller than that of the control group.

Conclusion
These findings suggest that second-generation CICPS have higher safety and stability than first-generation CICPS and may be a superior choice for the treatment of osteoporosis.
Correcting gradient-based interpretations of deep neural networks for genomics
Authors: Majdandzic Antonio , Rajesh Chandana , Koo Peter K. 
Published: May 2023

AbstractPost hoc attribution methods can provide insights into the learned patterns from deep neural networks (DNNs) trained on high-throughput functional genomics data. However, in practice, their resultant attribution maps can be challenging to interpret due to spurious importance scores for seemingly arbitrary nucleotides. Here, we identify a previously overlooked attribution noise source that arises from how DNNs handle one-hot encoded DNA. We demonstrate this noise is pervasive across various genomic DNNs and introduce a statistical correction that effectively reduces it, leading to more reliable attribution maps. Our approach represents a promising step towards gaining meaningful insights from DNNs in regulatory genomics.
Combined treatment of nerve growth factor and transcranical direct current stimulations to improve outcome in children with vegetative state after out-of-hospital cardiac arrest
Authors: Curatola Antonietta , Graglia Benedetta , Granata Giuseppe , Conti Giorgio , Capossela Lavinia , Manni Luigi , Ferretti Serena , Di Giuda Daniela , Romeo Domenico Marco , Calcagni Maria Lucia , Soligo Marzia , Castelli Enrico , Piastra Marco , Mantelli Flavio , Marca Giacomo Della , Staccioli Susanna , Romeo Tiziana , Pani Marcello , Cocciolillo Fabrizio , Mancino Aldo , Gatto Antonio , Chiaretti Antonio 
Published: May 2023

Abstract
Background
Out-of-hospital cardiac arrest (OHCA) is one of the most dramatic events in pediatric age and, despite advanced neurointensive care, the survival rate remains low. Currently, no effective treatments can restore neuronal loss or produce significant improvement in these patients. Nerve Growth Factor (NGF) is a neurotrophin potentially able to counteract many of the deleterious effects triggered by OHCA. Transcranial Direct Current Stimulation (tDCS) has been reported to be neuroprotective in many neurological diseases, such as motor deficit and cognitive impairment. Children with the diagnosis of chronic vegetative state after OHCA were enrolled. These patients underwent a combined treatment of intranasal administration of human recombinant NGF (hr-NGF), at a total dose of 50 gamma/kg, and tDCS, in which current intensity was increased from zero to 2 mA from the first 5 s of stimulation and maintained constant for 20 min. The treatment schedule was performed twice, at one month distance each. Neuroradiogical evaluation with Positron Emission Tomography scan (PET), Single Photon Emission Computed Tomography (SPECT), Electroencephalography (EEG) and Power Spectral Density of the brain (PSD) was determined before the treatment and one month after the end. Neurological assessment was deepened by using modified Ashworth Scale, Gross Motor Function Measure, and Disability Rating Scale.

Results
Three children with a chronic vegetative state secondary to OHCA were treated. The combined treatment with hr-NGF and tDCS improved functional (PET and SPECT) and electrophysiological (EEG and PSD) assessment. Also clinical conditions improved, mainly for the reduction of spasticity and with the acquisition of voluntary finger movements, improved facial mimicry and reaction to painful stimuli. No side effects were reported.

Conclusions
These promising preliminary results and the ease of administration of this treatment make it worthwhile to be investigated further, mainly in the early stages from OHCA and in patients with better baseline neurological conditions, in order to explore more thoroughly the benefits of this new approach on neuronal function recovery after OHCA.