bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-aza-2′-deoxycitidine inhibits cell proliferation, extracellular matrix formation and Wnt/β-catenin pathway in human uterine leiomyomas
Authors: Carbajo-García María Cristina , Corachán Ana , Segura-Benitez Marina , Monleón Javier , Escrig Julia , Faus Amparo , Pellicer Antonio , Cervelló Irene , Ferrero Hortensia 
Published: July 2021

Abstract
Background
Uterine leiomyoma is a benign tumor with unclear pathogenesis and inaccurate treatment. This tumor exhibits altered DNA methylation related to disease progression. DNMT inhibitors as 5-aza-2′-deoxycytidine (5-aza-CdR), have been suggested to treat tumors in which DNA methylation is altered. We aimed to evaluate whether DNA methylation reversion with 5-aza-CdR reduces cell proliferation and extracellular matrix (ECM) formation in uterine leiomyoma cells to provide a potential treatment option.

Methods
Prospective study using uterine leiomyoma and adjacent myometrium tissues and human uterine leiomyoma primary (HULP) cells (n = 16). In tissues, gene expression was analyzed by qRT-PCR and DNMT activity by ELISA. Effects of 5-aza-CdR treatment on HULP cells were assessed by CellTiter, western blot, and qRT-PCR.

Results
DNMT1 gene expression was higher in uterine leiomyoma vs myometrium. Similarly, DNMT activity was greater in uterine leiomyoma and HULP cells (6.5 vs 3.8 OD/h/mg; 211.3 vs 63.7 OD/h/mg, respectively). After 5-aza-CdR treatment on HULP cells, cell viability was reduced, significantly so at 10 μM (85.3%). Treatment with 10 μM 5-aza-CdR on HULP cells significantly decreased expression of proliferation marker PCNA (FC = 0.695) and of ECM proteins (COLLAGEN I FC = 0.654; PAI-1, FC = 0.654; FIBRONECTIN FC = 0.733). 5-aza-CdR treatment also decreased expression of Wnt/β-catenin pathway final targets, including WISP1 protein expression (10 μM, FC = 0.699), c-MYC gene expression (2 μM, FC = 0.745 and 10 μM, FC = 0.728), and MMP7 gene expression (5 μM, FC = 0.520 and 10 μM, FC = 0.577).

Conclusions
5-aza-CdR treatment inhibits cell proliferation, ECM formation, and Wnt/β-catenin signaling pathway targets in HULP cells, suggesting that DNA methylation inhibition is a viable therapeutic target in uterine leiomyoma.
Dissecting immune cell stat regulation network reveals biomarkers to predict ICB therapy responders in melanoma
Authors: Wang Jingwen , Li Feng , Xu Yanjun , Zheng Xuan , Zhang Chunlong , Hu Congxue , Xu Yingqi , Mi Wanqi , Li Xia , Zhang Yunpeng 
Published: July 2021

Abstract
Background
Immunotherapy is a revolutionary strategy in cancer therapy, but the resistance of which is one of the important challenges. Detecting the regulation of immune cells and biomarkers concerning immune checkpoint blockade (ICB) therapy is of great significance.

Methods
Here, we firstly constructed regulation networks for 11 immune cell clusters by integrating biological pathway data and single cell sequencing data in metastatic melanoma with or without ICB therapy. We then dissected these regulation networks and identified differently expressed genes between responders and non-responders. Finally, we trained and validated a logistic regression model based on ligands and receptors in the regulation network to predict ICB therapy response.

Results
We discovered the regulation of genes across eleven immune cell stats. Functional analysis indicated that these stat-specific networks consensually enriched in immune response corrected pathways and highlighted antigen processing and presentation as a core pathway in immune cell regulation. Furthermore, some famous ligands like SIRPA, ITGAM, CD247and receptors like CD14, IL2 and HLA-G were differently expressed between cells of responders and non-responders. A predictive model of gene sets containing ligands and receptors performed accuracy prediction with AUCs above 0.7 in a validation dataset suggesting that they may be server as biomarkers for predicting immunotherapy response.

Conclusions
In summary, our study presented the gene–gene regulation landscape across 11 immune cell clusters and analysis of these networks revealed several important aspects and immunotherapy response biomarkers, which may provide novel insights into immune related mechanisms and immunotherapy response prediction.
CHN1 promotes epithelial–mesenchymal transition via the Akt/GSK-3β/Snail pathway in cervical carcinoma
Authors: Zhao Haoqi , Wang Lan , Wang Shufang , Chen Xihua , Liang Min , Zhang Xin , Wang Jiedong , Xu Xiangbo 
Published: July 2021

AbstractBackgroundMetastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified.MethodsThe expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting.ResultsCHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002.ConclusionThese results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.
APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer’s disease and age-matched non-demented brains
Authors: Ojo Joseph O. , Reed Jon M. , Crynen Gogce , Vallabhaneni Prashanthi , Evans James , Shackleton Benjamin , Eisenbaum Maximillian , Ringland Charis , Edsell Anastasia , Mullan Michael , Crawford Fiona , Bachmeier Corbin 
Published: July 2021

AbstractCerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE variants (APOE2 and APOE3) has been largely unexplored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains with different APOE genotypes. We first interrogated changes between healthy control cases to identify underlying genotype specific effects in cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. Oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction were the top significant pathways in E2E2 vs E3/E3cases. We also identified AD-dependent changes and their interactions with APOE genotype and found the highest number of significant proteins from this interaction was observed in the E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell-type specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E3/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E4/E4 cases. These proteomic changes provide novel insights into the longstanding link between APOE4 and cerebrovascular dysfunction, implicating a role for impaired autophagy, ER stress, and mitochondrial bioenergetics. These APOE4 dependent changes we identified could provide novel cerebrovascular targets for developing disease modifying strategies to mitigate the effects of APOE4 genotype on AD pathogenesis.
Giardia duodenalis extracellular vesicles regulate the proinflammatory immune response in mouse macrophages in vitro via the MAPK, AKT and NF-κB pathways
Authors: Zhao Panpan , Cao Lili , Wang Xiaocen , Li Jianhua , Dong Jingquan , Zhang Nan , Li Xin , Li Shan , Sun Min , Zhang Xichen , Liang Min , Pu Xudong , Gong Pengtao 
Published: July 2021

Abstract
Background
Giardia duodenalis is an extracellular protozoan parasite that causes giardiasis in mammals. The presentation of giardiasis ranges from asymptomatic to severe diarrhea, and the World Health Organization lists it in the Neglected Diseases Initiative. Extracellular vesicles (EVs) are a key mediator of intracellular communication. Although previous studies have shown that G. intestinalis can regulate a host’s innate immune response, the role of G. intestinalis EVs (GEVs) in triggering a G. intestinalis-induced innate immune response remains to be further explored.

Methods
In this study, GEVs, G. intestinalis and GEVs + G. intestinalis were inoculated into macrophages, respectively. The transcription and secretion levels of proinflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNF-α), were measured using real-time quantitative PCR (qPCR) and enzyme-linked immunosorbent assays (ELISAs). The phosphorylation levels of the MAPK, AKT and NF-κB signaling pathways in GEV-stimulated mouse macrophages were examined using western blotting and immunofluorescence methods. The roles of activated pathways in the GEV-triggered inflammatory response were determined using inhibition assays, western blotting and ELISAs.

Results
The results showed that pretreatment with GEVs enhanced with G. intestinalis (GEVs + G. intestinalis) induced IL-1β, IL-6 and TNF-α transcription and secretion from mouse macrophages compared to stimulation with either GEVs or G. intestinalis alone. Inoculation of mouse macrophages with GEVs upregulated the phosphorylation levels of the p38 MAPK, p44/42 MAPK (Erk1/2), AKT and NF-κB signaling pathways and led to the nuclear translocation of NF-κB p65. Blocking the activated p38, Erk and NF-κB signaling pathways significantly downregulated the secretion of proinflammatory cytokines, and blocking the activated AKT signaling pathway demonstrated reverse effects.

Conclusions
The results of this study reveal that GEVs can enhance G. intestinalis-induced inflammatory response levels in mouse macrophages through activation of the p38, ERK and NF-κB signaling pathways. The role of GEVs in regulating host cell immune responses may provide insights into exploring the underlying mechanisms in G. intestinalis–host interactions.

Graphical abstract
Identification and prediction of difficult-to-treat rheumatoid arthritis patients in structured and unstructured routine care data: results from a hackathon
Authors: Messelink Marianne A. , Roodenrijs Nadia M. T. , van Es Bram , Hulsbergen-Veelken Cornelia A. R. , Jong Sebastiaan , Overmars L. Malin , Reteig Leon C. , Tan Sander C. , Tauber Tjebbe , van Laar Jacob M. , Welsing Paco M. J. , Haitjema Saskia 
Published: July 2021

Abstract
Background
The new concept of difficult-to-treat rheumatoid arthritis (D2T RA) refers to RA patients who remain symptomatic after several lines of treatment, resulting in a high patient and economic burden. During a hackathon, we aimed to identify and predict D2T RA patients in structured and unstructured routine care data.

Methods
Routine care data of 1873 RA patients were extracted from the Utrecht Patient Oriented Database. Data from a previous cross-sectional study, in which 152 RA patients were clinically classified as either D2T or non-D2T, served as a validation set. Machine learning techniques, text mining, and feature importance analyses were performed to identify and predict D2T RA patients based on structured and unstructured routine care data.

Results
We identified 123 potentially new D2T RA patients by applying the D2T RA definition in structured and unstructured routine care data. Additionally, we developed a D2T RA identification model derived from a feature importance analysis of all available structured data (AUC-ROC 0.88 (95% CI 0.82–0.94)), and we demonstrated the potential of longitudinal hematological data to differentiate D2T from non-D2T RA patients using supervised dimension reduction. Lastly, using data up to the time of starting the first biological treatment, we predicted future development of D2TRA (AUC-ROC 0.73 (95% CI 0.71–0.75)).

Conclusions
During this hackathon, we have demonstrated the potential of different techniques for the identification and prediction of D2T RA patients in structured as well as unstructured routine care data. The results are promising and should be optimized and validated in future research.
Switching from TNFα inhibitor to tacrolimus as maintenance therapy in rheumatoid arthritis after achieving low disease activity with TNFα inhibitors and methotrexate: 24-week result from a non-randomized, prospective, active-controlled trial
Authors: Jung Sang Youn , Koh Jung Hee , Kim Ki-Jo , Park Yong-Wook , Yang Hyung-In , Choi Sung Jae , Lee Jisoo , Choi Chan-Bum , Kim Wan-Uk 
Published: July 2021

Abstract
Background
Tapering or stopping biological disease-modifying anti-rheumatic drugs has been proposed for patients with rheumatoid arthritis (RA) in remission, but it frequently results in high rates of recurrence. This study evaluates the efficacy and safety of tacrolimus (TAC) as maintenance therapy in patients with established RA in remission after receiving combination therapy with tumor necrosis factor inhibitor (TNFi) and methotrexate (MTX).

Methods
This 24-week, prospective, open-label trial included patients who received TNFi and MTX at stable doses for ≥24 weeks and had low disease activity (LDA), measured by Disease Activity Score-28 for ≥12 weeks. Patients selected one of two arms: maintenance (TNFi plus MTX) or switched (TAC plus MTX). The primary outcome was the difference in the proportion of patients maintaining LDA at week 24, which was assessed using a logistic regression model. Adverse events were monitored throughout the study period.

Results
In efficacy analysis, 80 and 34 patients were included in the maintenance and switched arms, respectively. At week 24, LDA was maintained in 99% and 91% of patients in the maintenance and switched arms, respectively (odds ratio, 0.14; 95% confidence interval, 0.01–1.59). Drug-related adverse effects tended to be more common in the switched arm than in the maintenance arm (20.9% versus 7.1%, respectively) but were well-tolerated.

Conclusion
This controlled study tested a novel treatment strategy of switching from TNFi to TAC in RA patients with sustained LDA, and the findings suggested that TNFi can be replaced with TAC in most patients without the patients experiencing flare-ups for at least 24 weeks.

Trial registration
Korea CDC CRIS, KCT0005868. Registered 4 February 2021—retrospectively registered
Autoimmune pulmonary alveolar proteinosis successfully treated with lung lavage in an adolescent patient: a case report
Authors: Alasiri Abdalla Mohmed , Alasbali Reem Abdullah , Alaqil Meaad Ali , Alahmari Aishah Marei , Alshamrani Nouf Dagash , Badri Rabab Nasir 
Published: July 2021

Abstract
Background
Pulmonary alveolar proteinosis is a rare interstitial lung disease characterized by accumulating surfactant materials in the alveoli. The autoimmune form is by far the most common in adults, while in the pediatric age group, the vast majority of cases are congenital. We report a case of an adolescent patient diagnosed with autoimmune pulmonary alveolar proteinosis, which is unusual in this age group.

Case presentation
A-15 year-old Saudi male presented to the emergency department with a history of shortness of breath and low oxygen saturation. High-resolution computed tomography of his chest showed a global crazy-paving pattern. Autoantibodies against granulocyte-macrophage colony-stimulating factor were detected in his serum. A diagnosis of the autoimmune form of pulmonary alveolar proteinosis was confirmed after excluding other possible causes. The patient improved after he underwent whole lung lavage under general anesthesia, and he was independent of oxygen therapy after 6 months of follow-up.

Conclusion
The autoimmune form of pulmonary alveolar proteinosis is rare in the pediatric age group and should be considered when no apparent cause of this disease was found. Whole lung lavage should be the first treatment modality offered in this setting with close follow-up and monitoring.
Timestamp-aligning and keyword-biasing end-to-end ASR front-end for a KWS system
Authors: Shi Gui-Xin , Zhang Wei-Qiang , Wang Guan-Bo , Zhao Jing , Chai Shu-Zhou , Zhao Ze-Yu 
Published: July 2021

AbstractMany end-to-end approaches have been proposed to detect predefined keywords. For scenarios of multi-keywords, there are still two bottlenecks that need to be resolved: (1) the distribution of important data that contains keyword(s) is sparse, and (2) the timestamps of the detected keywords are inaccurate. In this paper, to alleviate the first issue and further improve the performance of the end-to-end ASR front-end, we propose the biased loss function for guiding the recognizer to pay more attention to the speech segments containing the predefined keywords. As for the second issue, we solve this problem by modifying the force alignment applied to the end-to-end ASR front-end. To get the frame-level alignment, we utilize a Gaussian Mixture Model-Hidden Markov Model (GMM-HMM) based acoustic model (AM) for auxiliary. The proposed system is evaluated in the OpenSAT20 held by the National Institute of Standards and Technology (NIST). The performance of our end-to-end KWS system is comparable to the conventional hybrid KWS system, sometimes even slightly better. With fusion results of the end-to-end and conventional KWS systems, we won the first prize in the KWS track. On the dev dataset (a part of SAFE-T corpus), the system outperforms the baseline by a large margin, i.e., our system with GMM-HMM aligner has a lower segmentation-aware word error rates (relatively 7.9–19.2% decrease) and higher overall Actual term-weighted values (relatively 3.6–11.0% increase), which demonstrates the effectiveness of the proposed method. For more precise alignments, we can use DNN-based AM as alignmentor at the cost of more computation.
Lie symmetry and μ-symmetry methods for nonlinear generalized Camassa–Holm equation
Authors: Jafari H. , Goodarzi K. , Khorshidi M. , Parvaneh V. , Hammouch Z. 
Published: July 2021

AbstractIn this paper, a Lie symmetry method is used for the nonlinear generalized Camassa–Holm equation and as a result reduction of the order and computing the conservation laws are presented. Furthermore,μ-symmetry andμ-conservation laws of the generalized Camassa–Holm equation are obtained.
TMEM263: a novel candidate gene implicated in human autosomal recessive severe lethal skeletal dysplasia
Authors: Mohajeri Mahsa Sadat Asl , Eslahi Atieh , Khazaii Zeinab , Moradi Mohammad Reza , Pazhoomand Reza , Farrokhi Shima , Feizabadi Masoumeh Heidari , Alizadeh Farzaneh , Mojarrad Majid 
Published: July 2021

Abstract
Introduction
Skeletal dysplasia is a common, clinically and genetically heterogeneous disorder in the human population. An increasing number of different genes are being identified causing this disorder. We used whole exome sequencing (WES) for detection of skeletal dysplasia causing mutation in a fetus affected to severe lethal skeletal dysplasia.

Patient
Fetus was assessed by ultrasonography in second trimester of pregnancy. He suffers from severe rhizomelic dysplasia and also pathologic shortening of ribs. WES was applied to finding of causal mutation. Furthermore, bioinformatics analysis was performed to predict mutation impact.

Results
Whole exome sequencing (WES) identified a homozygous frameshift mutation in the TMEM263 gene in a fetus with severe lethal skeletal dysplasia. Mutations of this gene have been previously identified in dwarf chickens, but this is the first report of involvement of this gene in human skeletal dysplasia. This gene plays a key role in the growth hormone signaling pathway.

Conclusion
TMEM263 can be considered as a new gene responsible for skeletal dysplasia. Given the complications observed in the affected fetus, the mutation of this gene appears to produce much more intense complications than that found in chickens and is likely to play a more important role in bone development in human.
Rapid standardized operating rooms (RAPSTOR) in thyroid and parathyroid surgery
Authors: Ernst Hannah , Sowerby Leigh , Sahovaler Axel , Macneil Danielle , Nichols Anthony , Yoo John , Hilsden Richard , Strychowsky Julie , Fung Kevin 
Published: July 2021

Objective To evaluate the impact of a high efficiency rapid standardized OR (RAPSTOR) for hemithyroid/parathyroid surgery using standardized equipment sets (SES) and consecutive case scheduling (CCS) on turnover times (TOT), average case volumes, patient outcomes, hospital costs and OR efficiency/stress. Methods Patients requiring hemithyroidectomy (primary or completion) or unilateral parathyroidectomy in a single surgeon's practice were scheduled consecutively with SES. Retrospective control groups were classified as sequential (CS) or non-sequential (CNS). A survey regarding OR efficiency/stress was administered. Phenomenography and descriptive statistics were conducted for time points, cost and patient outcome variables. Hospital cost minimization analysis was performed. Results The mean TOT of RAPSTOR procedures (16 min; n = 27) was not significantly different than CS (14 min, n = 14) or CNS (17 min, n = 6). Mean case number per hour was significantly increased in RAPSTOR (1.2) compared to both CS (0.9; p < 0.05) and CNS (0.7; p < 0.05). Average operative time was significantly reduced in RAPSTOR (32 min; n = 28) compared to CNS (48 min; p < 0.05) but not CS (33 min; p = 0.06). Time to discharge was reduced in RAPSTOR (595 min) compared to CNS (1210 min, p < 0.05). There was no difference in complication rate between all groups ( p = 0.27). Survey responses suggested improved efficiency, teamwork and workflow. Furthermore, there is associated decrease in direct operative costs for RAPSTOR vs. CS. Conclusion A high efficiency standardized OR for hemithyroid and parathyroid surgery using SES and CCS is associated with improved efficiency and, in this study, led to increased capacity at reduced cost without compromising patient safety. Level of evidence Level 2. Graphical Abstract