bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOX4: a potential therapeutic target for pancreatic cancer and its mechanism
Authors: Bi Yawei , Lei Xiao , Chai Ningli , Linghu Enqiang 
Published: December 2021

AbstractNicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.
Influence of the trajectory of the urine output for 24 h on the occurrence of AKI in patients with sepsis in intensive care unit
Authors: Zhang Luming , Xu Fengshuo , Han Didi , Huang Tao , Li Shaojin , Yin Haiyan , Lyu Jun 
Published: December 2021

AbstractBackgroundSepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. This condition is an independent cause of death. This study was performed to investigate the correlation between the trajectory of urine output within 24 h and S-AKI.MethodsPatients with sepsis were studied retrospectively based on the Medical Information Mart for Intensive Care IV. Latent growth mixture modeling was used to classify the trajectory of urine output changes within 24 h of sepsis diagnosis. The outcome of this study is AKI that occurs 24 h after sepsis. Cox proportional hazard model, Fine–Gray subdistribution proportional hazard model, and doubly robust estimation method were used to explore the risk of AKI in patients with different trajectory classes.ResultsA total of 9869 sepsis patients were included in this study, and their 24-h urine output trajectories were divided into five classes. The Cox proportional hazard model showed that compared with class 1, the HR (95% CI) values for classes 3, 4, and 5 were 1.460 (1.137–1.875), 1.532 (1.197–1.961), and 2.232 (1.795–2.774), respectively. Competing risk model and doubly robust estimation methods reached similar results.ConclusionsThe trajectory of urine output within 24 h of sepsis patients has a certain impact on the occurrence of AKI. Therefore, in the early treatment of sepsis, close attention should be paid to changes in the patient's urine output to prevent the occurrence of S-AKI.
Surgical outcomes in children under 10 years old in the treatment of congenital scoliosis due to single nonincarcerated thoracolumbar hemivertebra: according to the age at surgery
Authors: Li Haixia , Chen Zhiming , Gao Bo , Wang Jiaxu , Shao Shuilin , Wu Jigong 
Published: December 2021

Abstract
Purpose
Hemivertebra is one of the common pathogenesis of congenital scoliosis. The timing of operation is undefined. Our study compared the surgical outcomes in children under age 10 years with scoliosis due to single nonincarcerated thoracolumbar hemivertebra according to the age at surgery.

Methods
From January 2009 to August 2017, we retrospectively investigated 34 consecutive cases of congenital scoliosis treated by posterior hemivertebra resection and fusion with pedicle screw fixation. All cases were divided into two groups according to the age at surgery and followed-up for at least 2 years, group 1 (≤ 5 years old), and group 2 (5 to 10 years old).

Results
The mean Cobb angle of the main curve was improved from 48.58° to 15.53° (68.05%) in group 1, and from 43.73° to 11.33° (75.43%) in group 2. The segmental curve was improved from 44.16° to 11.53° (74.64%) in group 1, and the segmental curve was consistent with the main curve in group 2. The mean segmental kyphosis was improved from 27.50° to 8.42° (67.40%) in group 1, and from 29.00° to 5.00° (84.73%) in group 2. Five patients developed distal adding-on, and four patients were found proximal junctional kyphosis during the follow-up.

Conclusion
Not all the deformities caused by single nonincarcerated thoracolumbar hemivertebra would progress greatly with the spinal growth. No significant statistical differences were found in the coronal and sagittal correction rate between the two groups. A limited delayed surgery after 5 years but before 10 years of age with close follow-up can achieve satisfied results.
The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells
Authors: Naro Chiara , De Musso Monica , Delle Monache Francesca , Panzeri Valentina , de la Grange Pierre , Sette Claudio 
Published: December 2021

Abstract
Background
Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype.

Methods
To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value.

Results
Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells.

Conclusions
Our study uncovers an extensive splicing program modulated by NEK2 involving splice variants that confer an invasive phenotype to TNBCs and that might represent, together with NEK2 itself, valuable therapeutic targets for this disease.
The prognostic factor for recurrence in advanced-stage high-grade serous ovarian cancer after complete clinical remission: a nested case-control study
Authors: Wang Qiao , Zheng Ying , Wang Ping , Zhang Jiawen , Liu Hui , Li Qingli , Yin Rutie , Bian Ce , Peng Hongling , Peng Zhilan 
Published: December 2021

Abstract
Background
Women with advanced-stage high-grade serous ovarian cancer (HGSOC) are likely to have a bad prognosis. Relapses are common in patients even with no evidence of disease after primary treatment. We aimed to identify the prognostic factors for disease recurrence in these patients.

Methods
A nested case-control study was conducted in a large medical center in Southwest China. The primary outcome was recurrence of disease within 3 years after clinical remission (CR). Cox regression was used to calculate the time to event analysis in different groups.

Results
Ninety-seven patients were finally included. Fifty-seven patients (58.8%) relapsed within 3 years after CR. Among all the variables, the difference in posttreatment CA-125 level was statistically significant (P <0.05) between the recurrent group and the progression-free group in both univariate and multivariable analysis. A cutoff value was set at the median level in the recurrent group (10 U/ml) to categorize patients into two arms. In Cox regression, the posttreatment CA-125 level was identified as a prognostic factor for recurrence with an OR of 1.05 (95% CI: 1.02–1.10, P = 0.033). The median time (from initiation of treatment) until relapse was 25 months for patients whose posttreatment CA-125 levels were higher than 10 U/ml, while it was undefined for patients whose posttreatment CA-125 level were ≤ 10 U/ml. Patients with a higher posttreatment CA-125 level showed an increased risk for OC relapse compared to those with a lower posttreatment CA-125 level. Furthermore, as shown in line graphs recording serum CA-125 levels during follow-up in each recurrent case, the increments of serum CA-125 levels were delayed in recurrent OC patients who had a posttreatment CA125 level ≤ 10 U/ml compared with those with a higher CA-125 level.

Conclusion
A low serum CA-125 level after primary treatment was a potential prognostic factor in women with advanced HGSOC.
Intraosseous fluid resuscitation causes systemic fat emboli in a porcine hemorrhagic shock model
Authors: Kristiansen Steinar , Storm Benjamin , Dahle Dalia , Domaas Josefsen Terje , Dybwik Knut , Nilsen Bent Aksel , Waage-Nielsen Erik 
Published: December 2021

AbstractBackgroundIntraosseous cannulation can be life-saving when intravenous access cannot be readily achieved. However, it has been shown that the procedure may cause fat emboli to the lungs and brain. Fat embolization may cause serious respiratory failure and fat embolism syndrome. We investigated whether intraosseous fluid resuscitation in pigs in hemorrhagic shock caused pulmonary or systemic embolization to the heart, brain, or kidneys and if this was enhanced by open chest conditions.MethodsWe induced hemorrhagic shock in anesthetized pigs followed by fluid-resuscitation through bilaterally placed tibial (hind leg) intraosseous cannulas. The fluid-resuscitation was limited to intraosseous or i.v. fluid therapy, and did not involve cardiopulmonary resuscitation or other interventions. A subgroup underwent median sternotomy with pericardiectomy and pleurotomy before hemorrhagic shock was induced. We used invasive hemodynamic and respiratory monitoring including Swan Ganz pulmonary artery catheter and transesophageal echocardiography and obtained biopsies from the lungs, heart, brain, and left kidney postmortem.ResultsAll pigs exposed to intraosseous infusion had pulmonary fat emboli in postmortem biopsies. Additionally, seven of twenty-one pigs had coronary fat emboli. None of the pigs with open chest had fat emboli in postmortem lung, heart, or kidney biopsies. During intraosseous fluid-resuscitation, three pigs developed significant ST-elevations on ECG; all of these animals had coronary fat emboli on postmortem biopsies.ConclusionsSystemic fat embolism occurred in the form of coronary fat emboli in a third of the animals who underwent intraosseous fluid resuscitation. Open chest conditions did not increase the incidence of systemic fat embolization.
Low thyroid hormone receptor alpha-2 (THRα-2) tumor expression is associated with unfavorable tumor characteristics and high breast cancer mortality
Authors: Sandsveden Malte , Borgquist Signe , Rosendahl Ann H. , Manjer Jonas 
Published: December 2021

Abstract
Background
The active thyroid hormone triiodothyronine (T3) has been found to have an estrogen-like effect on breast cancer cells. Thyroid hormone receptor alpha-2 (THRα-2) acts as an antagonist for triiodothyronine (T3) signaling, and a low expression has been associated with unfavorable tumor characteristics and a higher mortality in breast cancer. However, the evidence are not conclusive. The present study evaluates tumor-specific THRα-2 expression in invasive breast cancers and its association with tumor characteristics and long-term mortality in a large population.

Method
The Malmö Diet and Cancer Study (MDCS), a population-based cohort in Sweden that included 17,035 women from 1991 to 1996, was used. Women diagnosed with breast cancer during 1991–2010 were eligible for inclusion. A tissue micro array was constructed from stored tumor material and stained for THRα-2 using immunohistochemistry. Tumors from 654 patients were scored regarding the intensity and the fraction of cells stained, then dichotomized into low or high expression. Date and cause of death were collected up until 2018-12-31. Tumor- and patient characteristics were available from the MDCS. Missing data was imputed using chained equations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for low vs high expression of THRα-2 related to specific tumor factors. Mortality was evaluated with Kaplan–Meier curves and Cox regression, rendering hazard ratios (HRs). Analyses were also stratified for estrogen receptor (ER) status.

Results
We found strong evidence of an association between low THRα-2 and unfavorable tumor characteristics, including estrogen receptor negativity: OR 4.04 (95% CI 2.28–7.15) and tumor size > 20–50 mm: OR 2.20 (95% CI 1.39–3.49). We found evidence of increased breast cancer-specific mortality for women with low THRα-2, HR 1.38 (95% CI 0.96–1.99), which remained after adjusting for age at diagnosis, HR 1.48 (95% CI 1.03–2.14), but not after adjusting for relevant prognostic factors, HR 0.98 (95% CI 0.66–1.45). THRα-2 expression in ER-negative tumors had an inverse correlation with overall mortality, HR 0.27 (95% CI 0.11–0.65).

Conclusion
Low tumor-specific THRα-2 expression was in this study associated with prognostically unfavorable tumor characteristics and a higher mortality in breast cancer, but not independent from other prognostic factors.
SCEPTRE improves calibration and sensitivity in single-cell CRISPR screen analysis
Authors: Barry Timothy , Wang Xuran , Morris John A. , Roeder Kathryn , Katsevich Eugene 
Published: December 2021

AbstractSingle-cell CRISPR screens are a promising biotechnology for mapping regulatory elements to target genes at genome-wide scale. However, technical factors like sequencing depth impact not only expression measurement but also perturbation detection, creating a confounding effect. We demonstrate on two single-cell CRISPR screens how these challenges cause calibration issues. We propose SCEPTRE: analysis of single-cell perturbation screens via conditional resampling, which infers associations between perturbations and expression by resampling the former according to a working model for perturbation detection probability in each cell. SCEPTRE demonstrates very good calibration and sensitivity on CRISPR screen data, yielding hundreds of new regulatory relationships supported by orthogonal biological evidence.
Salivary gland ultrasonography in primary Sjögren’s syndrome from diagnosis to clinical stratification: a multicentre study
Authors: Zhang Xia , Feng Ruiling , Zhao Jinxia , Wang Yu , He Juan , Liu Li , Cheng Yongjing , Yao Haihong , Tang Sumei , Chen Jiali , Zhang Shanshan , Zhang Zhiyi , Wang Qingwen , He Jing , Li Zhanguo 
Published: December 2021

Abstract
Background
To determine the diagnostic accuracy of major salivary gland ultrasonography (SGUS) in primary Sjögren’s syndrome (pSS) using the novel Outcome Measures in Rheumatology Clinical Trials (OMERACT) scoring system in a large-scale multicentre study.

Methods
SGUS was conducted for 246 pSS patients, 140 control subjects with conditions other than SS and 27 healthy control subjects. The echostructure features from the parotid and submandibular glands on both sides were graded using the novel OMERACT scoring system. Receiver operating characteristic curves were used to describe the diagnostic accuracy of the scoring system for pSS. The associations between the SGUS and disease characteristics were analysed to evaluate the clinical value of SGUS for pSS.

Results
The US scores in the pSS group were significantly higher than those in the non-pSS group (p < 0.001). The level of diagnostic accuracy was comparable with the scores of all four glands (AUC=0.908) when only the parotid and submandibular glands on either side were scored (AUC=0.910, 0.904, respectively). The optimal cut-off value for the left (right) parotid gland and the left (right) submandibular gland was 4, with maximal sensitivity (75.6% and 77.2%, respectively) and specificity (91.6% and 92.2%, respectively). The pSS patients with positive SGUS results presented a longer disease duration, parotid enlargement, dental loss and higher levels of serological markers, such as anti-SSA, anti-SSB, positive RF, IgG and γ-globulin%.

Conclusions
SGUS with the OMERACT scoring system yields high sensitivity and specificity, demonstrating high diagnostic feasibility for pSS. The SGUS may have implications for deciding disease severity and treatment efficacy.
Genomic characterization of bacteriophage BI-EHEC infecting strains of Enterohemorrhagic Escherichia coli
Authors: Dewanggana Marta Nisita , Waturangi Diana Elizabeth , Yogiara  
Published: December 2021

Abstract
Objective
The aims of this research were to determine the genomic properties of BI-EHEC to control Enterohemorrhagic Escherichia coli (EHEC), which was isolated from previous study. Genomic analysis of this phage is essential for the assessment of this bacteriophage for further application as food preservatives.

Results
Genome of BI-EHEC was successfully annotated using multiPhATE2. Structural and lytic cycle-related proteins such as head, tail, capsid, and lysozyme (lysin) were annotated. The phylogenetic tree of tail fiber protein and BRIG results showed that BI-EHEC was similar to phages of the same host in the bacteriophage genome database. There were no indications of virulence properties, antibiotic resistance genes and lysogenic protein among annotated genes which implied BI-EHEC followed a lytic life cycle. PHACTS analysis was done to confirm this notion further and yielded a lytic cycle result. Further analysis using CARD found that BI-EHEC does not contain residual ARGs per recommended parameter. Furthermore, BI-EHEC confirmed as lytic bacteriophage, making it a good candidate for biocontrol agent.
Reproductive history and blood cell DNA methylation later in life: the Young Finns Study
Authors: Harville Emily W. , Mishra Pashupati P. , Kähönen Mika , Raitoharju Emma , Marttila Saara , Raitakari Olli , Lehtimäki Terho 
Published: December 2021

Abstract
Background
Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications.

Methods
Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices.

Results
Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure.

Conclusions
Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.
DZNep promotes mouse bone defect healing via enhancing both osteogenesis and osteoclastogenesis
Authors: Cao Xiankun , He Wenxin , Rong Kewei , Xu Shenggui , Chen Zhiqian , Liang Yuwei , Han Shuai , Zhou Yifan , Yang Xiao , Ma Hui , Qin An , Zhao Jie 
Published: December 2021

AbstractBackgroundEnhancer of zeste homolog 2 (EZH2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. This study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing.MethodsBone marrow-derived macrophages (BMMs) cells were cultured, and their responsiveness to DZNep was evaluated by cell counting kit-8, TRAP staining assay, bone resorption assay, podosome actin belt. Bone marrow-derived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by cell counting kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection, and the effectiveness was evaluated by X-ray and micro-CT and histological staining.ResultsConsistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo.ConclusionDZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.