bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of glycolysis related pathways in pancreatic adenocarcinoma and liver hepatocellular carcinoma based on TCGA and GEO datasets
Authors: Li Ji , Zhu Chen , Yue Peipei , Zheng Tianyu , Li Yan , Wang Biao , Meng Xin , Zhang Yao 
Published: February 2021

Abstract
Background
Abnormal energy metabolism is one of the characteristics of tumor cells, and it is also a research hotspot in recent years. Due to the complexity of digestive system structure, the frequency of tumor is relatively high. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms.

Methods
Gene set variance analysis (GSVA) R package was used to establish the metabolic score, and the score was used to represent the metabolic level. The relationship between the metabolism and prognosis of digestive system tumors was explored using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Volcano plots and gene ontology (GO) analyze were used to show different genes and different functions enriched between different glycolysis levels, and GSEA was used to analyze the pathway enrichment. Nomogram was constructed by R package based on gene characteristics and clinical parameters. qPCR and Western Blot were applied to analyze gene expression. All statistical analyses were conducted using SPSS, GraphPad Prism 7, and R software. All validated experiments were performed three times independently.

Results
High glycolysis metabolism score was significantly associated with poor prognosis in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). The STAT3 (signal transducer and activator of transcription 3) and YAP1 (Yes1-associated transcriptional regulator) pathways were the most critical signaling pathways in glycolysis modulation in PAAD and LIHC, respectively. Interestingly, elevated glycolysis levels could also enhance STAT3 and YAP1 activity in PAAD and LIHC cells, respectively, forming a positive feedback loop.

Conclusions
Our results may provide new insights into the indispensable role of glycolysis metabolism in digestive system tumors and guide the direction of future metabolism–signaling target combined therapy.
Prognostic significance of pretreatment controlling nutritional status score in urological cancers: a systematic review and meta‐analysis
Authors: Niu Xinhao , Zhu Zhe , Bao Juan 
Published: February 2021

Abstract
Background
Controlling Nutritional Status (CONUT) score is a novel nutrition-based biomarker that has been reported for predicting survival in various cancers. However, the relationship between CONUT score and prognosis of urological cancers remains unclear. Hence, we performed this meta-analysis to evaluate the prognostic significance of CONUT score for patients with urological cancers.

Methods
PubMed, Embase, the Cochrane Library and National Knowledge Infrastructure (CNKI) were systematically searched up to October 2020. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the association of CONUT score with overall survival (OS), cancer-specific survival (CSS) and recurrence/disease/progress-free survival (RFS/DFS/PFS) in urological cancers.

Results
A total of 12 articles with 13 studies were included in the analysis. Pooled results indicated that increased CONUT score predicted poor OS (HR: 1.78, 95% CI 1.51–2.09, p < 0.001), CSS (HR: 2.14, 95% CI 1.55–2.97, p < 0.001) and RFS/DFS/PFS (HR: 1.57, 95% CI 1.35–1.84, p < 0.001). Subgroup analysis by cancer type revealed that high CONUT score associated with worse OS in renal cell carcinoma (RCC) and urothelial cancer (UC) (HR: 3.05, 95% CI 2.07–4.50, p < 0.001; HR: 1.58, 95% CI 1.32–1.89, p < 0.001). Similar results could be found in CSS (RCC HR: 2.67, 95% CI 1.87–3.81, p < 0.011; UC HR: 1.68, 95% CI 1.09–2.59, p = 0.011) and in RFS/DFS/PFS (RCC HR: 1.96, 95% CI 1.44–2.66, p < 0.001; UC HR: 1.42, 95% CI 1.18–1.71, p < 0.001).

Conclusions
These results illustrated that the high CONUT score may predict worse survival for patients suffering from urological cancers. Therefore, the CONUT score may represent an effective prognostic indicator in urological cancers.
Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma
Authors: Zhu Lei , Yang Fugui , Wang Lingwei , Dong Lin , Huang Zhiyuan , Wang Guangxue , Chen Guohan , Li Qinchuan 
Published: February 2021

Abstract
Background
Ferroptosis is a recently recognized non-apoptotic cell death that is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in esophageal adenocarcinoma (EAC) remains unclear. This study aims to explore the ferroptosis-related genes (FRG) expression profiles and their prognostic values in EAC.

Methods
The FRG data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regressions were used to identify the prognostic FRG, and the predictive ROC model was established using the independent risk factors. GO and KEGG enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and TIMER database. Finally, SDG were verified in clinical EAC specimens and normal esophageal mucosal tissues.

Results
Twenty-eight significantly different FRG were screened from 78 EAC and 9 normal tissues. Enrichment analyses showed these SDG were mainly related to the iron-related pathways and metabolisms of ferroptosis. Gene network demonstrated the TP53, G6PD, NFE2L2 and PTGS2 were the hub genes in the biology of ferroptosis. Cox regression analyses demonstrated four FRG (CARS1, GCLM, GLS2 and EMC2) had prognostic values for overall survival (OS) (all P < 0.05). ROC curve showed better predictive ability using the risk score (AUC = 0.744). Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significant different with those in the low-risk group (all P < 0.05). The experimental results confirmed the ALOX5, NOX1 were upregulated and the MT1G was downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P < 0.05).

Conclusions
We identified differently expressed ferroptosis-related genes that may involve in EAC. These genes have significant values in predicting the patients’ OS and targeting ferroptosis may be an alternative for therapy. Further studies are necessary to verify these results of our study.
LncRNA HOXA-AS3 promotes gastric cancer progression by regulating miR-29a-3p/LTβR and activating NF-κB signaling
Authors: Qu Feng , Zhu Bin , Hu Yi-Lin , Mao Qin-Sheng , Feng Ying 
Published: February 2021

Abstract
Background
Gastric cancer (GC) is among the most common and deadliest cancers globally. Many long non-coding RNAs (lncRNAs) are key regulators of GC pathogenesis. This study aimed to define the role of HOXA-AS3 in this oncogenic context.

Methods
Levels of HOXA-AS3 expression in GC were quantified via qPCR. The effects of HOXA-AS3 knockdown on GC cells function were evaluated in vitro using colony formation assays, wound healing assays and transwell assays. Subcutaneous xenograft and tail vein injection tumor model systems were generated in nude mice to assess the effects of this lncRNA in vivo. The localization of HOXA-AS3 within cells was confirmed by subcellular fractionation, and predicted microRNA (miRNA) targets of this lncRNA and its ability to modulate downstream NF-κB signaling in GC cells were evaluated via luciferase-reporter assays, immunofluorescent staining, and western blotting.

Results
GC cells and tissues exhibited significant HOXA-AS3 upregulation (P < 0.05), and the levels of this lncRNA were found to be correlated with tumor size, lymph node status, invasion depth, and Helicobacter pylori infection status. Knocking down HOXA-AS3 disrupted GC cell proliferation, migration, and invasion in vitro and tumor metastasis in vivo. At a mechanistic level, we found that HOXA-AS3 was able to sequester miR-29a-3p, thereby regulating the expression of LTβR and modulating NF-κB signaling in GC.

Conclusion
HOXA-AS3/miR-29a-3p/LTβR/NF-κB regulatory axis contributes to the progression of GC, thereby offering novel target for the prognosis and treatment of GC.
Inhibitory role of ATF3 in gastric cancer progression through regulating cell EMT and stemness
Authors: Huang Chuanqian , Chen Renli , Zheng Fangjing , Tang Yirong , Wang Xiukang , Chen Zichun , Lai Xiaolan 
Published: February 2021

Abstract
Background
Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer related mortality worldwide. The 5-year survival rate is rather low owing to advanced unresectable and distant metastasis. The EMT has been widely implicated in the stemness, metastatic dormancy, and chemoresistance of different solid tumors. Given the fact that activating transcription factor-3 (ATF3) is a member of the ATF/CREB family of transcription factors and its role in regulation of GC recurrence and metastasis remain poorly understood, the aim of the present study was to investigate its potential impact in epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties and GC aggression.

Methods
To elucidate the potential role of ATF3 in gastric cancer, we utilized SGC-7901 and MGC-803 gastric cancer cell lines as research models and constructed stable cell lines overexpressing ATF3. We conducted a series of assays including cell proliferation, colony formation, cell migration, tumorsphere formation, and invasion to investigate the functional roles of ATF3 in stemness of gastric cancer. The possible effect of ATF3 on epithelial–mesenchymal transition (EMT) was assessed through flow cytometry and qRT-PCR. In vivo functional effect of upregulation of ATF3 on tumor growth was examined in a mouse xenograft model.

Results
We found that overexpression of ATF3 inhibited cell proliferation, colony formation, cell migration and invasion. In addition, up-regulation of ATF3 attenuated tumorsphere formation, cell stemness, and potentially decreased expression of EMT markers. Moreover, ATF3 overexpression inhibited tumorigenesis in mouse xenograft model.

Conclusion
Our data suggest a suppressive role of ATF3 in gastric cancer development. Our findings will provide a potential therapeutic strategy and novel drug target for gastric cancer.
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones
Authors: Chen Yizhe , Zhu Fangyi , Hammill Jared , Holbrook Gloria , Yang Lei , Freeman Burgess , White Karen L. , Shackleford David M. , O’Loughlin Kathleen G. , Charman Susan A. , Mirsalis Jon C. , Guy R. Kiplin 
Published: February 2021

Abstract
Background
The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described.

Methods
The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs.

Results
Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg.

Conclusion
SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.
Computational flow cytometric analysis to detect epidermal subpopulations in human skin
Authors: Zhang Lidan , Cen Ying , Huang Qiaorong , Li Huifang , Mo Xianming , Meng Wentong , Chen Junjie 
Published: February 2021

AbstractBackgroundThe detection and dissection of epidermal subgroups could lead to an improved understanding of skin homeostasis and wound healing. Flow cytometric analysis provides an effective method to detect the surface markers of epidermal cells while producing high-dimensional data files.MethodsA 9-color flow cytometric panel was optimized to reveal the heterogeneous subgroups in the epidermis of human skin. The subsets of epidermal cells were characterized using automated methods based on dimensional reduction approaches (viSNE) and clustering with Spanning-tree Progression Analysis of Density-normalized Events (SPADE).ResultsThe manual analysis revealed differences in epidermal distribution between body sites based on a series biaxial gating starting with the expression of CD49f and CD29. The computational analysis divided the whole epidermal cell population into 25 clusters according to the surface marker phenotype with SPADE. This automatic analysis delineated the differences between body sites. The consistency of the results was confirmed with PhenoGraph.ConclusionA multicolor flow cytometry panel with a streamlined computational analysis pipeline is a feasible approach to delineate the heterogeneity of the epidermis in human skin.
Socio-economic factors do also matter: comments on the article “can climatic factors explain the differences in COVID-19 incidence and severity across the SPANISH regions?: an ecological study”
Authors: Cacho Pedro Muñoz , Hernández José L. , López-Hoyos Marcos , Martínez-Taboada Víctor M. 
Published: February 2021

AbstractPhosri et al., commented on our previous study about the influence of climate variables at the beginning of the SARS-CoV-2 pandemic in Spain. They showed the impact of the association of gross domestic product (GDP) with the cumulative COVID-19 incidence per 105 inhabitants in our country and the rise of several methodologic issues. Here we discussed the main advantages and disadvantages of ecological studies and we advocate to test the hypothesis created in this type of studies using individual-level research designs.
Gold nanoparticles reduce inflammation in cerebral microvessels of mice with sepsis
Authors: Di Bella Davide , Ferreira João P. S. , Silva Renee de Nazare O. , Echem Cinthya , Milan Aline , Akamine Eliana H. , Carvalho Maria H. , Rodrigues Stephen F. 
Published: February 2021

AbstractBackgroundSepsis is an emergency medical condition that can lead to death and it is defined as a life-threatening organ dysfunction caused by immune dysregulation in response to an infection. It is considered the main killer in intensive care units. Sepsis associated-encephalopathy (SAE) is mostly caused by a sepsis-induced systemic inflammatory response. Studies report SAE in 14–63% of septic patients. Main SAE symptoms are not specific and usually include acute impairment of consciousness, delirium and/or coma, along with electroencephalogram (EEG) changes. For those who recover from sepsis and SAE, impaired cognitive function, mobility and quality of life are often observed months to years after hospital discharge, and there is no treatment available today to prevent that. Inflammation and oxidative stress are key players for the SAE pathophysiology. Gold nanoparticles have been demonstrated to own important anti-inflammatory properties. It was also reported 20 nm citrate-covered gold nanoparticles (cit-AuNP) reduce oxidative stress. In this context, we tested whether 20 nm cit-AuNP could alleviate the acute changes caused by sepsis in brain of mice, with focus on inflammation. Sepsis was induced in female C57BL/6 mice by cecal ligation and puncture (CLP), 20 nm cit-AuNP or saline were intravenously (IV) injected 2 h after induction of sepsis and experiments performed 6 h after induction. Intravital microscopy was used for leukocyte and platelet adhesion study in brain, blood brain barrier (BBB) permeability carried out by Evans blue assay, cytokines measured by ELISA and real time PCR, cell adhesion molecules (CAMs) by flow cytometry and immunohistochemistry, and transcription factors, by western blotting.Results20 nm cit-AuNP treatment reduced leukocyte and platelet adhesion to cerebral blood vessels, prevented BBB failure, reduced TNF- concentration in brain, and ICAM-1 expression both in circulating polymorphonuclear (PMN) leukocytes and cerebral blood vessels of mice with sepsis. Furthermore, 20 nm cit-AuNP did not interfere with the antibiotic effect on the survival rate of mice with sepsis.ConclusionsCit-AuNP showed important anti-inflammatory properties in the brain of mice with sepsis, being a potential candidate to be used as adjuvant drug along with antibiotics in the treatment of sepsis to avoid SAE
Correlates of recent nonfatal overdose among people who inject drugs in West Virginia
Authors: Ahmad N. Jia , Allen Sean T. , White Rebecca Hamilton , Schneider Kristin E. , O’Rourke Allison , Perdue Michelle , Babcock Charles , Kilkenny Michael E. , Sherman Susan G. 
Published: February 2021

Abstract
Aim
Experiencing a nonfatal overdose (NFOD) is a significant risk factor for a subsequent nonfatal or fatal overdose. Overdose mortality rates in rural Appalachian states are some of the highest in the USA, but little is known about correlates of overdose among rural populations of people who inject drugs (PWID). Our study aimed to identify correlates of experiencing a recent (past 6 months) NFOD among rural PWID in Cabell County, West Virginia.

Methods
Using data from a June–July 2018 cross-sectional survey that was designed to estimate the size and characteristics of the PWID population in Cabell County, West Virginia, we used log binomial regression to identify correlates (e.g., structural vulnerabilities and substance use) of NFOD in the past 6 months.

Results
The majority of our sample of 420 PWID were male (61.2%), White, non-Hispanic (83.6%), and reported recent heroin injection (81.0%). More than two-fifths (42.6%) experienced a recent NFOD. Independent correlates of NFOD included witnessing an overdose in the past 6 months (adjusted prevalence ratio [aPR] = 2.28; 95% CI 1.48–3.50), attempting to quit using drugs in the past 6 months (aPR = 1.54; 95% CI 1.11–2.14), and the number of drugs injected (aPR = 1.16; 95% CI 1.10–1.23)

Conclusions
A large proportion of rural PWID in Appalachia reported having recently overdosed. The associations between witnessing an overdose, attempting to quit using drugs, and number of drugs injected with recent nonfatal overdose underscore the need for expanded access to overdose prevention resources that are tailored to the needs of this population. Expanding access to evidence-based overdose prevention strategies—such as take-home naloxone programs, treatment with methadone or buprenorphine, and harm reduction services—may decrease overdose morbidity and mortality among rural PWID in Appalachia.
Short Inflammatory Bowel Disease Questionnaire: translation and validation to the Portuguese language
Authors: Roseira Joana , Sousa Helena T. , Marreiros Ana , Contente Luís F. , Magro Fernando 
Published: February 2021

Abstract
Background
The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a widely used instrument to assess Health-related Quality of Life (HRQoL) among inflammatory bowel disease (IBD) patients. Our aim was to translate and adapt the SIBDQ so that it could be adequately used in Portugal.

Methods
This is a prospective design cohort study undertaken at a tertiary hospital. This study took place simultaneously with the first part of the SexIDI study, a study aiming to assess the impact of IBD on patients’ sexual QoL. The original SIBDQ was translated by two independent translators and adapted by an IBD expert panel following the opinions of a convenient sample of 5 IBD patients. Afterwards, IBD patients from the outpatient clinic were consecutively invited to fill the Portuguese version of the questionnaire (SIBDQ-PT) at three different timepoints (0, 2, 4 weeks). Ninety-two patients completed the SIBDQ-PT at baseline, whereas 33 did so after 2 and 4 weeks (approximately). Statistical analysis was performed using SPSS version 25, and the following aspects were analysed: reliability (through internal consistency, test–retest and intraclass correlation), validity (through exploratory factor analysis [EFA], and Pearson correlation coefficient for linear correlations), score distribution, and responsiveness analysis (through t-student tests).

Results
Overall, SIBDQ-PT was shown to have a high internal consistency (Cronbach's α = 0.80) and a high test–retest reliability (0.80 [CI 0.74–0.86] and 0.69 [CI 0.50–0.82]). EFA detected four dimensions—bowel, social, emotional and systemic. As expected, an overall SIBDQ-PT score was positively correlated with sexual satisfaction (r = 0.27; p < 0.05) and negatively correlated with depression (r = − 0.63; p < 0.01). Moreover, SIBDQ-PT was found to have an adequate score distribution, and to be responsive, as there was a significant subscore change for patients who reported an “overall worsening in general well-being” (0.93 ± 0.13 decrease; p < 0.01).

Conclusions
The Portuguese version of the SIBDQ hereby presented is a reliable, valid and responsive instrument that can be used to measure HRQoL among Portuguese IBD patients.
Surgical training model and safe implementation of robotic pancreatoduodenectomy in Japan: a technical note
Authors: Takagi Kosei , Umeda Yuzo , Yoshida Ryuichi , Yagi Takahito , Fujiwara Toshiyoshi , Zureikat Amer H. , Hogg Melissa E. , Koerkamp Bas Groot 
Published: February 2021

Abstract
Background
Growing evidence for the advantages of robotic pancreatoduodenectomy (RPD) has been demonstrated internationally. However, there has been no structured training program for RPD in Japan. Herein, we present the surgical training model of RPD and a standardized protocol for surgical technique.

Methods
The surgical training model and surgical technique were standardized in order to implement RPD safely, based on the Dutch training system collaborated with the University of Pittsburgh Medical Center.

Results
The surgical training model included various trainings such as basic robotic training, simulation training, biotissue training, and a surgical video review. Furthermore, a standardized protocol on the surgical technique was established to understand the tips, tricks, and pitfalls of RPD.

Conclusions
Safe implementation of RPD can be achieved through the completion of a structured training program and learning surgical technique. A nationwide structured training system should be developed to implement the program safely in Japan.