bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene in endometrial cancer
Authors: Tian Wenjuan , Ji Zhaodong , Wang Jingshu , Meng Jiao , Bi Rui , Ren Yulan , Shan Boer , Yang Gong , Wang Huaying 
Published: October 2022

ObjectiveThis study was aimed to profile hotspot exonuclease domain mutations (EDMs) of the DNA polymerase ϵ gene (POLE) in endometrial cancer (EC) and to investigate the effects of EDMs on tumor cell behavior and catalytic activities of Polϵ.MethodsPOLE sequencing was performed in tumor tissue samples from patients with EC to identify hotspot EDMs. Bioinformatics tools were used to select the potential pathogenic EDMs. The association of EDMs with the clinical outcomes of patients was assessed. EC cells were transfected with wildtype POLE or POLE variants to examine the effects of the EDMs on EC cell behavior, including cell cycle, migration, and invasion. Co-immunoprecipitation was employed to obtain FLAG-tagged wildtype and mutant catalytic subunits of Polϵ, followed by the assessment of polymerase and exonuclease activities.ResultsIn addition to previously reported P286R and V411L, R375Q and P452L were identified as novel, and deleterious POLE hotspot EDMs of EC. Patients in EDM group had significantly better clinical outcomes than the rest of the cohort. Compared with wildtype POLE, overexpression of POLE variants promoted cisplatin resistance, G0/G1 cell cycle arrest, and cell migration and invasion in EC cells. Overexpression of POLE variants significantly increased the abundance of 3’-OH and upregulated the expression of DNA mismatch repair genes in HEK293T cells. Compared with wildtype Polϵ, Pol ϵ mutants exhibited undermined polymerase and exonuclease abilities in the presence of mismatched nucleotides in HEK293 cells.ConclusionWe characterized the of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene and identified P286R, V411L, R375Q, and P452L as pathogenic POLE hotspot EDMs in endometrial cancer. These hotspot EDMs are associated with the malignant behavior of endometrial cancer cells in vitro and favorable prognosis in patients, suggesting that POLE affects a wide range of cellular processes beyond DNA replication and proofreading.
Multilevel impacts of a pediatric early warning system in resource-limited pediatric oncology hospitals
Authors: Mirochnick Emily , Graetz Dylan E. , Ferrara Gia , Puerto-Torres Maria , Gillipelli Srinithya R. , Elish Paul , Muniz-Talavera Hilmarie  , Gonzalez-Ruiz Alejandra , Armenta Miriam , Barra Camila , Diaz-Coronado Rosdali , Hernandez Cinthia , Juarez Susana , Loeza Jose de Jesus , Mendez Alejandra , Montalvo Erika , Penafiel Eulalia , Pineda Estuardo , Agulnik Asya 
Published: October 2022

BackgroundPediatric Early Warning Systems (PEWS) reduce clinical deterioration, improve interdisciplinary communication, and provide cost savings; however, little is known about how these impacts are achieved or related. This study evaluates the multi-level impacts of PEWS in resource-limited pediatric oncology centers.MethodsWe conducted 71 semi-structured interviews including physicians (45%), nurses (45%), and administrators (10%) from 5 resource-limited pediatric oncology centers in 4 Latin American countries. Interviews were conducted in Spanish, transcribed, and translated into English. A code book was developed using a priori and inductively derived codes. Transcripts were independently coded by 2 coders, achieving a kappa of 0.8-0.9. Thematic content analysis explored perceived impacts of PEWS at the level of the patient, clinician, healthcare team, and institution.ResultsPEWS improved the quality of attention for patients, reducing morbidity and mortality. Clinicians felt more knowledgeable, confident, and empowered providing patient care, resulting in greater job satisfaction. PEWS affected team dynamics by improving interdisciplinary (ward and intensive care unit) and interprofessional (physicians and nurses) relationships and communication. This ultimately led to institutional culture change with emphasis on patient safety, collaboration with other centers, and receipt of institutional awards. Together, these impacts led to hospital-wide support of ongoing PEWS use.ConclusionsIn resource-limited hospitals, PEWS use results in multi-level positive impacts on patients, clinicians, teams, and institutions, creating a feedback loop that further supports ongoing PEWS use. These findings can guide advocacy for PEWS to various stakeholders, improve PEWS effectiveness, and inform assessment of other interventions to improve childhood cancer outcomes.
The role of neoadjuvant chemotherapy in patients with locally advanced colon cancer: A systematic review and meta-analysis
Authors: Liang Zongyu , Li Zhu , Yang Qingshui , Feng Jiahao , Xiang Deyu , Lyu Haina , Mai Guangzhi , Wang Wanchuan 
Published: October 2022

BackgroundControversy persists about neoadjuvant chemotherapy (NAC) within the field of locally advanced colon cancer (LACC). The purpose of this study was to assess the existing and latest literature with high quality to determine the role of NAC in various aspects.MethodsA comprehensive literature search of the PubMed, Embase, Web of Science, and the Cochrane Library databases was conducted from inception to April 2022. Review Manager 5.3 was applied for meta-analyses with a random-effects model whenever possible.ResultsOverall, 8 studies were included in this systematic review and meta-analysis, comprising 4 randomized controlled trials (RCTs) and 4 retrospective studies involving 40,136 participants. The 3-year overall survival (OS) (HR: 0.90, 95% CI: 0.66-1.23, P = 0.51) and 5-year OS (HR: 0.89, 95% CI: 0.53-1.03, P = 0.53) were comparable between two groups. Mortality in 30 days was found less frequent in the NAC group (OR: 0.43, 95% CI: 0.20-0.91, P = 0.03), whereas no significant differences were detected concerning other perioperative complications, R0 resection, or adverse events. In terms of subgroup analyses for RCTs, less anastomotic leak (OR: 0.51, 95% CI: 0.31-0.86, P = 0.01) and higher R0 resection rate (OR: 2.35, 95% CI: 1.04-5.32, P = 0.04) were observed in the NAC group.ConclusionsNAC is safe and feasible for patients with LACC, but no significant survival benefit could be demonstrated. The application of NAC still needs to be prudent until significant evidence supporting the oncological outcomes is presented.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier (CRD42022333306).
Extracellular vesicles from gastric epithelial GES-1 cells infected with Helicobacter pylori promote changes in recipient cells associated with malignancy
Authors: González María Fernanda , Burgos-Ravanal Renato , Shao Baohai , Heinecke Jay , Valenzuela-Valderrama Manuel , Corvalán Alejandro H. , Quest Andrew F. G. 
Published: October 2022

Chronic Helicobacter pylori (H. pylori) infection is considered the main risk factor for the development of gastric cancer. Pathophysiological changes in the gastric mucosa initiated by this bacterium can persist even after pharmacological eradication and are likely attributable also to changes induced in non-infected cells as a consequence of intercellular communication via extracellular vesicles (EVs). To better understand what such changes might entail, we isolated EVs from immortalized normal gastric GES-1 cells infected (EVHp+) or not with H. pylori (EVHp-) by ultracentrifugation and characterized them. Infection of GES-1 cells with H. pylori significantly increased the release of EVs and slightly decreased the EV mean size. Incubation with EVHp+ for 24 h decreased the viability of GES-1 cells, but increased the levels of IL-23 in GES-1 cells, as well as the migration of GES-1 and gastric cancer AGS cells. Furthermore, incubation of GES-1 and AGS cells with EVHp+, but not with EVHp-, promoted cell invasion and trans-endothelial migration in vitro. Moreover, stimulation of endothelial EA.hy926 cells for 16 h with EVHp+ promoted the formation of linked networks. Finally, analysis by mass spectrometry identified proteins uniquely present and others enriched in EVHp+ compared to EVHp-, several of which are known targets of hypoxia induced factor-1α (HIF-1α) that may promote the acquisition of traits important for the genesis/progression of gastric pre-neoplastic changes associated with H. pylori infection. In conclusion, the harmful effects of H. pylori infection associated with the development of gastric malignancies may spread via EVs to non-infected areas in the early and later stages of gastric carcinogenesis.
Prognosis of clear cell renal cell carcinoma patients stratified by age: A research relied on SEER database
Authors: Liao Zhouning , Wang Dang , Song Ning , Xu Yang , Ge Heming , Peng Zhangzhe 
Published: October 2022

ObjectiveClear cell renal cell carcinoma may affect patients of any age. To date, there are only a limited number of large data studies on renal clear cell carcinoma in different age groups. This study assessed CCRCC risk factors in different age groups using the Surveillance Epidemiology and End Results (SEER) database.MethodsWe selected 58372 cases from the SEER database. These patients were divided into seven different age groups. Cox regression models were used to find independent risk factors for the survival of CCRCC patients. Based on independent risk factors, a nomogram was drawn with R software. Kaplan-Meier method for survival analysis and X-tile software were used to find the optimal age group for diagnosis.ResultsUnivariate analysis revealed that patients’ age, sex, race, marital status, grade, TNM (tumor, node, metastasis) stage, surgery, WHO/ISUP grade were correlated with survival (P&lt;0.01). Age was an independent risk factor for survival in patients with CCRCC according to multivariate Cox regression analysis (p&lt;0.01). All-cause mortality and tumor-specific mortality increased according to the increasing age of the patients. The optimal cut-off values for age were defined as 58 and 76 years and 51 and 76 years, respectively, according to overall survival (OS) and cause-specific survival (CSS).ConclusionThere is a negative correlation between age and survival of CCRCC patients. The difference in prognosis of patients in different age groups has important implications for clinical treatment. Therefore, the diagnosis and treatment plan should be based on more detailed age grouping, which is more beneficial to improving the prognosis and survival of patients.
Electroacupuncture induces weight loss by regulating tuberous sclerosis complex 1-mammalian target of rapamycin methylation and hypothalamic autophagy in high-fat diet-induced obese rats
Authors: Yao Junpeng , Yan Xiangyun , Xiao Xianjun , You Xi , Li Yanqiu , Yang Yuqing , Zhang Wei , Li Ying 
Published: October 2022

Background: Obesity can be caused by abnormalities of hypothalamic autophagy, which is closely regulated by the epigenetic modification of TSC1-mTOR. However, whether the weight-reducing effect of EA may relate to the modification of TSC1-mTOR methylation and hypothalamic autophagy remain unclear. This study was conducted to reveal the possible mechanism by which EA reduces BW by measuring the levels of TSC1-mTOR methylation and hypothalamic autophagy-related components.Methods: The weight-reducing effect of EA was investigated in high-fat diet (HFD)-induced obese (DIO) rats by monitoring the BW, food consumption, and epididymal white adipose tissue (eWAT)/BW ratio. Hematoxylin and eosin staining was performed for morphological evaluation of eWAT. Immunofluorescence was utilized to observe the localization of LC3 in the hypothalamus. The expressions of autophagy components (Beclin-1, LC3, and p62) and mTOR signaling (mTOR, p-mTOR, p70S6K, and p-p70S6K) were assessed by western blot. The methylation rate of the TSC1 promoter was detected by bisulfite genomic sequencing.Results: Treatment with EA significantly reduced the BW, food consumption, and eWAT/BW ratio; attenuated the morphological alternations in the adipocytes of DIO rats. While HFD downregulated the expression levels of Beclin-1 and LC3 and upregulated those of p62, these changes were normalized by EA treatment. EA markedly decreased the methylation rate of the TSC1 gene promoter and suppressed the protein expressions of mTOR, p-mTOR, p70S6K, and p-p70S6K in the hypothalamus.Conclusion: EA could reduce BW and fat accumulation in DIO rats. This ameliorative effect of EA may be associated with its demethylation effect on TSC1-mTOR and regulation of autophagy in the hypothalamus.
Based on network pharmacology and molecular docking to explore the protective effect of Epimedii Folium extract on cisplatin-induced intestinal injury in mice
Authors: Xia Juan , Hu Jun-Nan , Wang Zi , Cai En-Bo , Ren Shen , Wang Ying-Ping , Lei Xiu-Juan , Li Wei 
Published: October 2022

Background: Epimedii Folium, as a natural botanical medicine, has been reported to have protective effects on intestinal diseases by modulating multiple signaling pathways. This study aimed to explore the potential targets and molecular mechanisms of Epimedii Folium extract (EFE) against cisplatin-induced intestinal injury through network pharmacology, molecular docking, and animal experiments.Methods: Network pharmacology was used to predict potential candidate targets and related signaling pathways. Molecular docking was used to simulate the interactions between significant potential candidate targets and active components. For experimental validation, mice were intraperitoneally injected with cisplatin 20 mg/kg to establish an intestinal injury model. EFE (100, 200 mg/kg) was administered to mice by gavage for 10 days. The protective effect of EFE on intestinal injury was analyzed through biochemical index detection, histopathological staining, and western blotting.Results: Network pharmacology analysis revealed that PI3K-Akt and apoptosis signaling pathways were thought to play critical roles in EFE treatment of the intestinal injury. Molecular docking results showed that the active constituents of Epimedii Folium, including Icariin, Epimedin A, Epimedin B, and Epimedin C, stably docked with the core AKT1, p53, TNF-α, and NF-κB. In verified experiments, EFE could protect the antioxidant defense system by increasing the levels of glutathione peroxidase (GSH-Px) and catalase (CAT) while reducing the content of malondialdehyde (MDA). EFE could also inhibit the expression of NF-κB and the secretion of inflammatory factors, including TNF-α, IL-1β, and IL-6, thereby relieving the inflammatory damage. Further mechanism studies confirmed that EFE had an excellent protective effect on cisplatin-induced intestinal injury by regulating PI3K-Akt, caspase, and NF-κB signaling pathways.Conclusion: In summary, EFE could mitigate cisplatin-induced intestinal damage by modulating oxidative stress, inflammation, and apoptosis.
The effects of aqueous extract of Labisia Pumila (Blume) Fern.-Vill. Var. Alata on wound contraction, hydroxyproline content and histological assessments in superficial partial thickness of second-degree burn model
Authors: Ibrahim Nurul ‘Izzah , Mohamed Isa Naina , Mohamed Norazlina , Mohd Ramli Elvy Suhana , Shuid Ahmad Nazrun 
Published: October 2022

Background: Burns are considered a critical care problem in emergency medicine, resulting in physical, psychological, and chronic disabilities. Silver sulfadiazine is the gold standard in topical burn treatment but was associated with toxicity to keratinocytes and fibroblasts, which may delay wound healing. In discovering potential alternative treatments for burn wound healing, this study was performed to determine the effect of Labisia Pumila (Blume) Fern.-Vill. Var. Alata (LPVa) extract on thermal-burn wounds in rats.Methods: A total of 50 Sprague-Dawley male rats were categorized into five groups. There were three control groups; normal control (left untreated), negative control (given ointment base) and positive control (given silver sulfadiazine). Meanwhile, the two intervention groups were given with 2% LPVa leaf and root extracts, respectively. Burn wounds were inflicted on the loin region of the rat by applying a heated steel rod at 80°C for 10 s. On days 3, 7, 14, and 21, wounds were measured macroscopically using a digital calliper and one animals of each group were sacrificed, and the wounded skin were excised for histomorphological assessments. The wounds were excised for hydroxyproline content on Day 14 of treatment.Result: For wound contraction percentage, both the leaf and root extracts of LPVa showed a significant reduction in burn wound size on Day 7 onwards, when compared to other groups. For hydroxyproline content, only the leaf extract of LPVa produced significantly higher content compared to both negative and normal control groups. In terms of histological examination, the leaf extract group demonstrated a superior healing effect than the root extract group.Conclusion: Both leaf and root extracts of LPVa could promote wound healing in the thermal-burn wound rat model, with leaf extract being superior to root extract.
Artificial intelligence analysis of the impact of fibrosis in arrhythmogenesis and drug response
Authors: Sánchez de la Nava Ana María , Gómez-Cid Lidia , Domínguez-Sobrino Alonso , Fernández-Avilés Francisco , Berenfeld Omer , Atienza Felipe 
Published: October 2022

Background: Cardiac fibrosis has been identified as a major factor in conduction alterations leading to atrial arrhythmias and modification of drug treatment response.Objective: To perform an in silico proof-of-concept study of Artificial Intelligence (AI) ability to identify susceptibility for conduction blocks in simulations on a population of models with diffused fibrotic atrial tissue and anti-arrhythmic drugs.Methods: Activity in 2D cardiac tissue planes were simulated on a population of variable electrophysiological and anatomical profiles using the Koivumaki model for the atrial cardiomyocytes and the Maleckar model for the diffused fibroblasts (0%, 5% and 10% fibrosis area). Tissue sheets were of 2 cm side and the effect of amiodarone, dofetilide and sotalol was simulated to assess the conduction of the electrical impulse across the planes. Four different AI algorithms (Quadratic Support Vector Machine, QSVM, Cubic Support Vector Machine, CSVM, decision trees, DT, and K-Nearest Neighbors, KNN) were evaluated in predicting conduction of a stimulated electrical impulse.Results: Overall, fibrosis implementation lowered conduction velocity (CV) for the conducting profiles (0% fibrosis: 67.52 ± 7.3 cm/s; 5%: 58.81 ± 14.04 cm/s; 10%: 57.56 ± 14.78 cm/s; p &lt; 0.001) in combination with a reduced 90% action potential duration (0% fibrosis: 187.77 ± 37.62 ms; 5%: 93.29 ± 82.69 ms; 10%: 106.37 ± 85.15 ms; p &lt; 0.001) and peak membrane potential (0% fibrosis: 89.16 ± 16.01 mV; 5%: 70.06 ± 17.08 mV; 10%: 82.21 ± 19.90 mV; p &lt; 0.001). When the antiarrhythmic drugs were present, a total block was observed in most of the profiles. In those profiles in which electrical conduction was preserved, a decrease in CV was observed when simulations were performed in the 0% fibrosis tissue patch (Amiodarone ΔCV: −3.59 ± 1.52 cm/s; Dofetilide ΔCV: −13.43 ± 4.07 cm/s; Sotalol ΔCV: −0.023 ± 0.24 cm/s). This effect was preserved for amiodarone in the 5% fibrosis patch (Amiodarone ΔCV: −4.96 ± 2.15 cm/s; Dofetilide ΔCV: 0.14 ± 1.87 cm/s; Sotalol ΔCV: 0.30 ± 4.69 cm/s). 10% fibrosis simulations showed that part of the profiles increased CV while others showed a decrease in this variable (Amiodarone ΔCV: 0.62 ± 9.56 cm/s; Dofetilide ΔCV: 0.05 ± 1.16 cm/s; Sotalol ΔCV: 0.22 ± 1.39 cm/s). Finally, when the AI algorithms were tested for predicting conduction on input of variables from the population of modelled, Cubic SVM showed the best performance with AUC = 0.95.Conclusion:In silico proof-of-concept study demonstrates that fibrosis can alter the expected behavior of antiarrhythmic drugs in a minority of atrial population models and AI can assist in revealing the profiles that will respond differently.
Physiological factors affecting the mechanical performance of peripheral muscles: A perspective for long COVID patients through a systematic literature review
Authors: Suba Rao Harinivas Rao , Hamzaid Nur Azah , Ahmad Mohd Yazed , Hamzah Norhamizan 
Published: October 2022

Background: Peripheral muscle weakness can be measured quantitatively in long COVID patients. Mechanomyography (MMG) is an alternative tool to measure muscle strength non-invasively.Objective: This literature review aims to provide evidence on the efficacy of MMG in measuring muscle strength for long COVID patients and to determine the physiological factors that may affect the use of MMG in assessing muscle performance.Methods: A systematic literature review was conducted using EBSCO’s MEDLINE Complete. A total of five out of 2,249 potential publications fulfilled the inclusion criteria.Results: The selected studies addressed muscle performance based on the physiological effects of age, gender, and physical activity level. MMG is sensitive in measuring muscle strength for long COVID patients due to its higher signal-to-noise ratio and lightweight accelerometers. Its neglectable skin impedance and low risk of influences during the recording of surface motions make MMG a reliable tool.Conclusion: Muscle performance is affected by age, gender, and physical activity level. Sensors, such as MMG, as well as the length of the muscle and the characteristics of the muscle activity, are important considerations when choosing a sensor for diagnostic evaluation. The efficacy of MMG in measuring muscle strength for long COVID patients and the physiological factors that may affect the use of MMG in assessing muscle performance are discussed.
Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis
Authors: Labes Robert , Dong Lei , Mrowka Ralf , Bachmann Sebastian , von Vietinghoff Sibylle , Paliege Alexander 
Published: October 2022

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far.Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry.Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion.Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.