bluuebunny/crossref_metadata_2025_split huggingface dataset:
Digital gene expression analysis of NSCLC-patients reveals strong immune pressure, resulting in an immune escape under immunotherapy
Authors: Wessolly Michael , Stephan-Falkenau Susann , Streubel Anna , Wiesweg Marcel , Borchert Sabrina , Mairinger Elena , Kollmeier Jens , Reis Henning , Bauer Torsten , Schmid Kurt Werner , Mairinger Thomas , Schuler Martin , Mairinger Fabian D. 
Published: January 2022

Abstract
Background
Immune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. Although the first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. PD-L1 expression and tumor mutational burden (TMB) were proven to be sometimes-unreliable biomarkers. We have previously suggested the analysis of processing escapes, a qualitative measurement of epitope structure alterations under immune system pressure, to provide predictive information on ICI response. Here, we sought to further validate this approach and characterize interactions with different forms of immune pressure.

Methods
We identified a cohort consisting of 48 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab as ICI monotherapy. Tumor samples were subjected to targeted amplicon-based sequencing using a panel of 22 cancer-associated genes covering 98 mutational hotspots. Altered antigen processing was predicted by NetChop, and MHC binding verified by NetMHC. The NanoString nCounter® platform was utilized to provide gene expression data of 770 immune-related genes. Patient data from 408 patients with NSCLC were retrieved from The Cancer Genome Atlas (TCGA) as a validation cohort.

Results
The two immune escape mechanisms of PD-L1 expression (TPS score) (n = 18) and presence of altered antigen processing (n = 10) are mutually non-exclusive and can occur in the same patient (n = 6). Both mechanisms have exclusive influence on different genes and pathways, according to differential gene expression analysis and gene set enrichment analysis, respectively. Interestingly, gene expression patterns associated with altered processing were enriched in T cell and NK cell immune activity. Though both mechanisms influence different genes, they are similarly linked to increased immune activity.

Conclusion
Pressure from the immune system will lay the foundations for escape mechanisms, leading to acquisition of resistance under therapy. Both PD-L1 expression and altered antigen processing are induced similarly by pronounced immunoactivity but in different context. The present data help to deepen our understanding of the underlying mechanisms behind those immune escapes.
Blood routine risk factors for coronary artery aneurysm in infants younger than 8 months with Kawasaki disease
Authors: Haiyan Ge , Jianming Lai , Suqian Tong , Dong Qu , Shuang Liu , Jin Zhang 
Published: January 2022

Abstract
Objective
The aims of this study were to characterize the evolution of routine blood values within the first 10 days of illness and coronary artery outcome in infants < 8 months with Kawasaki disease (KD) and to identify risk factors for coronary artery aneurysm (CAA).

Methods
Laboratory data, clinical features and coronary artery outcomes from 78 infants < 8 months old and 86 patients between 8 months and 7 years old were retrospectively analyzed. Logistic regression analysis was conducted to evaluate the potential risk factors for CAA.

Results
Infants < 8 months old were more likely to present with incomplete KD (37.2% vs 4.7%, P < 0.001), erythema and induration at the BCG inoculation site (24.4% vs 3.5%, P < 0.001) and CAA (47.4% vs 15.1%, P < 0.001) even with timely diagnosis and treatment with intravenous immunoglobulin (IVIG) compared with patients ≥8 months old. Clinical feature related to diagnostic criteria for KD including bilateral conjunctival injection, oral changes, unilateral cervical lymphadenopathy and extremity changes were less common in the younger group. During the acute phase, the percentage neutrophils and neutrophil to lymphocyte ratio [NLR] peaked on median illness day 3, followed by white blood cell (WBC) and CRP on median illness day 4, hemoglobin on median illness day 7 and platelet count on median illness day 9. CAA occurred on median illness day 6 and regressed on median illness day 28. Multivariate logistic regression analysis revealed that the peak percentage neutrophils (odds ratio [OR] per 0.1: 1.597, 95% confidence interval [CI]: 1.041–2.452, P = 0.032) and the peak platelet count (OR per 10 × 109/L: 1.029, 95% CI: 1.004–1.055, P = 0.024) were independent risk factors for CAA. Hemoglobin on the 5th day was associated with persistent CAA at 1 year after KD onset.

Conclusion
Factors associated with CAA include a high peak percentage neutrophils, increased peak platelet count, and reduced hemoglobin within 4–6 days during the acute phase of KD. Therefore, this population should receive primary therapy with IVIG and adjunctive anti-inflammatory medications.
An informed approach to the development of primary care pediatric firearm safety messages
Authors: Fuzzell Lindsay N. , Dodd Sherry , Hu Sisi , Hinnant Amanda , Lee Sungkyoung , Cameron Glen , Garbutt Jane M. 
Published: January 2022

Abstract
Background
Firearm ownership is prevalent in the US and many children spend time in areas where firearms are not stored safely. The AAP recommends firearm safety counseling at pediatric well-visits.

Methods
We developed and tested six contextual messages to promote safe firearm storage based on: absence of harm, collective appeal to understanding child behavior, pediatrician’s authority, evidence-based, fear appeal, and general safety considerations. One hundred four parents who keep firearms at home were recruited from Amazon Mechanical Turk Prime and viewed video messages and reported behavioral intentions and emotional reactions following each message.

Results
All six contextual messages were perceived as important and believable and increased parents’ intentions to follow safety advice provided, but also elicited negative emotions. The authority message elicited more negative emotions and resulted in lower intentions to follow safe storage advice.

Conclusions
Including firearm messages with other child safety advice merits further evaluation. Authority messages should be avoided.
A novel circ_MACF1/miR-942-5p/TGFBR2 axis regulates the functional behaviors and drug sensitivity in gefitinib-resistant non-small cell lung cancer cells
Authors: Fan Daping , Yang Yue , Zhang Wei 
Published: January 2022

AbstractBackgroundResistance to gefitinib remains a major obstacle for the successful treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In this paper, we studied the precise actions of circular RNA (circRNA) microtubule actin crosslinking factor 1 (circ_MACF1) in gefitinib resistance.MethodsWe established gefitinib-resistant NSCLC cells (PC9/GR and A549/GR). The levels of circ_MACF1, microRNA (miR)-942-5p, and transforming growth factor beta receptor 2 (TGFBR2) were gauged by quantitative real-time PCR (qRT-PCR) or western blot. Subcellular fractionation and Ribonuclease R (RNase R) assays were done to characterize circ_MACF1. Cell survival, proliferation, colony formation, apoptosis, migration, and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2’-Deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. Dual-luciferase reporter assays were used to verify the direct relationship between miR-942-5p and circ_MACF1 or TGFBR2. The xenograft assays were used to assess the role of circ_MACF1 in vivo.ResultsCirc_MACF1 was down-regulated in A549/GR and PC9/GR cells. Overexpression of circ_MACF1 repressed proliferation, migration, invasion, and promoted apoptosis and gefitinib sensitivity of A549/GR and PC9/GR cells in vitro, as well as inhibited tumor growth under gefitinib in vivo. Circ_MACF1 directly targeted miR-942-5p, and miR-942-5p mediated the regulatory effects of circ_MACF1. TGFBR2 was identified as a direct and functional target of miR-942-5p. Circ_MACF1 modulated TGFBR2 expression through miR-942-5p.ConclusionOur findings demonstrated that circ_MACF1 regulated cell functional behaviors and gefitinib sensitivity of A549/GR and PC9/GR cells at least partially by targeting miR-942-5p to induce TGFBR2 expression.
Risk factor analysis and nomogram for predicting in-hospital mortality in ICU patients with sepsis and lung infection
Authors: Ren Yinlong , Zhang Luming , Xu Fengshuo , Han Didi , Zheng Shuai , Zhang Feng , Li Longzhu , Wang Zichen , Lyu Jun , Yin Haiyan 
Published: January 2022

Abstract
Background
Lung infection is a common cause of sepsis, and patients with sepsis and lung infection are more ill and have a higher mortality rate than sepsis patients without lung infection. We constructed a nomogram prediction model to accurately evaluate the prognosis of and provide treatment advice for patients with sepsis and lung infection.

Methods
Data were retrospectively extracted from the Medical Information Mart for Intensive Care (MIMIC-III) open-source clinical database. The definition of Sepsis 3.0 [10] was used, which includes patients with life-threatening organ dysfunction caused by an uncontrolled host response to infection, and SOFA score ≥ 2. The nomogram prediction model was constructed from the training set using logistic regression analysis, and was then internally validated and underwent sensitivity analysis.

Results
The risk factors of age, lactate, temperature, oxygenation index, BUN, lactate, Glasgow Coma Score (GCS), liver disease, cancer, organ transplantation, Troponin T(TnT), neutrophil-to-lymphocyte ratio (NLR), and CRRT, MV, and vasopressor use were included in the nomogram. We compared our nomogram with the Sequential Organ Failure Assessment (SOFA) score and Simplified Acute Physiology Score II (SAPSII), the nomogram had better discrimination ability, with areas under the receiver operating characteristic curve (AUROC) of 0.743 (95% C.I.: 0.713–0.773) and 0.746 (95% C.I.: 0.699–0.790) in the training and validation sets, respectively. The calibration plot indicated that the nomogram was adequate for predicting the in-hospital mortality risk in both sets. The decision-curve analysis (DCA) of the nomogram revealed that it provided net benefits for clinical use over using the SOFA score and SAPSII in both sets.

Conclusion
Our new nomogram is a convenient tool for accurate predictions of in-hospital mortality among ICU patients with sepsis and lung infection. Treatment strategies that improve the factors considered relevant in the model could increase in-hospital survival for these ICU patients.
Healthcare providers’ perception of advance care planning for patients with critical illnesses in acute-care hospitals: a cross-sectional study
Authors: Yamamoto Kanako , Yonekura Yuki , Nakayama Kazuhiro 
Published: January 2022

Abstract
Background
In acute-care hospitals, patients treated in an ICU for surgical reasons or sudden deterioration are treated in an outpatient ward, ICU, and other multiple departments. It is unclear how healthcare providers are initiating advance care planning (ACP) for such patients and assisting them with it. The purpose of this study is to clarify healthcare providers’ perceptions of the ACP support provided to patients receiving critical care in acute-care hospitals.

Methods
A cross-sectional study was conducted using questionnaires. In this study, 400 acute-care hospitals with ICUs in Japan were randomly selected, and 1490 subjects, including intensivists, surgeons, ICU nurses, surgical floor nurses, and surgical outpatient nurses, participated. Survey items examined whether ICU patients received ACP support, the participants’ degree of confidence in providing ACP support, the patients’ treatment preferences, and the decision-making process, and whether any discussion was conducted on change of values.

Results
Responses were obtained from 598 participants from 157 hospitals, 41.4% of which reportedly supported ACP provision to ICU patients. The subjects with the highest level of ACP understanding were surgeons (45.8%), and differences in understanding were observed across specialties (P < 0.001). Among the respondents, physicians and nurses expressed high levels of confidence in providing ACP support to patients requiring critical care. However, 15.2% of all the subjects mentioned that they would not attempt to resuscitate the patients. In addition, 25.7% of the participants handed over patients’ values to other departments or hospitals, whereas 25.3% handed over the decision-making process.

Conclusions
Among the participating hospitals, 40% provided ACP support to patients receiving critical care. The low number is possibly because support providers lack understanding of the content of patients’ ACP or about how to support and use ACP. Second, it is sometimes too late to start providing ACP support after ICU admission. Third, healthcare providers differ in their perception of ACP, widely considered an ambiguous concept. Finally, in acute-care hospitals with different healthcare settings, it is necessary to confirm and integrate the changes in feelings and thoughts of patients.
The relationship between genetic variants associated with primary ovarian insufficiency and lipid profile in women recruited from MASHAD cohort study
Authors: Mirinezhad Mohammad Reza , Ghazizadeh Hamideh , Aghsizadeh Maliheh , Zamiri Bidary Mohammad , Naghipour Alireza , Hasanzadeh Elahe , Yaghooti-Khorasani Mahdiyeh , Ebrahimi Dabagh Ali , Moghadam Mohammad Reza Shadmand Foumani , Sheikh Andalibi Nazanin , Naseri Far Zeynab , Esmaily Habibollah , Ferns Gordon A. , Hamzehloei Tayebeh , Pasdar Alireza , Ghayour-Mobarhan Majid 
Published: January 2022

Abstract
Background and aim
Primary Ovarian Insufficiency (POI) is defined by the occurrence of menopause before the age of 40 years. It is often associated with cardiovascular disease (CVD). The purpose of this study was to explore the relationship between POI-associated genotypes cardiometabolic disorder risk factors.

Methods
One hundred seventeen women with POI and one hundred eighty-three healthy women without POI were recruited in this study. DNA was extracted and analyzed using ASO-PCR or Tetra ARMS-PCR. Lipid profiles were also assessed.

Results
Multivariate logistic regression analysis showed that individuals with GG vs. TT genotype of the rs1046089 SNP were more likely to have a higher serum LDL (p = 0.03) compared to the control group. There was also a significant association between low serum HDL and rs2303369 and rs4806660 SNP genotypes in the POI group. In the POI group, the percentage of those with high total cholesterol was lower in those with a CC genotype compared to those with a TT genotype (p = 0.03).

Conclusion
Some SNPs reported to be associated with POI appear to be independently associated with dyslipidemia. These results may be helpful to identify subjects with POI who may be susceptible to CVD.
Discovery and identification of potential anti-melanogenic active constituents of Bletilla striata by zebrafish model and molecular docking
Authors: Luo Yiyuan , Wang Juan , Li Shuo , Wu Yue , Wang Zhirui , Chen Shaojun , Chen Hongjiang 
Published: January 2022

Abstract
Background
Bletilla striata is the main medicine of many skin whitening classic formulas in traditional Chinese medicine (TCM) and is widely used in cosmetic industry recently. However, its active ingredients are still unclear and its fibrous roots are not used effectively. The aim of the present study is to discover and identify its potential anti-melanogenic active constituents by zebrafish model and molecular docking.

Methods
The antioxidant activities were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2′-azino-bis-(3-ethylbenthiazoline-6-sulphonic acid) (ABTS) radical scavenging activity and ferric reducing antioxidant power (FRAP) assay. The anti-melanogenic activity was assessed by tyrosinase inhibitory activity in vitro and melanin inhibitory in zebrafish. The chemical profiles were performed by ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Meanwhile, the potential anti-melanogenic active constituents were temporary identified by molecular docking.

Results
The 95% ethanol extract of B. striata fibrous roots (EFB) possessed the strongest DPPH, ABTS, FRAP and tyrosinase inhibitory activities, with IC50 5.94 mg/L, 11.69 mg/L, 6.92 mmol FeSO4/g, and 58.92 mg/L, respectively. In addition, EFB and 95% ethanol extract of B. striata tuber (ETB) significantly reduced the melanin synthesis of zebrafish embryos in a dose-dependent manner. 39 chemical compositions, including 24 stilbenoids were tentatively identified from EFB and ETB. Molecular docking indicated that there were 83 (including 60 stilbenoids) and 85 (including 70 stilbenoids) compounds exhibited stronger binding affinities toward tyrosinase and adenylate cyclase.

Conclusion
The present findings supported the rationale for the use of EFB and ETB as natural skin-whitening agents in pharmaceutical and cosmetic industries.
Impacts of bariatric surgery in health outcomes and health care costs in Brazil: Interrupted time series analysis of multi-panel data
Authors: Turri José Antonio Orellana , Anokye Nana Kwame , dos Santos Lionai Lima , Júnior José Maria Soares , Baracat Edmund Chada , Santo Marco Aurélio , Sarti Flavia Mori 
Published: January 2022

Abstract
Background
The increasing burden of obesity generates significant socioeconomic impacts for individuals, populations, and national health systems worldwide. The literature on impacts and cost-effectiveness of obesity-related interventions for prevention and treatment of moderate to severe obesity indicate that bariatric surgery presents high costs associated with high effectiveness in improving health status referring to certain outcomes; however, there is a lack of robust evidence at an individual-level estimation of its impacts on multiple health outcomes related to obesity comorbidities.

Methods
The study encompasses a single-centre retrospective longitudinal analysis of patient-level data using micro-costing technique to estimate direct health care costs with cost-effectiveness for multiple health outcomes pre-and post-bariatric surgery. Data from 114 patients who had bariatric surgery at the Hospital of Clinics of the University of Sao Paulo during 2018 were investigated through interrupted time-series analysis with generalised estimating equations and marginal effects, including information on patients' characteristics, lifestyle, anthropometric measures, hemodynamic measures, biochemical exams, and utilisation of health care resources during screening (180 days before) and follow-up (180 days after) of bariatric surgery.

Results
The preliminary statistical analysis showed that health outcomes presented improvement, except cholesterol and VLDL, and overall direct health care costs increased after the intervention. However, interrupted time series analysis showed that the rise in health care costs is attributable to the high cost of bariatric surgery, followed by a statistically significant decrease in post-intervention health care costs. Changes in health outcomes were also statistically significant in general, except in cholesterol and LDL, leading to significant improvements in patients' health status after the intervention.

Conclusions
Trends multiple health outcomes showed statistically significant improvements in patients' health status post-intervention compared to trends pre-intervention, resulting in reduced direct health care costs and the burden of obesity.
mtIF3 is locally translated in axons and regulates mitochondrial translation for axonal growth
Authors: Lee Soyeon , Park Dongkeun , Lim Chunghun , Kim Jae-Ick , Min Kyung-Tai 
Published: January 2022

Abstract
Background
The establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites. In particular, mitochondria are transported to axons and support local energy production to maintain energy-demanding neuronal processes including axon branching, growth, and regeneration. Additionally, local protein synthesis is required for structural and functional changes in axons, with nuclear-encoded mitochondrial mRNAs having been found localized in axons. However, it remains unclear whether these mRNAs are locally translated and whether the potential translated mitochondrial proteins are involved in the regulation of mitochondrial functions in axons. Here, we aim to further understand the purpose of such compartmentalization by focusing on the role of mitochondrial initiation factor 3 (mtIF3), whose nuclear-encoded transcripts have been shown to be present in axonal growth cones.

Results
We demonstrate that brain-derived neurotrophic factor (BDNF) induces local translation of mtIF3 mRNA in axonal growth cones. Subsequently, mtIF3 protein is translocated into axonal mitochondria and promotes mitochondrial translation as assessed by our newly developed bimolecular fluorescence complementation sensor for the assembly of mitochondrial ribosomes. We further show that BDNF-induced axonal growth requires mtIF3-dependent mitochondrial translation in distal axons.

Conclusion
We describe a previously unknown function of mitochondrial initiation factor 3 (mtIF3) in axonal protein synthesis and development. These findings provide insight into the way neurons adaptively control mitochondrial physiology and axonal development via local mtIF3 translation.