bluuebunny/crossref_metadata_2025_split huggingface dataset:
RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer
Authors: Manzano Ramon Gonzalez , Catalan-Latorre Ana , Brugarolas Antonio 
Published: April 2021

Abstract
Background
Muscle invasive urothelial bladder carcinoma (MIBC) present RB1 and TP53 somatic alterations in a variable percentage of tumors throughout all molecular subtypes. MIBCs with neuroendocrine features have a high response rate to immunity checkpoint inhibitors (ICIs). Whether the presence of somatic co-alterations in these 2 genes in MIBCs is relevant to their responsiveness to ICIs is not known.

Methods
The potential correlation of different genomic biomarkers of response to ICIs like tumor mutational burden (TMB), single nucleotide variants (SNV) predicted neoantigens, DNA damage response (DDR) genes, DNA somatic signatures and TILs infiltrate was explored in patients with somatic co-alterations in RB1 and TP53 (RB1&TP53) as compared with patients with no alterations in any (double wild type, DWT) or with alterations in just one of the 2 genes. The Cancer Genome Atlas (TCGA) pancancer BLCA dataset of cystectomy specimens (n = 407) with mutation, copy number alterations and transcriptomic (RNA sequencing) data as well as the IMVigor 210 study (n = 348) of metastatic urothelial bladder cancers treated with atezolizumab (PD-L1 inhibitor) with clinical response data containing transcriptomic (RNA sequencing), along with a subset (n = 274) with mutation and copy number data were used for this purpose. A novel tumor microenvironment metascore (TMM) was developed based in a LASSO regularized Cox model with predictive and prognostic ability.

Results
Samples with co-altered RB1&TP53: a) were enriched in immunity effectors (CD8 cytotoxic lymphocytes, NK cells) and display higher scores of a T cell inflamed signature; b) have a higher TMB, higher number of SNV predicted neoantigens and higher TILs fractions; c) have a higher number of DDR mutated and deep deleted DDR genes; d) have DNA somatic signatures 2 and 13 related to APOBEC mutagenesis. Using the IMVigor 210 dataset, RB1&TP53 samples had the highest response rate to atezolizumab and a strong correlation with TMB and TMM. The consensus molecular subtype classification in the IMVigor 210 dataset showed a significant correlation with both the response to treatment (p = 0.001, Chisquare) and the presence of RB1 and TP53 genomic alterations (p < 0.001, Chisquare).

Conclusions
RB1&TP53 co-alterations are strongly associated with genomic biomarkers of response to ICIs in MIBCs.
Risk prediction in medically treated chronic thromboembolic pulmonary hypertension
Authors: Quan Ruilin , Yang Yuanhua , Yang Zhenwen , Tian Hongyan , Li Shengqing , Shen Jieyan , Ji Yingqun , Zhang Gangcheng , Zhang Caojin , Wang Guangyi , Liu Yuhao , Cheng Zhaozhong , Yu Zaixin , Song Zhiyuan , Zheng Zeqi , Cui Wei , Chen Yucheng , Liu Shuang , Chen Xiaoxi , Qian Yuling , Xiong Changming , Shan Guangliang , He Jianguo 
Published: April 2021

Abstract
Background
At present, there is no generally accepted comprehensive prognostic risk prediction model for medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients.

Methods
Consecutive medically treated CTEPH patients were enrolled in a national multicenter prospective registry study from August 2009 to July 2018. A multivariable Cox proportional hazards model was utilized to derive the prognostic model, and a simplified risk score was created thereafter. Model performance was evaluated in terms of discrimination and calibration, and compared to the Swedish/COMPERA risk stratification method. Internal and external validation were conducted to validate the model performance.

Results
A total of 432 patients were enrolled. During a median follow-up time of 38.73 months (IQR: 20.79, 66.10), 94 patients (21.8%) died. The 1-, 3-, and 5-year survival estimates were 95.5%, 83.7%, and 70.9%, respectively. The final model included the following variables: the Swedish/COMPERA risk stratum (low-, intermediate- or high-risk stratum), pulmonary vascular resistance (PVR, ≤ or > 1600 dyn·s/cm5), total bilirubin (TBIL, ≤ or > 38 µmol/L) and chronic kidney disease (CKD, no or yes). Compared with the Swedish/COMPERA risk stratification method alone, both the derived model [C-index: 0.715; net reclassification improvement (NRI): 0.300; integrated discriminatory index (IDI): 0.095] and the risk score (C-index: 0.713; NRI: 0.300; IDI: 0.093) showed improved discriminatory power. The performance was validated in a validation cohort of 84 patients (C-index = 0.707 for the model and 0.721 for the risk score).

Conclusions
A novel risk stratification strategy can serve as a useful tool for determining prognosis and guide management for medically treated CTEPH patients.
Trial registration: ClinicalTrials.gov (Identifier: NCT01417338).
Evaluating health service outcomes of public involvement in health service design in high-income countries: a systematic review
Authors: Lloyd Nicola , Kenny Amanda , Hyett Nerida 
Published: April 2021

Abstract
Background
Internationally, it is expected that health services will involve the public in health service design. Evaluation of public involvement has typically focused on the process and experiences for participants. Less is known about outcomes for health services. The aim of this systematic review was to a) identify and synthesise what is known about health service outcomes of public involvement and b) document how outcomes were evaluated.

Methods
Searches were undertaken in MEDLINE, EMBASE, The Cochrane Library, PsycINFO, Web of Science, and CINAHL for studies that reported health service outcomes from public involvement in health service design. The review was limited to high-income countries and studies in English. Study quality was assessed using the Mixed Methods Appraisal Tool and critical appraisal guidelines for assessing the quality and impact of user involvement in health research. Content analysis was used to determine the outcomes of public involvement in health service design and how outcomes were evaluated.

Results
A total of 93 articles were included. The majority were published in the last 5 years, were qualitative, and were located in the United Kingdom. A range of health service outcomes (discrete products, improvements to health services and system/policy level changes) were reported at various levels (service level, across services, and across organisations). However, evaluations of outcomes were reported in less than half of studies. In studies where outcomes were evaluated, a range of methods were used; most frequent were mixed methods. The quality of study design and reporting was inconsistent.

Conclusion
When reporting public involvement in health service design authors outline a range of outcomes for health services, but it is challenging to determine the extent of outcomes due to inadequate descriptions of study design and poor reporting. There is an urgent need for evaluations, including longitudinal study designs and cost-benefit analyses, to fully understand outcomes from public involvement in health service design.
Long-term cigarette smoke exposure dysregulates pulmonary T cell response and IFN-γ protection to influenza virus in mouse
Authors: Wu Wenxin , Tian Lili , Zhang Wei , Booth J. Leland , Ainsua-Enrich Erola , Kovats Susan , Brown Brent R. , Metcalf Jordan P. 
Published: April 2021

AbstractBackgroundInfluenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models.MethodsC57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration.ResultsAlthough long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection.ConclusionsOur results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.
Defective monocyte-derived macrophage phagocytosis is associated with exacerbation frequency in COPD
Authors:   COPDMAP consortium, Singh R. , Belchamber K. B. R. , Fenwick P. S. , Chana K. , Donaldson G. , Wedzicha J. A. , Barnes P. J. , Donnelly L. E. 
Published: April 2021

Abstract
Background
Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.

Methods
Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR.

Results
Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state.

Conclusion
Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.
SNRPD1 confers diagnostic and therapeutic values on breast cancers through cell cycle regulation
Authors: Dai Xiaofeng , Yu Lihui , Chen Xiao , Zhang Jianying 
Published: April 2021

Abstract
Background
SNRPD1 is a spliceosome-associated protein and has previously been implicated with important roles in cancer development.

Methods
Through analyzing the differential expression patterns and clinical association of splicing associated genes among tumor and tumor adjacent samples across different tumors and among different breast cancer subtypes, we identify the tumor promotive role of SNRPD1 using multiple publicly available datasets. Through pathway, gene ontology enrichment analysis and network construction, we linked the onco-therapeutic role of SNRPD1 with cell cycle. Via a series of experimental studies including knockdown assay, qPCR, western blotting, cell cycle, drug response assay, we confirmed the higher expression of SNPRD1 at both gene and protein expression levels in triple negative breast cancer cells, as well as its roles in promoting cell cycle and chemotherapy response.

Results
Our study revealed that SNRPD1 over-expression was significantly associated with genes involved in cell cycle, cell mitosis and chromatin replication, and silencing SNRPD1 in breast cancer cells could lead to halted tumor cell growth and cell cycle arrest at the G0/G1 stage. We also found that triple negative breast cancer cells with reduced SNRPD1 expression lost certain sensitivity to doxorubicin whereas luminal cancer cells did not.

Conclusions
Our results suggested the prognostic value of SNRPD1 on breast cancer survival, its potential as the therapeutic target halting cell cycle progression for breast cancer control, and warranted special attention on the combined use of doxorubicin and drugs targeting SNRPD1.
NEIL3 may act as a potential prognostic biomarker for lung adenocarcinoma
Authors: Zhao Cui , Liu Jian , Zhou Haomiao , Qian Xin , Sun Hui , Chen Xuewen , Zheng Miaosen , Bian Tingting , Liu Lei , Liu Yifei , Zhang Jianguo 
Published: April 2021

Abstract
Background
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death. This study aimed to develop and validate reliable prognostic biomarkers and signature.

Methods
Differentially expressed genes were identified based on three Gene Expression Omnibus (GEO) datasets. Based on 1052 samples’ data from our cohort, GEO and The Cancer Genome Atlas, we explored the relationship of clinicopathological features and NEIL3 expression to determine clinical effect of NEIL3 in LUAD. Western blotting (22 pairs of tumor and normal tissues), Real-time quantitative PCR (19 pairs of tumor and normal tissues), and immunohistochemical analyses (406-tumor tissues subjected to microarray) were conducted. TIMER and ImmuCellAI analyzed relationship between NEIL3 expression and the abundance of tumor-infiltrating immune cells in LUAD. The co-expressed-gene prognostic signature was established based on the Cox regression analysis.

Results
This study identified 502 common differentially expressed genes and confirmed that NEIL3 was significantly overexpressed in LUAD samples (P < 0.001). Increased NEIL3 expression was related to advanced stage, larger tumor size and poor overall survival (p < 0.001) in three LUAD cohorts. The proportions of natural T regulatory cells and induced T regulatory cells increased in the high NEIL3 group, whereas those of B cells, Th17 cells and dendritic cells decreased. Gene set enrichment analysis indicated that NEIL3 may activate cell cycle progression and P53 signaling pathway, leading to poor outcomes. We identified nine prognosis-associated hub genes among 370 genes co-expressed with NEIL3. A 10-gene prognostic signature including NEIL3 and nine key co-expressed genes was constructed. Higher risk-score was correlated with more advanced stage, larger tumor size and worse outcome (p < 0.05). Finally, the signature was verified in test cohort (GSE50081) with superior diagnostic accuracy.

Conclusions
This study suggested that NEIL3 has the potential to be an immune-related therapeutic target and an independent predictor of LUAD prognosis. We also developed a prognostic signature for LUAD with a precise diagnostic accuracy.
Costing electronic private sector malaria surveillance in the Greater Mekong Subregion
Authors: Levin Ann , Potter Rebecca , Tesfazghi Kemi , Phanalangsy Saysana , Keo Phally , Filip Elijah , Phone Si Hein , Eliades M. James 
Published: April 2021

AbstractBackgroundPrivate sector malaria programmes contribute to government-led malaria elimination strategies in Cambodia, Lao PDR, and Myanmar by increasing access to quality malaria services and surveillance data. However, reporting from private sector providers remains suboptimal in many settings. To support surveillance strengthening for elimination, a key programme strategy is to introduce electronic surveillance tools and systems to integrate private sector data with national systems, and enhance the use of data for decision-making. During 2013–2017, an electronic surveillance system based on open source software, District Health Information System 2 (DHIS2), was implemented as part of a private sector malaria case management and surveillance programme. The electronic surveillance system covered 16,000 private providers in Myanmar (electronic reporting conducted by 200 field officers with tablets), 710 in Cambodia (585 providers reporting through mobile app), and 432 in Laos (250 providers reporting through mobile app).MethodsThe purpose of the study was to document the costs of introducing electronic surveillance systems and mobile reporting solutions in Cambodia, Lao PDR, and Myanmar, comparing the cost in different operational settings, the cost of introduction and maintenance over time, and assessing the affordability and financial sustainability of electronic surveillance. The data collection methods included extracting data from PSI’s financial and operational records, collecting data on prices and quantities of resources used, and interviewing key informants in each setting. The costing study used an ingredients-based approach and estimated both financial and economic costs.ResultsAnnual economic costs of electronic surveillance systems were $152,805 in Laos, $263,224 in Cambodia, and $1,310,912 in Myanmar. The annual economic cost per private provider surveilled was $82 in Myanmar, $371 in Cambodia, and $354 in Laos. Cost drivers varied depending on operational settings and number of private sector outlets covered in each country; whether purchased or personal mobile devices were used; and whether electronic (mobile) reporting was introduced at provider level or among field officers who support multiple providers for case reporting.ConclusionThe study found that electronic surveillance comprises about 0.5–1.5% of national malaria strategic plan cost and 7–21% of surveillance budgets and deemed to be affordable and financially sustainable.
TWIST2 and the PPAR signaling pathway are important in the progression of nonalcoholic steatohepatitis
Authors: Zhang Yanmei , Ge Xiaoxiao , Li Yongqing , Zhang Bingyang , Wang Peijun , Hao Mingju , Gao Peng , Zhao Yueyi , Sun Tao , Lu Sumei , Ma Wanshan 
Published: April 2021

Abstract
Background
To investigate the roles of the transcription factors twist family bHLH transcription factor 1 (TWIST1), twist family bHLH transcription factor 2 (TWIST2), and peroxisome proliferator activated receptor gamma (PPARγ) in the progression of nonalcoholic steatohepatitis.

Methods
The protein levels of TWIST1, TWIST2 and PPARγ were determined in the serum of nonalcoholic fatty liver disease (NAFLD) patients and healthy controls by enzyme-linked immunosorbent assay (ELISA). An in vivo model for fatty liver was established by feeding C57BL/6 J mice a high-fat diet (HFD). An in vitro model of steatosis was established by treating LO-2 cells with oleic acid (OA). RNA sequencing was performed on untreated and OA-treated LO-2 cells followed by TWIST1, TWIST2 and PPARγ gene mRNA levels analysis, Gene Ontology (GO) enrichment and pathway analysis.

Results
The TWIST2 serum protein levels decreased significantly in all fatty liver groups (P < 0.05), while TWIST1 varied. TWIST2 tended to be lower in mice fed an HFD and was significantly lower at 3 months. Similarly, in the in vitro model, the TWIST2 protein level was downregulated significantly at 48 and 72 h after OA treatment. RNA sequencing of LO-2 cells showed an approximately 2.3-fold decrease in TWIST2, with no obvious change in TWIST1 and PPARγ. The PPAR signaling pathway was enriched, with 4 genes upregulated in OA-treated cells (P = 0.0018). The interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways were enriched in OA-treated cells.

Conclusions
The results provide evidence that the TWIST2 and PPAR signaling pathways are important in NAFLD and shed light on a potential mechanism of steatosis.
Overexpression of CRABP2 inhibits dexamethasone-induced apoptosis in human osteoblast cells
Authors: Zhang Haiping , Yu Ziliang , Sun Farui , Jin Jin 
Published: April 2021

Abstract
Background
The purpose of the current study was to explore the role and underlying mechanism of cellular retinoic acid binding protein 2 (CRABP2) in dexamethasone (DEX)-induced apoptosis in human osteoblast cells.

Methods
GSE10311 was downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs) by the limma/R package. Primary human osteoblast was isolated and treated with different concentration of DEX (0, 10-8, 10-7, 10-6, 10-5, and 10-4 mol/L), and cell viability and flow cytometry were used to detect cell proliferation and apoptosis. A CRABP2 overexpression plasmid (oe-CRABP2) was used to overexpress CRABP2, and western blotting was conducted to detect protein expression.

Results
We found that CRABP2 was downregulated in the DEX-treated group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that DEGs were associated with PI3K/Akt signaling pathway. DEX downregulated CRABP2 gene and protein expression, inhibited viability, and induced human osteoblast apoptosis. Overexpression of CRABP2 reversed DEX-induced apoptosis in human osteoblast. Moreover, overexpression of CRABP2 delayed the progression of DEX-induced osteonecrosis of the femoral head (ONFH) animal model.

Conclusion
In conclusion, CRABP2 is effective at inhibiting DEX-induced human osteoblast apoptosis and delayed ONFH progression.