bluuebunny/crossref_metadata_2025_split huggingface dataset:
PMMA-Based Continuous Hemofiltration Modulated Complement Activation and Renal Dysfunction in LPS-Induced Acute Kidney Injury
Authors: Stasi Alessandra , Franzin Rossana , Divella Chiara , Sallustio Fabio , Curci Claudia , Picerno Angela , Pontrelli Paola , Staffieri Francesco , Lacitignola Luca , Crovace Antonio , Cantaluppi Vincenzo , Medica Davide , Ronco Claudio , de Cal Massimo , Lorenzin Anna , Zanella Monica , Pertosa Giovanni B. , Stallone Giovanni , Gesualdo Loreto , Castellano Giuseppe 
Published: April 2021

Sepsis-induced acute kidney injury (AKI) is a frequent complication in critically ill patients, refractory to conventional treatments. Aberrant activation of innate immune system may affect organ damage with poor prognosis for septic patients. Here, we investigated the efficacy of polymethyl methacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune activation in a swine model of LPS-induced AKI. After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic Complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by Real-time PCR. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative Complement pathways were found in endotoxemic animals. PMMA-CVVH treatment significantly reduced tissue and systemic Complement activation limiting renal damage and fibrosis. By microarray analysis, we identified 711 and 913 differentially expressed genes with a fold change &gt;2 and a false discovery rate &lt;0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process. Our data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in LPS-induced AKI.
Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans
Authors: Sawyer Andrew J. , Garand Mathieu , Chaussabel Damien , Feng Carl G. 
Published: April 2021

Cystatin F encoded by CST7 is a cysteine peptidase inhibitor known to be expressed in natural killer (NK) and CD8+ T cells during steady-state conditions. However, little is known about its expression during inflammatory disease states in humans. We have developed an analytic approach capable of not only identifying previously poorly characterized disease-associated genes but also defining regulatory mechanisms controlling their expression. By exploring multiple cohorts of public transcriptome data comprising 43 individual datasets, we showed that CST7 is upregulated in the blood during a diverse set of infectious and non-infectious inflammatory conditions. Interestingly, this upregulation of CST7 was neutrophil-specific, as its expression was unchanged in NK and CD8+ T cells during sepsis. Further analysis demonstrated that known microbial products or cytokines commonly associated with inflammation failed to increase CST7 expression, suggesting that its expression in neutrophils is induced by an endogenous serum factor commonly present in human inflammatory conditions. Overall, through the identification of CST7 upregulation as a marker of acute inflammation in humans, our study demonstrates the value of publicly available transcriptome data in knowledge generation and potential biomarker discovery.
The Diagnostic Yield of the Multidisciplinary Discussion in Patients With COVID-19 Pneumonia
Authors: Calabrese Fiorella , Pezzuto Federica , Giraudo Chiara , Vedovelli Luca , Fortarezza Francesco , Del Vecchio Claudia , Lunardi Francesca , Fraia Anna Sara , Cocconcelli Elisabetta , Vuljan Stefania Edith , Gregori Dario , Crisanti Andrea , Balestro Elisabetta , Spagnolo Paolo 
Published: April 2021

Purpose: The hypothesis of the study was that a multidisciplinary approach involving experienced specialists in diffuse parenchymal lung disease might improve the diagnosis of patients with COVID-19 pneumonia.Methods: Two pulmonologists, two radiologists, and two pathologists reviewed 27 patients affected by severe COVID-19 pneumonia as the main diagnosis made by non-pulmonologists. To evaluate whether the contribution of specialists, individually and/or in combination, might modify the original diagnosis, a three-step virtual process was planned. The whole lung examination was considered the gold standard for the final diagnosis. The probability of a correct diagnosis was calculated using a model based on generalized estimating equations. The effectiveness of a multidisciplinary diagnosis was obtained by comparing diagnoses made by experienced pulmonologists with those made by non-pulmonologists.Results: In 19% of cases, the diagnosis of COVID-19-related death was mainly incorrect. The probability of a correct diagnosis increased strikingly from an undedicated clinician to an expert specialist. Every single specialist made significantly more correct diagnoses than any non-pulmonologist. The highest level of accuracy was achieved by the combination of 3 expert specialists (p = 0.0003).Conclusion: The dynamic interaction between expert specialists may significantly improve the diagnostic confidence and management of patients with COVID-19 pneumonia.
Spectrum and Clinical Characteristics of Symptomatic and Asymptomatic Coronavirus Disease 2019 (COVID-19) With and Without Pneumonia
Authors: Zeng Huihui , Ma Yiming , Zhou Zhiguo , Liu Wenlong , Huang Peng , Jiang Mingyan , Liu Qimi , Chen Ping , Luo Hong , Chen Yan 
Published: April 2021

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has become a global pandemic. Based on symptoms, COVID-19 cases can be classified as symptomatic or asymptomatic. However, there is limited information about the differences between COVID-19 patients with and without pneumonia. Our study aimed to further discuss the spectrum and clinical characteristics of symptomatic and asymptomatic COVID-19 patients with and without pneumonia.Methods: In China, all COVID-19 cases are hospitalized in designated hospitals until two continuous negative oropharyngeal swabs obtained, which allows the professional monitoring of symptoms and clinical characteristics. We stratified all COVID-19 cases in our database and evaluated clinical characteristics in different COVID-19 subgroups (symptomatic with pneumonia, symptomatic without pneumonia, asymptomatic with pneumonia, and asymptomatic without pneumonia).Results: According to symptoms and laboratory and radiologic findings, COVID-19 cases were defined as symptomatic with pneumonia, symptomatic without pneumonia, asymptomatic with pneumonia, or asymptomatic without pneumonia. There were differences in the clinical characteristics and prognosis among the four groups. Both non-invasive mechanical ventilation (18, 4.2%) and invasive mechanical ventilation (11, 2.6%) were applied in only the symptomatic with pneumonia group. Likewise, extracorporeal membrane oxygenation and continuous renal replacement therapy were applied in only the symptomatic with pneumonia group. There were no differences in viral load, the durations of viral shedding, and hospitalization among the four groups.Conclusion: We have defined a comprehensive spectrum of COVID-19 with and without pneumonia. The symptomatic with pneumonia group consumed more medical resources than the other groups, and extra caution and monitoring should be applied in this group. The asymptomatic COVID-19 group had a similar viral load and viral shedding duration as the symptomatic COVID-19 group.
Three Immune-Related Prognostic mRNAs as Therapeutic Targets for Pancreatic Cancer
Authors: Zhang Cangang , Zou Yueji , Zhu Yanan , Liu Yi , Feng Hui , Niu Fan , He Pengcheng , Liu Haibo 
Published: April 2021

Objective: Pancreatic cancer is a highly lethal malignancy globally. This study aimed to probe and validate immune-related prognostic mRNAs as therapeutic targets for pancreatic cancer.Methods: Gene transcriptome data of pancreatic cancer and normal pancreas were retrieved from TCGA-GTEx projects. Two thousand four hundred and ninety-eight immune-related genes were obtained from the IMMUPORT database. Abnormally expressed immune-related genes were then identified. Under univariate and multivariate cox models, a gene signature was constructed. Its predictive efficacy was assessed via ROCs. The interactions between the 21 genes were analyzed by Spearson analysis and PPI network. Using the GEPIA and The Human Protein Atlas databases, their expression and prognostic value were evaluated. The TIMER database was utilized to determine the relationships between MET, OAS1, and OASL mRNAs and immune infiltrates. Finally, their mRNA expression was externally verified in the GSE15471 and GSE62452 datasets.Results: An immune-related 21-gene signature was developed for predicting patients' prognosis. Following verification, this signature exhibited the well predictive performance. There were physical and functional interactions between them. MET, OAS1, and OASL mRNAs were all up-regulated in pancreatic cancer and associated with unfavorable prognosis. They showed strong correlations with tumor progression. Furthermore, the three mRNAs were distinctly associated with immune infiltrates. Their up-regulation was confirmed in the two external datasets.Conclusion: These findings identified three immune-related prognostic mRNAs MET, OAS1, and OASL, which may assist clinicians to choose targets for immunotherapy and make personalized treatment strategy for pancreatic cancer patients.
Neurotrophic Factor Levels in Preterm Infants: A Systematic Review and Meta-Analysis
Authors: Krey Francieli Cristina , Stocchero Bruna Alvim , Creutzberg Kerstin Camile , Heberle Bernardo Aguzzoli , Tractenberg Saulo Gantes , Xiang Li , Wei Wei , Kluwe-Schiavon Bruno , Viola Thiago Wendt 
Published: April 2021

Objectives: Through a systematic review and meta-analysis of the literature we aimed to compare the levels of BDNF, NGF, NT-3, NT-4, and GDNF between human term and preterm infants, and investigate factors implicated in the variability of effect size estimates.Methods: The analysis was performed in three online databases, MEDLINE Complete, PsycINFO, and CINAHL. A random effects model was used to calculate the standardized mean difference (SMD) of neurotrophic factor levels in preterm infants vs. term within a 95% confidence interval (CI). To explore sources of heterogeneity meta-regression models were implemented.Results: Sixteen studies were included in this meta-analysis. A combined sample of 1,379 preterm and 1,286 term newborns were evaluated. We identified significant lower BDNF (SMD = −0.32; 95% CI: −0.59, −0.06; p = 0.014) and NT-3 (SMD = −0.31; 95% CI: −0.52, −0.09; p = 0.004) levels in preterm compared to term infants. No significant difference was observed in NGF and NT-4 levels between groups. Given that only two effect sizes were generated for GDNF levels, no meta-analytical model was performed. Meta-regression models revealed sample type (placental tissue, cerebrospinal fluid, peripheral blood, and umbilical cord blood) as a significant moderator of heterogeneity for BDNF meta-analysis. No significant associations were found for gestational week, birth weight, and clinical comorbidity of newborns with effect sizes.Conclusions: Our findings indicated that lower BDNF and NT-3 levels may be associated with preterm birth. Future studies with larger samples sizes should investigate neurodevelopmental manifestations resulting from neurotrophic factor dysregulation among preterm infants.
Association of Body Mass Index With Somatic Mutations in Breast Cancer
Authors: Chen Bo , Guo Liping , Li Kai , Xiao Weikai , Li Yingzi , Li Cheukfai , Mok Hsiaopei , Cao Li , Lin Jiali , Wei Guangnan , Zhang Guochun , Liao Ning 
Published: April 2021

BackgroundThe relationship between body mass index (BMI) and the prognosis or treatment response in patients with breast cancer has been demonstrated in previous studies, but the somatic mutation profiles in breast cancer patients with different BMIs have not been explored.MethodsIn the present study, the somatic mutation profiles in 421 female breast cancer patients who were stratified into three subgroups based on BMI (normal weight, overweight/obese, and underweight) were investigated. Capture-based targeted sequencing was performed using a panel comprising 520 cancer-related genes.ResultsA total of 3547 mutations were detected in 390 genes. In breast cancer patients with different BMI statuses, the tumors exhibited high mutation frequency and burden. TP53 was the most common gene in the three groups, followed by PIK3CA, ERBB2, and CDK12. Meanwhile, the mutation hotspots in TP53 and PIK3CA were the same in the three BMI groups. More JAK1 mutations were identified in underweight patients than those in normal patients. Except for JAK1, differentially mutated genes in postmenopausal patients were completely different from those in premenopausal patients. The distribution of mutation types was significantly different among BMI groups in the postmenopausal group. Underweight patients in the postmenopausal group harbored more TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway.ConclusionsOur next-generation sequencing (NGS)-based gene panel analysis revealed the gene expression profiles of breast cancer patients with different BMI statuses. Although genes with high mutation frequency and burden were found in different BMI groups, some subtle differences could not be ignored. JAK1 mutations might play a vital role in the progression of breast cancer in underweight patients, and this needs further analysis. Postmenopausal underweight patients with breast cancer have more aggressive characteristics, such as TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway. This study provides new evidence for understanding the characteristics of breast cancer patients with different BMIs.
Characterization of the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma Using Imaging Mass Cytometry
Authors: Li Ran , Lin Ying , Wang Yu , Wang Shaoyuan , Yang Yang , Mu Xinlin , Chen Yusheng , Gao Zhancheng 
Published: April 2021

BackgroundLung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer. The tumor immune microenvironment (TIME) affects the anti-tumor immune response and the patient’s prognosis, although the TIME in LUSC patients is incompletely understood.MethodsWe retrospectively collected surgical specimens from patients with previously untreated primary LUSC. Histopathological examination was used to identify tumor regions and adjacent regions, and imaging mass cytometry was used to characterize the immune cells in those regions. The results were compared between regions and between patients.ResultsWe identified heterogeneity in the TIME on comparing different patients with LUSC, although the tumor region and adjacent region both exhibited an immune response to the tumor. The TIME typically included a large number of infiltrating and activated T-cells, especially CD8+ T-cells, which closely interacted with the tumor cells in the tumor region. There was limited infiltration of B-cells, NK cells, and NKT cells, while the major immune suppressor cells were CD33+ myeloid-derived cells. We also identified a novel population of CD3−CD4+ cells with high expression of Foxp3 and TNFα, which might modulate the tumor microenvironment and play a proinflammatory role in the TIME.ConclusionsThe TIME of LUSC appears to be immunogenic and heterogenous, with predominant infiltration of activated CD8+ T-cells. The interactions between the tumor cells and T-cells facilitate the anti-tumor activity. A novel subpopulation of CD3−CD4+ cells with high TNFα and Foxp3 expression may modulate the tumor microenvironment and play a proinflammatory role.
Use of Chronic Prescription Medications and Prevalence of Polypharmacy in Survivors of Childhood Cancer
Authors: Ewig Celeste L. Y. , Cheng Yi Man , Li Hoi Shan , Wong Jasper Chak Ling , Cho Alex Hong Yu , Poon Freddie Man Hong , Li Chi Kong , Cheung Yin Ting 
Published: April 2021

BackgroundAs survivors of childhood cancer age, development of cancer treatment-related chronic health conditions often occur. This study aimed to describe the pattern of chronic prescription medication use and identify factors associated with polypharmacy among survivors of childhood cancer.MethodsThis was a retrospective study conducted at the pediatric oncology long-term follow-up clinic in Hong Kong. Eligible subjects included survivors who were (1) diagnosed with cancer before 18 years old, (2) were at least 3 years post-cancer diagnosis and had completed treatment for at least 30 days, and (3) receiving long-term follow-up care at the study site between 2015 and 2018. Dispensing records of eligible survivors were reviewed to identify medications taken daily for ≥30 days or used on an “as needed” basis for ≥6 months cumulatively within the past 12-month period. Polypharmacy was defined as the concurrent use of ≥5 chronic medications. Multivariable log-binomial modeling was conducted to identify treatment and clinical factors associated with medication use pattern and polypharmacy.ResultsThis study included 625 survivors (mean current age = 17.9 years, standard deviation [SD] = 7.2 years) who were 9.2 [5.2] years post-treatment. Approximately one-third (n = 219, 35.0%) of survivors were prescribed at least one chronic medication. Frequently prescribed medication classes include systemic antihistamines (26.5%), sex hormones (19.2%), and thyroid replacement therapy (16.0%). Overall prevalence of polypharmacy was 5.3% (n = 33). A higher rate of polypharmacy was found in survivors of CNS tumors (13.6%) than in survivors of hematological malignancies (4.3%) and other solid tumors (5.3%) (P = .0051). Higher medication burden was also observed in survivors who had undergone cranial radiation (RR = 6.31; 95% CI = 2.75–14.49) or hematopoietic stem-cell transplantation (HSCT) (RR = 3.53; 95% CI = 1.59–7.83).ConclusionAlthough polypharmacy was observed in a minority of included survivors of childhood cancer, chronic medication use was common. Special attention should be paid to survivors of CNS tumors and survivors who have undergone HSCT or cranial radiation. These individuals should be monitored closely for drug–drug interactions and adverse health outcomes that may result from multiple chronic medications, particularly during hospitalization in an acute care setting.
Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy
Authors: Loosen Sven H. , Gorgulho Joao , Jördens Markus S. , Schulze-Hagen Maximilian , Beier Fabian , Vucur Mihael , Schneider Anne T. , Koppe Christiane , Mertens Alexander , Kather Jakob N. , Tacke Frank , Keitel Verena , Brümmendorf Tim H. , Roderburg Christoph , Luedde Tom 
Published: April 2021

BackgroundImmune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors.MethodsA total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy.ResultsBaseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome.ConclusionOur data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.