Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of Mononuclear Phagocytes Disclosed the Establishment Processes of Two Macrophage Subsets in the Adult Murine Kidney

The interstitium of kidney involves a variety of components including resident immune cells, in particular mononuclear phagocytes. However, many proposed markers for distinguishing macrophages or dendritic cells are, in fact, shared by the majority of renal mononuclear phagocytes, which impedes the research of kidney diseases. Here, by employing a flow cytometry strategy and techniques of fate mapping, imaging and lineage depletion, we were able to demarcate renal monocytes, macrophages and dendritic cells and their subsets in mice. In particular, using this strategy, we found that even in steady state, the renal macrophage pool was continuously replenished by bone marrow-derived monocytes in a stepwise process, i.e., from infiltration of classical monocyte, to development of nonclassical monocyte and eventually to differentiation to macrophages. In mechanism, we demonstrated that the ligation of tissue-anchored CX3CL1 and monocytic CX3CR1 was required for promoting monocyte differentiation to macrophages in the kidney, but CX3CL1-CX3CR1 signaling was dispensable in monocyte infiltrating into the kidney. In addition to the bone marrow-derived macrophages, fate mapping in adult mice revealed another population of renal resident macrophages which were embryo-derived and self-maintaining. Thus, the dissecting strategies developed by us would assist in exploration of the biology of renal mononuclear phagocytes.
Is There Evidence for the Specificity of Closed-Loop Brain Training in the Treatment of Internalizing Disorders? A Systematic Review

Introduction Internalizing disorders (IDs), e.g., major depressive disorder (MDD), posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) are the most prevalent psychopathologies experienced worldwide. Current first-line therapies (i.e., pharmacotherapy and/or psychotherapy) offer high failure rates, limited accessibility, and substantial side-effects. Electroencephalography (EEG) guided closed-loop brain training, also known as EEG-neurofeedback (EEG-NFB), is believed to be a safe and effective alternative, however, there is much debate in the field regarding the existence of specificity [i.e., clinical effects specific to the modulation of the targeted EEG variable(s)]. This review was undertaken to determine if there is evidence for EEG-NFB specificity in the treatment of IDs. Methods We considered only randomized, double-blind, sham-controlled trials. Outcomes of interest included self/parent/teacher reports and clinician ratings of ID-related symptomatology. Results Of the four reports (total participant number = 152) meeting our eligibility criteria, three had point estimates suggesting small to moderate effect sizes favoring genuine therapy over sham, however, due to small sample sizes, all 95% confidence intervals (CIs) were wide and spanned the null. The fourth trial had yet to post results as of the submission date of this review. The limited overall number of eligible reports (and participants), large degree of inter-trial heterogeneity, and restricted span of ID populations with published/posted outcome data (i.e., PTSD and OCD) precluded a quantitative synthesis. Discussion The current literature suggests that EEG-NFB may induce specific effects in the treatment of some forms of IDs, however, the evidence is very limited. Ultimately, more randomized, double-blind, sham-controlled trials encompassing a wider array of ID populations are needed to determine the existence and, if present, degree of EEG-NFB specificity in the treatment of IDs. Systematic Review Registration [https://www.crd. york.ac. uk/prospero], identifier [CRD42020159702].
Biomarkers for Diagnosing Febrile Illness in Immunocompromised Children: A Systematic Review of the Literature

Objective This study aims to assess the performance of biomarkers used for the prediction of bacterial, viral, and fungal infection in immunocompromised children upon presentation with fever. Methods We performed a literature search using PubMed and MEDLINE and In-Process & Other Non-indexed Citations databases. Cohort and case–control studies assessing biomarkers for the prediction of bacterial, viral, or fungal infection in immunocompromised children vs. conventional microbiological investigations were eligible. Studies including adult patients were eligible if pediatric data were separately assessable. Data on definitions used for infections, fever, and neutropenia and predictive values were collected. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Results Fifty-two studies involving 13,939 febrile episodes in 7,059 children were included. In total, 92.2% were in cancer patients (n = 48), and 15.7% also included hematopoietic stem cell transplantation patients (n = 8). Forty-three biomarkers were investigated, of which 6 (CRP, PCT, IL-8, IL-6, IL-10, and TNFα) were significantly associated with bacterial infection at admission, studied in multiple studies, and provided predictive data. Literature on the prediction of viral and fungal infection was too limited. Eight studies compared C-reactive protein (CRP) and procalcitonin (PCT), with PCT demonstrating superiority in 5. IL-6, IL-8, and IL-10 were compared with CRP in six, four, and one study, respectively, with mixed results on diagnostic superiority. No clear superior biomarker comparing PCT vs. IL-6, IL-8, or IL-10 was identified. Discussion There is great heterogeneity in the biomarkers studied and cutoff values and definitions used, thus complicating the analysis. Literature for immunocompromised children with non-malignant disease and for non-bacterial infection is sparse. Literature on novel diagnostics was not available. We illustrated the challenges of diagnosing fever adequately in this study population and the need for improved biomarkers and clinical decision-making tools.
Inhibition of Anti-Inflammatory Macrophage Phenotype Reduces Tumour Growth in Mouse Models of Brain Metastasis

Breast cancer brain metastasis is a significant clinical problem and carries a poor prognosis. Although it is well-established that macrophages are a primary component of the brain metastasis microenvironment, the role of blood-derived macrophages (BDM) and brain-resident microglia in the progression of brain metastases remains uncertain. The aim of this study, therefore, was to determine the role, specifically, of pro- and anti-inflammatory BDM and microglial phenotypes on metastasis progression. Initial in vitro studies demonstrated decreased migration of EO771 metastatic breast cancer cells in the presence of pro-inflammatory, but not anti-inflammatory, stimulated RAW 264.7 macrophages. In vivo, suppression of the anti-inflammatory BDM phenotype, specifically, via myeloid knock out of Krüppel-like Factor 4 (KLF4) significantly reduced EO771 tumour growth in the brains of C57BL/6 mice. Further, pharmacological inhibition of the anti-inflammatory BDM and/or microglial phenotypes, via either Colony Stimulating Factor 1 Receptor (CSF-1R) or STAT6 pathways, significantly decreased tumour burden in two different syngeneic mouse models of breast cancer brain metastasis. These findings suggest that switching BDM and microglia towards a more pro-inflammatory phenotype may be an effective therapeutic strategy in brain metastasis.
A Multimodal Score Accurately Classifies Fontan Failure and Late Mortality in Adult Fontan Patients

Objectives Despite the outstanding success of the Fontan operation, it is a palliative procedure and a substantial number of patients experience late failure of the Fontan circulation. Clinical presentation and hemodynamic phenotypes of Fontan failure are considerably variable. While various parameters have been identified as risk factors for late Fontan failure, a feasible score to classify Fontan failure and possibly allow timely risk stratification is lacking. Here, we explored the possibility of developing a score based on hemodynamic, clinical and laboratory parameters to classify Fontan failure and mortality. Methods We performed a retrospective study in our cohort of adult Fontan patients from two institutions [n = 198, median follow-up after Fontan 20.3 (IQR 15.6–24.3) years], identifying those patients with clinical Fontan failure (n = 52, 26.3%). Various hemodynamic, echocardiographic, laboratory and clinical data were recorded and differences between patients with and without Fontan failure were analyzed. We composed a Fontan Failure Score containing 15 parameters associated with Fontan failure and/or mortality and assessed its accuracy to discriminate between patients with and without late Fontan failure as well as late mortality and survival. Results Late failure occurred at a median of 18.2 (IQR 9.1–21.1) years after Fontan completion. Mortality associated with Fontan failure was substantial (25/52, 48.1%) with freedom of death/transplantation/take-down of 64% at 5 years and 36% at 10 years after onset of Fontan failure, respectively. Patients with Fontan failure had a significantly higher median Fontan Failure Score compared to non-failing Fontan patients [8 points (IQR 5–10) vs. 2 points (IQR 1-5), p < 0.001]. The score accurately classifies Fontan failure as well as mortality as assessed with receiver operating characteristic analysis. Area under the curve of the Fontan Failure Score was 0.963 (95% CI 0.921; 0.985, p < 0.001) to discriminate failure and 0.916 (95% CI 0.873; 0.959, p < 0.001) to classify mortality. Conclusion We have developed an uncomplex yet remarkably accurate score to classify Fontan failure and late mortality in adult Fontan patients. Prospective validation and most likely refinement and calibration of the score in larger and preferably multi-institutional cohorts is required to assess its potential to predict the risk of Fontan failure and late mortality.
Accessory and Expiratory Muscles Activation During Spontaneous Breathing Trial: A Physiological Study by Surface Electromyography

Background The physiological and prognostical significance of accessory and expiratory muscles activation is unknown during a spontaneous breathing trial (SBT). We hypothesized that, in patients experiencing weaning failure, accessory and expiratory muscles are activated to cope with an increased respiratory workload. Purpose To describe accessory and expiratory muscle activation non-invasively by surface electromyography (sEMG) during an SBT and to assess differences in electrical activity (EA) of the inspiratory and expiratory muscles in successful vs. failing weaning patients. Methods Intubated patients on mechanical ventilation for more than 48 h undergoing an SBT were enrolled in a medical and surgical third-level ICU of the University Teaching Hospital. Baseline characteristics and physiological variables were recorded in a crossover physiologic prospective clinical study. Results Of 37 critically ill mechanically ventilated patients, 29 (78%) patients successfully passed the SBT. Rapid shallow breathing index (RSBI) was higher in patients who failed SBT compared with the successfully weaned patients at baseline and over time (group-by-time interaction p < 0.001). EA of both the diaphragm (EAdisurf) and of accessory muscles (ACCsurf) was higher in failure patients compared with success (group-by-time interaction p = 0.0174 and p < 0.001, respectively). EA of expiratory muscles (ESPsurf) during SBT increased more in failure than in weaned patients (group-by-time interaction p < 0.0001). Conclusion Non-invasive respiratory muscle monitoring by sEMG was feasible during SBT. Respiratory muscles EA increased during SBT, regardless of SBT outcome, and patients who failed the SBT had a higher increase of all the inspiratory muscles EA compared with the patients who passed the SBT. Recruitment of expiratory muscles—as quantified by sEMG—is associated with SBT failure.
What Is the Optimal Timing of Transplantation of Neural Stem Cells in Spinal Cord Injury? A Systematic Review and Network Meta-Analysis Based on Animal Studies

Objective The optimal transplantation timing of neural stem cells in spinal cord injury is fully explored in animal studies to reduce the risk of transformation to clinical practice and to provide valuable reference for future animal studies and clinical research. Method Seven electronic databases, namely, PubMed, Web of Science, Embase, Wanfang, Chinese Scientific Journal Database (CSJD-VIP), China Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI), were searched. The studies were retrieved from inception to November 2021. Two researchers independently screened the literature, extracted data, and evaluated the methodological quality based on the inclusion criteria. Results and Discussion Thirty-nine studies were incorporated into the final analyses. Based on the subgroup of animal models and transplantation dose, the results of network meta-analysis showed that the effect of transplantation in the subacute phase might be the best. However, the results of traditional meta-analysis were inconsistent. In the moderate-dose group of moderate spinal cord injury model and the low-dose group of severe spinal cord injury model, transplantation in the subacute phase did not significantly improve motor function. Given the lack of evidence for direct comparison between different transplantation phases, the indirectness of our network meta-analysis, and the low quality of evidence in current animal studies, our confidence in recommending cell transplantation in the subacute phase is limited. In the future, more high-quality, direct comparative studies are needed to explore this issue in depth.
Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML

Mitochondria-related metabolic reprogramming plays a major role in the occurrence, development, drug resistance, and recurrence of acute myeloid leukemia (AML). However, the roles of mitochondria-related genes (MRGs) in the prognosis and immune microenvironment for AML patients remain largely unknown. In this study, by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, 4 MRGs’ (HPDL, CPT1A, IDH3A, and ETFB) signature was established that demonstrated good robustness in TARGET AML datasets. The univariate and multivariate Cox regression analyses both demonstrated that the MRG signature was a robust independent prognostic factor in overall survival prediction with high accuracy for AML patients. Based on the risk score calculated by the signature, samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA) suggested that the MRG signature is involved in the immune-related pathways. Via immune infiltration analysis and immunosuppressive genes analysis, we found that MRG risk of AML patients was strikingly positively correlated with an immune cell infiltration and expression of critical immune checkpoints, indicating that the poor prognosis might be caused by immunosuppressive tumor microenvironment (TME). In summary, the signature based on MRGs could act as an independent risk factor for predicting the clinical prognosis of AML and could also reflect an association with the immunosuppressive microenvironment, providing a novel method for AML metabolic and immune therapy based on the regulation of mitochondrial function.
Body Pose Estimation Integrated With Notational Analysis: A New Approach to Analyze Penalty Kicks Strategy in Elite Football

Body orientation of football players has proven to be an informative resource related to successful penalty kicks. OpenPose is one of the most popular open-source pose estimation technologies. This study aims: (i) to verify whether OpenPose can detect relevant body orientation angles from video data of penalty kicks in elite football and (ii) to investigate the relationship between these body angles and observable behaviors analyzed via an observational system for penalty kick analysis in football (OSPAF) with the penalty taker and goalkeeper strategy. A total of 34 penalty videos, with standardized viewing angle, from the main European leagues (2017–2020) were analyzed. Relevant body orientation variables were selected for penalty kicks analysis and were extracted from video data through OpenPose technique. The OSPAF, previously validated by experts, was used. The mean confidence score of OpenPose measures was 0.80 ± 0.14. The mean kappa value for repeated measurements of OpenPose was 0.96 ± 0.04. Logistic regressions were performed to investigate the relationship between OpenPose investigated variables (penalty taker: shoulder, hips, and nonkicking foot orientation; goalkeeper: right and left foot, anticipation), observable behaviors (OSPAF variables), and the strategy (penalty taker: goalkeeper dependent or independent; goalkeeper: shooter dependent or independent) in penalty kicks. The selected body orientation angle (goalkeeper anticipation) measured through OpenPose correlated significantly with the goalkeeper strategy. The prediction model of the goalkeeper's strategy had its accuracy increased to 97% when the variable goalkeeper anticipation was included [χ(35)2 = 49.648, p < 0.001]. Lower degrees of goalkeeper anticipation, the goalkeeper tactical action (awaiting), and run up speed (slow) were associated with a kicker-dependent strategy. Regarding the penalty taker, the selected body angles measured through OpenPose did not associate significantly with the shooter strategy. Body orientation analysis by using OpenPose has shown sufficient reliability and provides practical applications for analyzing the strategies adopted by goalkeepers in penalty kicks in elite football.
PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

Background Programmed death-ligand 1 (PD-L1) regulates immune homeostasis by promoting T-cell exhaustion. It is involved in chronic infections and tumor progression. Nuclear imaging using radiolabeled anti-PD-L1 antibodies can monitor PD-L1 tissue expression and antibody distribution. However, physiological PD-L1 can cause rapid antibody clearance from blood at imaging doses. Therefore, we hypothesized that inflammatory responses, which can induce PD-L1 expression, affect anti-PD-L1 antibody distribution. Here, we investigated the effects of three different infectious stimuli on the pharmacokinetics and tumor targeting of radiolabeled anti-PD-L1 antibodies in tumor-bearing mice. Materials/Methods Anti-mouse-PD-L1 and isotype control antibodies were labelled with indium-111 ([111In]In-DTPA-anti-mPD-L1 and [111In]In-DTPA-IgG2a, respectively). We evaluated the effect of inflammatory responses on the pharmacokinetics of [111In]In-DTPA-anti-mPD-L1 in RenCa tumor-bearing BALB/c mice in three conditions: lipopolysaccharide (LPS), local Staphylococcus aureus, and heat-killed Candida albicans. After intravenous injection of 30 or 100 µg of [111In]In-DTPA-anti-mPD-L1 or [111In]In-DTPA-IgG2a, blood samples were collected 1, 4, and 24 h p.i. followed by microSPECT/CT and ex vivo biodistribution analyses. PD-L1 expression, neutrophil, and macrophage infiltration in relevant tissues were evaluated immunohistochemically. Results In 30 µg of [111In]In-DTPA-anti-mPD-L1 injected tumor-bearing mice the LPS-challenge significantly increased lymphoid organ uptake compared with vehicle controls (spleen: 49.9 ± 4.4%ID/g versus 21.2 ± 6.9%ID/g, p < 0.001), resulting in lower blood levels (3.6 ± 1.6%ID/g versus 11.5 ± 7.2%ID/g; p < 0.01) and reduced tumor targeting (8.1 ± 4.5%ID/g versus 25.2 ± 5.2%ID/g, p < 0.001). Local S. aureus infections showed high PD-L1+ neutrophil influx resulting in significantly increased [111In]In-DTPA-anti-mPD-L1 uptake in affected muscles (8.6 ± 2.6%ID/g versus 1.7 ± 0.8%ID/g, p < 0.001). Heat-killed Candida albicans (Hk-C. albicans) challenge did not affect pharmacokinetics. Increasing [111In]In-DTPA-anti-mPD-L1 dose to 100 µg normalized blood clearance and tumor uptake in LPS-challenged mice, although lymphoid organ uptake remained higher. Infectious stimuli did not affect [111In]In-DTPA-IgG2a pharmacokinetics. Conclusions This study shows that anti-PD-L1 antibody pharmacokinetics and tumor targeting can be significantly altered by severe inflammatory responses, which can be compensated for by increasing the tracer dose. This has implications for developing clinical PD-L1 imaging protocols in onco-immunology. We further demonstrate that radiolabeled anti-PD-L1 antibodies can be used to evaluate PD-L1 expression changes in a range of infectious diseases. This supports the exploration of using these techniques to assess hosts’ responses to infectious stimuli.
Deleterious AHNAK2 Mutation as a Novel Biomarker for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs) have exhibited promising efficacy in non-small cell lung cancer (NSCLC), but the response occurs in only a minority of patients. In clinic, biomarkers such as TMB (tumor mutation burden) and PD-L1 (programmed cell death 1 ligand 1) still have their limitations in predicting the prognosis of ICI treatment. Hence, reliable predictive markers for ICIs are urgently needed. A public immunotherapy dataset with clinical information and mutational data of 75 NSCLC patients was obtained from cBioPortal as the discovery cohort, and another immunotherapy dataset of 249 patients across multiple cancer types was collected as the validation. Integrated bioinformatics analysis was performed to explore the potential mechanism, and immunohistochemistry studies were used to verify it. AHNAK nucleoprotein 2 (AHNAK2) was reported to have pro-tumor growth effects across multiple cancers, while its role in tumor immunity was unclear. We found that approximately 11% of the NSCLC patients harbored AHNAK2 mutations, which were associated with promising outcomes to ICI treatments (ORR, p = 0.013). We further found that AHNAK2 deleterious mutation (del-AHNAK2 mut) possessed better predictive function in NSCLC than non-deleterious AHNAK2 mutation (PFS, OS, log-rank p < 0.05), potentially associated with stronger tumor immunogenicity and an activated immune microenvironment. This work identified del-AHNAK2 mut as a novel biomarker to predict favorable ICI response in NSCLC.
Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism

Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites – insulin and methionine - using non-invasive optical techniques. By conjugating heavy water (D2O) probed Raman scattering with label-free two-photon fluorescence (TPF) microscopy, we observed altered de novo lipogenesis, 3D lipid droplet morphology, and lipid peroxidation under various methionine and insulin concentrations. Quantitative interrogation of both spatial and chemometric lipid metabolism under tandem metabolite modulation confirms significant interaction of insulin and methionine, which may prove to be critical therapeutic targets, and proposes a powerful optical imaging platform with subcellular resolution for metabolic and cancer research.