Miracle-dz/UniFAR-FTUs huggingface dataset:
miRNA-148a-3p Regulates Immunosuppression in DNA Mismatch Repair–Deficient Colorectal Cancer by Targeting PD-L1

Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n = 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n = 148), and formalin-fixed, paraffin-embedded samples (n = 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3′-untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNγ-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNγ-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer. Implications: This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment.
Improving Pediatric Diabetic Ketoacidosis Management in Community Emergency Departments Using a Simulation-Based Collaborative Improvement Program

Supplemental digital content is available in the text. Objectives The majority of pediatric patients with diabetic ketoacidosis (DKA) present to community emergency departments (CEDs) that are less prepared to care for acutely ill children owing to low pediatric volume and limited pediatric resources and guidelines. This has impacted the quality of care provided to pediatric patients in CEDs. We hypothesized that a simulation-based collaborative program would improve the quality of the care provided to simulated pediatric DKA patients presenting to CEDs. Methods This prospective interventional study measured adherence of multiprofessional teams caring for pediatric DKA patients preimplementation and postimplementation of an improvement program in simulated setting. The program consisted of (a) a postsimulation debriefing, (b) assessment reports, (c) distribution of educational materials and access to pediatric resources, and (d) ongoing communication with the academic medical center (AMC). All simulations were conducted in situ (in the CED resuscitation bay) and were facilitated by a collaborative team from the AMC. A composite adherence score was calculated using a critical action checklist. A mixed linear regression model was performed to examine the impact of CED and team-level variables on the scores. Results A total of 91 teams from 13 CEDs participated in simulated sessions. There was a 22-point improvement of overall adherence to the DKA checklist from the preintervention to the postintervention simulations. Six of 9 critical checklist actions showed statistically significant improvement. Community emergency departments with medium pediatric volume showed the most overall improvement. Teams from CEDs that are further from the AMC showed the least improvement from baseline. Conclusions This study demonstrated a significant improvement in adherence to pediatric DKA guidelines in CEDs across the state after execution of an in situ simulation-based collaborative improvement program.
Application of the Sepsis-3 Consensus Criteria in a Geriatric Acute Care Unit: A Prospective Study

The prognostic value of quick Sepsis-related Organ Failure Assessment (qSOFA) score in geriatric patients is uncertain. We aimed to compare qSOFA vs. Systemic Inflammatory Response Syndrome (SIRS) criteria for mortality prediction in older multimorbid subjects, admitted for suspected sepsis in a geriatric ward. We prospectively enrolled 272 patients (aged 83.7 ± 7.4). At admission, qSOFA and SIRS scores were calculated. Mortality was assessed during hospital stay and three months after discharge. The predictive capacity of qSOFA and SIRS was assessed by calculating the Area Under the Receiver Operating Characteristic Curve (AUROC), through pairwise AUROC comparison, and multivariable logistic regression analysis. Both qSOFA and SIRS exhibited a poor prognostic performance (AUROCs 0.676, 95% CI 0.609–0.738, and 0.626, 95% CI 0.558–0.691 for in-hospital mortality; 0.684, 95% CI 0.614–0.748, and 0.596, 95% CI 0.558–0.691 for pooled three-month mortality, respectively). The predictive capacity of qSOFA showed no difference to that of SIRS for in-hospital mortality (difference between AUROCs 0.05, 95% CI −0.05 to 0.14, p = 0.31), but was superior for pooled three-month mortality (difference between AUROCs 0.09, 95% CI 0.01–0.17, p = 0.029). Multivariable logistic regression analysis, accounting for possible confounders, including frailty, showed that both scores were not associated with in-hospital mortality, although qSOFA, unlike SIRS, was associated with pooled three-month mortality. In conclusion, neither qSOFA nor SIRS at admission were strong predictors of mortality in a geriatric acute-care setting. Traditional geriatric measures of frailty may be more useful for predicting adverse outcomes in this setting.
Prolonged Duration of Brain Death was Associated with Better Kidney Allograft Function and Survival: A Prospective Cohort Analysis

Background Brain death initiates hemodynamic, immunological, and hormonal changes that potentially compromise organ quality for transplantation. Therefore, it is generally believed that organs should be procured as soon as possible after the declaration of brain death. However, conflicting data exist regarding the impact of brain death duration on long-term graft function and survival. Material/Methods The effect of duration of brain death on graft survival and function of 1869 adult transplant recipients receiving kidneys from deceased donors after brain death was analyzed, using relevant donor and recipient characteristics and allograft related factors. Results Duration of brain death was a significant predictor for long-term graft survival, whilst there was no significant effect of duration of brain death on the incidence of delayed graft function or acute graft rejection after kidney transplantation. After dividing the study population into a “short durBD” (<10.6 hours) group and a “long durBD” (>10.6 hours) group, the 15-year graft survival estimates were significantly higher and the serum creatinine at 3 months after transplantation was significantly lower in the “long durBD” group. Conclusions Duration of brain death does not affect the incidence of delayed graft function or acute rejection after kidney transplantation. However, longer duration of brain death is associated with better kidney allograft function and survival.
Long noncoding RNA CDKN2B‐AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription

The effective therapeutic approach of cerebral infarction is limited because of its underlying complexity. Recently, multiple long noncoding RNAs (lncRNAs) have been identified in the pathogenesis of cerebral infarction. Here, the current study aims to explore the interaction among lncRNA cyclin‐dependent kinase inhibitor‐2B–antisense RNA 1 (CDKN2B‐AS1), transcription factor B‐cell lymphoma/leukemia 11A (BCL11A), and MAPKK kinase kinase 1 (MAP4K1) and further investigate whether they affect cerebral infarction progression. The expression of CDKN2B‐AS1, BCL11A, and MAP4K1 was altered in lymphocytes extracted from patients with cerebral infarction. In order to identify their roles in regulatory T (Treg) cells, the proliferation and apoptosis of the CD4+CD25+ Treg cells were examined, and levels of IL‐4, IL‐10, and TGF‐β were determined. Also, the RNA crosstalk among CDKN2B‐AS1, BCL11A, and MAP4K1 was validated. Finally, we established a rat model of middle cerebral arterial occlusion to evaluate the neurologic impairment and cerebral infarction volume. The results revealed that lymphocytes in patients with cerebral infarction presented with the up‐regulated expression of CDKN2B‐AS1. Moreover, BCL11A could specifically bind to CDKN2B‐AS1 and MAP4K1 promoter so as to inhibit MAP4K1. Moreover, it was observed that down‐regulated CDKN2B‐AS1 inhibited CD4+CD25+ Treg‐cell proliferation, reduced levels of IL‐4, IL‐10, and TGF‐β and cerebral infarction volume, and elevated MAP4K1 expression. Collectively, our study provides evidence that CDKN2B‐AS1 silencing could increase MAP4K1 expression to inhibit the CD4+CD25+ Treg‐cell proliferation by reducing enrichment of transcription factor BCL11A, thereby protecting against cerebral infarction progression, highlighting a promising therapeutic strategy for treating cerebral infarction. —Lei, J.‐J., Li, H. ‐Q. , Mo, Z. ‐H. , Liu, K. ‐J., Zhu, L. ‐J., Li, C. ‐Y. , Chen, W. ‐L. , Zhang, L. Long noncoding RNA CDKN2B‐AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription. FASEB J. 33, 7037–7048 (2019). www.fasebj. org
Proteome and Phosphoproteome Analysis in TNF Long Term-Exposed Primary Human Monocytes

To better understand the inflammation-associated mechanisms modulating and terminating tumor necrosis factor (TNF-)induced signal transduction and the development of TNF tolerance, we analyzed both the proteome and the phosphoproteome in TNF long term-incubated (i.e., 48 h) primary human monocytes using liquid chromatography-mass spectrometry. Our analyses revealed the presence of a defined set of proteins characterized by reproducible changes in expression and phosphorylation patterns in long term TNF-treated samples. In total, 148 proteins and 569 phosphopeptides were significantly regulated (103 proteins increased, 45 proteins decreased; 377 peptides with increased and 192 peptides with decreased phosphorylation). A variety of these proteins are associated with the non-canonical nuclear factor κB (NF-κB) pathway (nuclear factor κB (NFKB) 2, v-rel reticuloendotheliosis viral oncogene homolog (REL) B, indolamin-2,3-dioxygenase (IDO), kynureninase (KYNU)) or involved in the negative regulation of the canonical NF-κB system. Within the phosphopeptides, binding motifs for specific kinases were identified. Glycogen synthase kinase (GSK) 3 proved to be a promising candidate, since it targets NF-κB inhibiting factors, such as CCAAT/enhancer binding protein (C/EBP) β. Our experiments demonstrate that both proteome and phosphoproteome analysis can be effectively applied to study protein/phosphorylation patterns of primary monocytes. These results provide new regulatory candidates and evidence for a complex network of specific but synergistically acting/cooperating mechanisms enabling the affected cells to resist sustained TNF exposure and resulting in the resolution of inflammation.
A clinical analysis on 40 cases of spontaneous intracranial hypotension syndrome

Abstract Objective: To investigate clinical and imaging features of 40 patients with spontaneous intracranial hypotension (SIH). Methods: 40 cases of spontaneous intracranial hypotension (SIH) diagnosed in our hospital from June 2013 to September 2017 were collected and retrospectively analyzed. Results: In our study, the male to female ratio was 2:3. The average age of onset was 43.0 ± 15.0 years. There were 12 (30.0%) patients with clear incentives, mostly catching cold. The average length of hospital stay was 11.2 ± 6.3 days. All the patients showed orthostatic headaches, 62.5% patients with nausea or vomiting, 40.0% patients with neck stiffness, 17.5% patients with dizziness and vertigo, 10.0% patients with numbness and weakness of limbs, 5% patients with neck discomfort, and 2.5% patients with visual symptoms (visual impairment, photophobia, diplopia). 24 patients underwent CT scans which showed no abnormalities in 20 cases (83.3%), subdural fluid accumulation in 3 cases (12.5%), and subdural haematoma in 1 case (2.5%). Cranial contrast-enhanced MR scans showed diffuse pachymeningeal enhancement (95.83%, 23/24), signs of pituitary hyperaemia in 5 cases (20.8%), subdural fluid accumulation and subdural hematoma in 4 cases (16.7%), sagging of the brain in 3 cases (12.5%), and engorgement of venous structures in 1 case (4.1%). Six patients underwent plain and contrast-enhanced spinal MR scans which showed varying degrees of dural thickening and enhanced performance in all the patients. 92.5% (37/40) of patients had cerebrospinal fluid pressure <60 mmH2O on lumbar puncture. 97.5% of patients underwent conservative treatment with drugs and had a good outcome. Conclusion: Orthostatic headache and cranial MRI diffuse pachymeningeal enhancement are characteristic features of SIH. Cranial contrast-enhanced MR scan is recognized as the first and non-invasive investigation in the diagnosis of SIH. Most patients had cerebrospinal fluid pressure <60 mmH2O. The vast majority of patients improved with fluid replacement.
Factors influencing caregiver decision making to change the communication method of their child with hearing loss

ABSTRACT The communication journey of a child with hearing loss is often a complex, interwoven process in which the child's use of language or method of communication may change numerous times. As there has been limited research exploring the caregiver decision-making process behind making such changes, this qualitative descriptive study aimed to explore the factors which influence the caregiver decision making-process to change the communication method of their child with hearing loss. Individual semi-structured in-depth interviews were conducted with seven caregivers of children with hearing loss in Australia. Thematic analysis revealed five key themes which influenced caregiver decisions regarding changes to their child's method of communication, including: (1) family characteristics; (2) family access to information; (3) family strengths; (4) family beliefs; and (5) family-centered practice. The overall finding that the family unit is at the core of decision-making has important clinical implications regarding early intervention professionals’ provision of family-centered services when working with the families of children with hearing loss.
Effects of piperonyl butoxide on exploratory behaviour in female mice

Previous studies reported that piperonyl butoxide (PBO) induces adverse effects on exploratory behaviour in male mice. However, no consistent effects of PBO treatment were observed in female mice. This study aimed to evaluate PBO’s neurobehavioral effects in female mice. Female mice were exposed to PBO through diet to provide levels of 0 (control), 0.025%, 0.1%, and 0.4% from 5 to 12 weeks of age, and selected behavioural parameters were measured. The average female body weight showed no significant effect from PBO treatment through the experimental periods. Regarding multiple-T water maze performance at 10 weeks of age, no significant effect caused by PBO treatment was observed. Exploratory behaviour examination of 8-week-old female mice indicated that the average speed declined in a significant dose-related manner, and the longitudinal pattern indicated a significant difference between the control and high-dose groups. For exploratory behaviour examination at 11 weeks of age, the total exploration distance shortened in a significant dose-related manner, and the average speed declined similarly. These longitudinal patterns showed significant differences between the control and high-dose groups. The PBO dose levels in this study produced several adverse effects on exploratory behaviour in female mice.
IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α–dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra–deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.
Automatic segmentation of optical coherence tomography pullbacks of coronary arteries treated with bioresorbable vascular scaffolds: Application to hemodynamics modeling

Background / Objectives Automatic algorithms for stent struts segmentation in optical coherence tomography (OCT) images of coronary arteries have been developed over the years, particularly with application on metallic stents. The aim of this study is three-fold: (1) to develop and to validate a segmentation algorithm for the detection of both lumen contours and polymeric bioresorbable scaffold struts from 8-bit OCT images, (2) to develop a method for automatic OCT pullback quality assessment, and (3) to demonstrate the applicability of the segmentation algorithm for the creation of patient-specific stented coronary artery for local hemodynamics analysis. Methods The proposed OCT segmentation algorithm comprises four steps: (1) image pre-processing, (2) lumen segmentation, (3) stent struts segmentation, (4) strut-based lumen correction. This segmentation process is then followed by an automatic OCT pullback image quality assessment. This method classifies the OCT pullback image quality as ‘good’ or ‘poor’ based on the number of regions detected by the stent segmentation. The segmentation algorithm was validated against manual segmentation of 1150 images obtained from 23 in vivo OCT pullbacks. Results When considering the entire set of OCT pullbacks, lumen segmentation showed results comparable with manual segmentation and with previous studies (sensitivity ~97%, specificity ~99%), while stent segmentation showed poorer results compared to manual segmentation (sensitivity ~63%, precision ~83%). The OCT pullback quality assessment algorithm classified 7 pullbacks as ‘poor’ quality cases. When considering only the ‘good’ classified cases, the performance indexes of the scaffold segmentation were higher (sensitivity >76%, precision >86%). Conclusions This study proposes a segmentation algorithm for the detection of lumen contours and stent struts in low quality OCT images of patients treated with polymeric bioresorbable scaffolds. The segmentation results were successfully used for the reconstruction of one coronary artery model that included a bioresorbable scaffold geometry for computational fluid dynamics analysis.
Systematic Review and Meta-Analysis of the Prognostic Value of Serum High-Density Lipoprotein Cholesterol Levels for Solid Tumors

Abstract Numerous studies have demonstrated that serum high-density lipoprotein cholesterol (HDL-C) levels correlate strongly with cancer patient survival. However, other studies have had the opposite results. We therefore conducted a systematic review and meta-analysis to assess the prognostic value of HDL-C levels in people with cancer. We searched PubMed, Embase, and the Cochrane Library (last update by December 28, 2017) for studies evaluating the effect of serum HDL-C levels on cancer patient prognosis. Data from 25 studies covering13,140 patients were included. Combined hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were assessed using fixed-effects and random-effects models. High serum HDL-C levels were associated with better OS (pooled HR = 0.70; 95% confidence interval (CI) (0.60–0.82). In the subgroup, the relative high level of HDL-C yielded a favorable outcome in most of tumor types. However, in the nasopharyngeal carcinoma subgroup, the correlation was not significant (combined HR = 1.31; 95% CI (0.91–1.90)). High serum HDL-C levels were associated with better DFS (pooled HR = 0.64; 95% confidence interval (CI) (0.50–0.81)). This meta-analysis demonstrates that high serum HDL-C levels are associated with better OS in patients with solid tumors, but not nasopharyngeal carcinoma; and high serum HDL-C levels are associated with better DFS.
Does the Bilingual Advantage in Cognitive Control Exist and If So, What Are Its Modulating Factors? A Systematic Review

Recently, doubts were raised about the existence of the bilingual advantage in cognitive control. The aim of the present review was to investigate the bilingual advantage and its modulating factors. We searched the Medline, ScienceDirect, Scopus, and ERIC databases for all original data and reviewed studies on bilingualism and cognitive control, with a cut-off date of 31 October 2018, thereby following the guidelines of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol. The results of the 46 original studies show that indeed, the majority, 54.3%, reported beneficial effects of bilingualism on cognitive control tasks; however, 28.3% found mixed results and 17.4% found evidence against its existence. Methodological differences seem to explain these mixed results: Particularly, the varying selection of the bilingual participants, the use of nonstandardized tests, and the fact that individual differences were often neglected and that longitudinal designs were rare. Therefore, a serious risk for bias exists in both directions (i.e., in favor of and against the bilingual advantage). To conclude, we found some evidence for a bilingual advantage in cognitive control; however, if significant progress is to be made, better study designs, bigger data, and more longitudinal studies are needed.