Intestinal recruitment of CCR6-expressing Th17 cells by suppressing miR-681 alleviates endotoxemia-induced intestinal injury and reduces mortality.

INTRODUCTION: Sepsis or endotoxemia can induce intestinal dysfunction in the epithelial and immune barrier. Th17 cells, a distinct subset of CD4+ T-helper cells, act as "border patrol" in the intestine under pathological condition and in the previous studies, Th17 cells exhibited an ambiguous function in intestinal inflammation. Our study will explore a specific role of Th17 cells and its relevant mechanism in endotoxemia-induced intestinal injury. MATERIALS AND METHODS: Lipopolysaccharide was used to establish mouse model of endotoxemia. miR-681 was analyzed by RT-PCR and northern blot analysis and its regulation by HIF-1α was determined by chromatin immunoprecipitation and luciferase reporter assay. Intestinal Th17 cells isolated from endotoxemic mice were quantitatively evaluated by flow cytometry and its recruitment to the intestine controlled by miR-681/CCR6 pathway was assessed by using anti-miRNA treatment and CCR6 knockout mice. Intestinal histopathology, villus length, intestinal inflammation, intestinal permeability, bacterial translocation and survival were investigated, by histology and TUNEL analysis, ELISA, measurement of diamine oxidase, bacterial culture, with or without anti-miR-681 treatment in endotoxemic wild-type and (or) CCR6 knockout mice. RESULTS: In this study, we found that miR-681 was significantly promoted in intestinal Th17 cells during endotoxemia, which was dependent on hypoxia-inducible factor-1α (HIF-1α). Interestingly, miR-681 could directly suppress CCR6, which was a critical modulator for Th17 cell recruitment to the intestines. In vivo, anti-miR-681 enhanced survival, increased number of intestinal Th17 cells, reduced crypt and villi apoptosis, decreased intestinal inflammation and bacterial translocation, resulting in protection against endotoxemia-induced intestinal injury in mice. However, CCR6 deficiency could neutralize the beneficial effect of anti-miR-681 on the intestine during endotoxemia, suggesting that the increment of intestinal Th17 cells caused by anti-miR-681 relies on CCR6 expression. CONCLUSION: The results of the study indicate that control of intestinal Th17 cells by regulating novel miR-681/CCR6 signaling attenuates endotoxemia-induced intestinal injury.

Ultrathin, Washable, and Large-Area Graphene Papers for Personal Thermal Management.

Freestanding, flexible/foldable, and wearable bifuctional ultrathin graphene paper for heating and cooling is fabricated as an active material in personal thermal management (PTM). The promising electrical conductivity grants the superior Joule heating for extra warmth of 42 °C using a low supply voltage around 3.2 V. Besides, based on its high out-of-plane thermal conductivity, the graphene paper provides passive cooling via thermal transmission from the human body to the environment within 7 s. The cooling effect of graphene paper is superior compared with that of the normal cotton fiber, and this advantage will become more prominent with the increased thickness difference. The present bifunctional graphene paper possesses high durability against bending cycles over 500 times and wash time over 1500 min, suggesting its great potential in wearable PTM.

The prognostic value of pretreatment 18F-FDG PET-CT parameters with peripheral blood markers in patients with de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To develop and validate a prognostic nomogram based on pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)radiomics parameters and peripheral blood markers for risk stratification in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC). MATERIALS AND METHODS: A total of 558 patients with dmNPC were retrospectively enrolled between 2011 and 2019. Eligible patients were randomly divided into training and validation cohorts (7:3 ratio). A Cox regression model was used to identify prognostic factors for overall survival (OS). The predictive accuracy and discriminative ability of the prognostic nomogram were determined using the concordance index (C-index) and calibration curve. RESULTS: Independent factors derived from multivariable analysis of the training cohort to predict death were lactate dehydrogenase levels, pretreatment Epstein-Barr virus DNA, total lesion glycolysis of locoregional lesions, number of metastatic lesions, and age, all of which were assembled into a nomogram with (nomogram B) or without PET-CT parameters (nomogram A). The C-index of nomogram B for predicting death was 0.70, which was significantly higher than the C-index values for nomogram A. Patients were then stratified into low- and high-risk groups based on the scores calculated using nomogram B for OS. The median OS was significantly higher in the low-risk group than in the high-risk group (69.60 months [95 % CI: 58.50-108.66] vs. 21.40 months [95 % CI: 19.20-23.90]; p＜0.01). All the results were confirmed in the validation cohort. CONCLUSION: The proposed nomogram including PET-CT parameters yielded accurate prognostic predictions for patients with dmNPC, enabling effective risk stratification for these patients.

Integrating Baseline Nutritional and Inflammatory Parameters with Post-Treatment EBV DNA Level to Predict Outcomes of Patients with De Novo Metastatic Nasopharyngeal Carcinoma Receiving Chemotherapy Combination PD-1 Inhibitor.

OBJECTIVES: To develop and validate a prognostic nomogram based on baseline nutritional and inflammatory parameters for risk stratification in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) receiving chemotherapy combination programmed death-1 (PD-1) inhibitor. METHODS: This retrospective study analyzed 131 patients with dmNPC (88 and 43 in the training and validation cohorts, respectively) between March 2017 and November 2020. All these patients received chemotherapy combined with PD-1 inhibitor treatment. We identified independent risk factors using univariate and multivariate Cox regression analyses and established a nomogram to predict the progression-free survival (PFS). The predictive accuracy of the nomogram was evaluated and independently validated. RESULTS: Baseline nutritional risk index (NRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), uric acid (UA), and post-treatment Epstein-Barr virus (EBV) DNA were used to develop a nomogram that could divide patients into favorable- and unfavorable-prognosis groups. The median PFS (mPFS) was significantly longer in the favorable-prognosis group compared to the unfavorable-prognosis group (35.10 months [95% CI: 27.36-42.84] vs. 7.23 months [95% CI: 6.50-7.97]; p = 0.001). All results were confirmed in the validation cohort. CONCLUSIONS: The proposed model improved the prognostic risk stratification for patients with dmNPC undergoing chemotherapy combined with PD-1 inhibitor treatment.

Neutrophil extracellular traps (NETs)-related lncRNAs signature for predicting prognosis and the immune microenvironment in breast cancer.

Background: Neutrophil extracellular traps (NETs) are closely associated to tumorigenesis and development. However, the relationship between NETs-related long non-coding RNAs (lncRNAs) and the characteristics of breast tumor remains an enigma. This study aimed to explore the clinical prognostic value of NETs-related lncRNAs, their correlation with the tumor microenvironment (TME) and their predictive ability of drug sensitivity in patients with breast cancer (BC). Methods: The expression profiles of RNA-sequencing and relevant clinical data of BC patients were extracted from TCGA database. The co-expression network analysis, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were employed to construct the NETs-related lncRNAs signature. A nomogram was established and validated to explore the clinical application. Furthermore, the immune microenvironment and drug sensitivity for BC with different prognostic risks were explored. Finally, the expression pattern of lncRNAs was validated using qRT-PCR in BC tissues and their adjacent non-cancerous tissues. Results: Based on NETs-related lncRNAs, a prognostic risk model consisted of 10 lncRNAs (SFTA1P, ACTA2-AS1, AC004816.2, AC000067.1, LINC01235, LINC01010, AL133467.1, AC092919.1, AL591468.1, and MIR200CHG) was established. The Kaplan-Meier analysis showed that the overall survival (OS) was significantly better in low-risk BC patients than in high-risk BC patients (P training cohort < 0.001, P validation cohort = 0.009). The nomogram also showed good predictive accuracy for OS of BC individuals in both training and validation cohorts. The function enrichment analysis revealed that high-risk group was mainly enriched in immune-related functions and pathways, and the tumor mutation burden in this group was markedly higher than that in the low-risk group (p = 0.022). Moreover, significant differences were observed in immune cells, immune functions and immune checkpoint genes among BC patients at different risks (p < 0.05). The response to chemotherapeutic agents and immunotherapy were also closely related with the expression of NETs-related lncRNAs (p < 0.001). The expression of lncRNAs from experimental validation were generally consistent with the bioinformatics analysis results. Conclusion: Our study provided a novel prognostic model for BC and yielded strong scientific rationale for individualized treatment strategies, elucidating immunotherapy in BC patients.

Clinical treatment considerations in the intensity-modulated radiotherapy era for parotid lymph node metastasis in patients with nasopharyngeal carcinoma.

PURPOSE: No specific irradiation guidelines have been proposed for parotid lymph node (PLN) metastasis in patients with nasopharyngeal carcinoma (NPC). This study aimed to explore the dose prescription and target delineation for PLN metastasis in patients with NPC. METHODS: With the NPC database from a big-data platform, 10,685 patients with primarily diagnosed, non-distant metastatic, histologically proven NPC and treated with intensity modulated radiotherapy (IMRT) at our center from 2008 to 2019 were reviewed and those with PLN metastasis were enrolled in this study. Dosimetry parameters were collected from the dose-volume histograms (DVH). The primary endpoint was overall survival (OS). Least absolute shrinkage and selection operator regression (LASSO) was operated for variable selection. Multivariate Cox regression analysis was applied to identify the independent prognostic factors. RESULTS: PLN metastases were identified in 275/10685 (2.5%) patients. Of 367 positive PLN, 199 were in superficial intra-parotid, followed by 70 in deep intra-parotid, 54 in subparotid and 44 in subcutaneous pre-auricular. Better survival outcome was observed in PLN-radical IMRT group, compared with PLN-sparing group. In 190 patients received PLN-radical IMRT, multivariate analysis revealed that D95% of level VIII > 55 Gy was an independent beneficial prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and parotid relapse-free survival (PRFS). CONCLUSION: Based on the distribution pattern of PLN metastasis in NPC and the result of dose-finding study, involving the ipsilateral level VIII into low-risk clinical target volume (CTV2) is recommended for NPC with PLN metastasis.

Scale development of apparel customization brand value: From the perspectives of practitioners and consumers.

China apparel customization brands (CACBs) have been recently growing in massive quantities despite being in their infancy stages of brand value building. Although scholars have proven brand value's importance in sustainable brand growth, studies on the specific context of CACBs are still limited. This research proposes a conceptual framework of CACBs' brand value measured dimension based on previous studies and divides brand value into both general and specific dimensions. Accordingly, qualitative (semi-structured interviews) and quantitative (online survey) studies were conducted from the perspectives of practitioners and consumers. Ultimately, a scale of 30 items with nine dimensions was generated. Results reveal that brand association in the general dimensions and brand service in the special dimensions were the largest promoters of CACB brand value. Hence, practitioners should pay more attention to dimensions of cognitive conflicts. Practical suggestions for apparel customization marketers are proposed to build and enhance brand value.

1,25(OH)2D3 promotes the elimination of Klebsiella pneumoniae infection by inducing autophagy through the VDR-ATG16L1 pathway.

OBJECTIVE: Previous studies have shown that vitamin D has regulatory functions in both innate and adaptive immune responses, indicating that it can perform essential roles in host resistance to pathogen infections. This study aimed to verify its effects on Klebsiella pneumoniae (Kp) infection and explore the underlying mechanisms. METHODS: THP-1-derived macrophages were infected with Kp and then incubated with 1,25(OH)2D3. Autophagy induced by 1,25(OH)2D3 was investigated by western blotting and immunofluorescence. Real-time PCR (qPCR) was performed to determine the expression of inflammatory mediators. Baf A1 and 3-MA were used to inhibit autophagy. The intracellular killing of Kp was measured using qPCR and colony-forming unit assays. RNA interference assays were used to silence VDR or ATG16L1. The lungs of C57BL/6 mice were infected with Kp via intratracheal instillation, and the established pneumonia models were used for in vivo validation experiments. RESULTS: Treatment with 1,25(OH)2D3 enhanced the bactericidal activity of macrophages and concomitantly reduced the expression of the pro-inflammatory mediators TNF-α and IL-6. Kp infection led to a lower expression level of VDR in macrophages than in the control, whereas co-treatment with 1,25(OH)2D3 up-regulated VDR expression and robustly induced autophagy via the VDR signaling pathway. Silencing ATG16L1 significantly counteracted autophagy induced by 1,25(OH)2D3 in Kp-infected macrophages. Furthermore, we found that when autophagy activity was diminished by ATG16L1 siRNA or blocked by Baf A1, the ability of 1,25(OH)2D3 to promote macrophages to eliminate Kp infection was obviously impaired, as were its anti-inflammatory effects. These protective efficacies of 1,25(OH)2D3 against Kp infection were also validated in vivo using a mouse model of pneumonia. CONCLUSIONS: The present study demonstrated the protective features of 1,25(OH)2D3 in macrophages against Kp infection and may provide evidence for further exploration of its potential as an adjunctive therapy agent for the treatment of bacterial infections.

Out-of-hospital cardiac arrest patients with implantable cardioverter-defibrillators: What are their outcomes?

THE AIM OF THE STUDY: To identify the prognostic factors and effects of implantable cardioverter-defibrillators (ICDs) in out-of-hospital cardiac arrest (OHCA) patients with ICDs because the clinical characteristics and outcomes of OHCA patients with ICDs are unknown. METHODS: The North American Resuscitation Outcomes Consortium (ROC) Cardiac Epistry Version 3 dataset was analyzed. Eligible patients were divided into OHCA patients with and without ICDs. Multivariable regressions were employed to analyze. RESULTS: Of 51,634 eligible OHCA patients, 581 (1.13%) had implanted ICDs. Among them, 53 (9.1%) patients survived to hospital discharge, and 40 (6.9%) patients had favorable neurological outcome at hospital discharge. Multivariable regression showed ICDs were not associated with OHCA outcomes in the total OHCA patients. In the OHCA patients with ICDs, shockable initial emergency medical services (EMS)-recorded rhythms and the ICD-shock-only defibrillation pattern were independent favorable factors for survival to hospital discharge(OR = 3.3, 95%CI 1.7-6.2, P < 0.001; OR = 2.4, 95%CI 1.1-5.5, P = 0.035, respectively) and neurological outcome at hospital discharge (OR = 6.5, 95%CI 2.9-14.4, P < 0.001; OR = 3.6, 95%CI 1.4-9.1, P = 0.006, respectively). During field resuscitation in OHCA patients with ICDs, at least 34.9% of total patients and 64.6% of patients with initial EMS-recorded VT/VF rhythms needed additional external shocks. CONCLUSIONS: Shockable initial EMS-recorded rhythms and ICD-shock-only defibrillation pattern were independent factors for the favorable outcomes of OHCA patients with ICDs. ICDs were not associated with the outcomes of OHCA, and additional external shocks were needed in a substantial number of OHCA patients with ICDs during field resuscitation.

Conversion from Nonshockable to Shockable Rhythms and Out-of-Hospital Cardiac Arrest Outcomes by Initial Heart Rhythm and Rhythm Conversion Time.

BACKGROUND: The conversion from a nonshockable rhythm (asystole or pulseless electrical activity (PEA)) to a shockable rhythm (pulseless ventricular tachycardia or ventricular fibrillation) may be associated with better out-of-hospital cardiac arrest (OHCA) outcomes. There are insufficient data on the prognostic significance of such conversions by initial heart rhythm and different rhythm conversion time. METHODS: Among 24,849 adult OHCA patients of presumed cardiac etiology with initial asystole or PEA in the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (version 3, 2011-2015), we examined the association of shockable rhythm conversion with prehospital return of spontaneous circulation (ROSC), survival, and favorable functional outcome (modified Rankin Scale score ≤3) at hospital discharge by initial rhythm and rhythm conversion time (time from cardiopulmonary resuscitation (CPR) initiation by emergency medical providers to first shock delivery), using logistic regression adjusting for key clinical characteristics. RESULTS: Of 16,516 patients with initial asystole and 8,333 patients with initial PEA, 16% and 20% underwent shockable rhythm conversions; the median rhythm conversion time was 12.0 (IQR: 6.7-18.7) and 13.2 (IQR: 7.0-20.5) min, respectively. No difference was found in odds of prehospital ROSC across rhythm conversion time, regardless of initial heart rhythm. Shockable rhythm conversion was associated with survival and favorable functional outcome at hospital discharge only when occurred during the first 15 min of CPR, for those with initial asystole, or the first 10 min of CPR, for those with initial PEA. The associations between shockable rhythm conversion and outcomes were stronger among those with initial asystole compared with those with initial PEA. CONCLUSIONS: The conversion from a nonshockable rhythm to a shockable rhythm was associated with better outcomes only when occurred early in initial nonshockable rhythm OHCA, and it has greater prognostic significance when the initial rhythm was asystole.

Intravenous versus intraosseous adrenaline administration in out-of-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND: Adrenaline is an important component in the resuscitation of individuals experiencing out-of-hospital cardiac arrest (OHCA). The 2018 Advanced Cardiac Life Support (ACLS) algorithm gives the option of either intravenous (IV) or intraosseous (IO) routes for adrenaline administration during cardiac arrest. However, the optimal route during prehospital resuscitation remains controversial. This study aims to investigate whether IV and IO routes lead to different outcomes in OHCA patients who received prehospital adrenaline. METHODS: This retrospective analysis included adult patients with OHCA of presumed cardiac origin who had Emergency Medical Services (EMS) CPR, received adrenaline, and were enrolled in the Resuscitation Outcomes Consortium (ROC) Cardiac Epistry version 3 database between 2011 and 2015. We divided the study population into IV and IO groups based on the administration route. Logistic regression analysis was performed to evaluate the association between adrenaline delivery routes and prehospital return of spontaneous circulation (ROSC), survival to hospital discharge, and favorable neurological outcome. RESULTS: Of the 35,733 patients included, 27,758 (77.7%) had adrenaline administered via IV access and 7975 (22.3%) via IO access. With the IO group as a reference in the logistic regression model, the adjusted odds ratios of the IV group for prehospital ROSC, survival and favorable neurological outcome were 1.367 (95%CI, 1.276-1.464), 1.468 (95%CI, 1.264-1.705) and 1.849 (95%CI, 1.526-2.240), respectively. Similar results were found in the propensity score matched population and subgroup analysis. CONCLUSION: Compared with the IO approach, the IV approach appears to be the optimal route for adrenaline administration in advanced life support for OHCA during prehospital resuscitation.