Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury.

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.

Alcohol use disorder and time perception: The mediating role of attention and working memory.

Alcohol use disorder (AUD) has been associated with attentional deficits and impairments of working memory. Meanwhile, attention and working memory are critical for time perception. However, it remains unclear how time perception alters in AUD patients and how attention and working memory affect their time perception. The current study aims to clarify the time perception characteristics of AUD patients and the cognitive mechanisms underlying their time perception dysfunction. Thirty-one patients (three of them were excluded) with AUD and thirty-one matched controls completed the Time Bisection Task, Attention Network Test and Digital Span Backward Test to assess their abilities in time perception, attention network and working memory, respectively. The results showed that, after controlling for anxiety, depression, and impulsivity, AUD patients had a lower proportion of 'long' responses at intervals of 600, 750, 900, 1050 and 1200 ms. Furthermore, they displayed higher subjective equivalence points and higher Weber ratios compared to controls. Moreover, AUD patients showed impaired alerting and executive control networks as well as reduced working memory resources. Only working memory resources mediated the impact of AUD on time perception. In conclusion, our findings suggested that the duration underestimation in AUD patients is predominantly caused by working memory deficits.

Intense green light emission in Sr2 ZnGe2 O7 :Mn2+ phosphors by the design of high symmetry melilite structure.

A green phosphor Sr2 ZnGe2 O7 :Mn2+ with a melilite structure was prepared using a high-temperature solid-state reaction. When the 535 nm emission was monitored, the excitation spectrum of the Sr2 ZnGe2 O7 :Mn2+ was found to contain two excitation bands in the ultraviolet (UV) region. When excited by UV light, the sample shows bright green emission at 535 nm, which corresponds to the distinctive transition of Mn2+ (4 T1 →6 A1 ). Moreover, the quantum efficiency of Sr2 ZnGe2 O7 :Mn2+ could reach 67.6%. Finally, a high-performance white-light-emitting diode (WLED) with a low correlated colour temperature of 4632 K and a high colour rendering index (CRI) of 92.3 were packaged by coating commercial blue and red phosphors with an optimized Sr2 ZnGe2 O7 :Mn2+ sample on a 310 nm UV chip. This indicated that Sr2 ZnGe2 O7 :Mn2+ has the potential application as a green component in the WLED lighting field.

The longitudinal relationship between loneliness and both social anxiety and mobile phone addiction among rural left-behind children: A cross-lagged panel analysis.

INTRODUCTION: Left-behind children are a special group that needs urgent attention. Due to enduring separation from their parents, loneliness is considered the most common and prevalent developmental hurdle in the experiences of left-behind children. This longitudinal cross-lagged study examined the direction of the association between loneliness and both internalizing and externalizing symptoms, with considering gender and left-behind status differences. METHODS: A total of 1175 rural Chinese children (48.3% boys, 39.9% left-behind children, Mage = 14.54 ± 1.18 at baseline) completed self-reported loneliness, social anxiety, and mobile phone addiction at two-time points with 6 months intervals. Descriptive statistics, cross-lagged panel analysis, and multiple group analysis were estimated in the present study. RESULTS: Loneliness exacerbated social anxiety and mobile phone addiction, and vice versa. In addition, gender and left-behind status moderated these relationships, with boys more likely to be mobile phone addicted due to loneliness and girls more likely to be lonely due to mobile phone addiction. More importantly, left-behind children with loneliness are more prone to social anxiety and mobile phone addiction, and vice versa, compared with non-left-behind children. CONCLUSIONS: The targeted interventions should be carried out for different genders and left-behind statuses. Particularly for left-behind children, neglecting to address both the symptoms of loneliness and both social anxiety and mobile phone addiction could significantly undermine the efficacy of intervention programs that solely target either one of these afflictions.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

Exploration of the radiosensitivity-related prognostic risk signature in patients with glioma: evidence from microarray data.

BACKGROUND: Gene expression signatures can be used as prognostic biomarkers in various types of cancers. We aim to develop a gene signature for predicting the response to radiotherapy in glioma patients. METHODS: Radio-sensitive and radio-resistant glioma cell lines (M059J and M059K) were subjected to microarray analysis to screen for differentially expressed mRNAs. Additionally, we obtained 169 glioblastomas (GBM) samples and 5 normal samples from The Cancer Genome Atlas (TCGA) database, as well as 80 GBM samples and 4 normal samples from the GSE7696 set. The "DESeq2" R package was employed to identify differentially expressed genes (DEGs) between the normal brain samples and GBM samples. Combining the prognostic-related molecules identified from the TCGA, we developed a radiosensitivity-related prognostic risk signature (RRPRS) in the training set, which includes 152 patients with glioblastoma. Subsequently, we validated the reliability of the RRPRS in a validation set containing 616 patients with glioma from the TCGA database, as well as an internal validation set consisting of 31 glioblastoma patients from the Nanfang Hospital, Southern Medical University. RESULTS: Based on the microarray and LASSO COX regression analysis, we developed a nine-gene radiosensitivity-related prognostic risk signature. Patients with glioma were divided into high- or low-risk groups based on the median risk score. The Kaplan-Meier survival analysis showed that the progression-free survival (PFS) of the high-risk group was significantly shorter. The signature accurately predicted PFS as assessed by time-dependent receiver operating characteristic curve (ROC) analyses. Stratified analysis demonstrated that the signature is specific to predict the outcome of patients who were treated using radiotherapy. Univariate and multivariate Cox regression analysis revealed that the predictor was an independent predictor for the prognosis of patients with glioma. The prognostic nomograms accompanied by calibration curves displayed the 1-, 2-, and 3-year PFS and OS in patients with glioma. CONCLUSION: Our study established a new nine-gene radiosensitivity-related prognostic risk signature that can predict the prognosis of patients with glioma who received radiotherapy. The nomogram showed great potential to predict the prognosis of patients with glioma treated using radiotherapy.

Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC.

BACKGROUND AND AIMS: Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). APPROACH AND RESULTS: Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio-resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling-mediated translational control of hypoxia inducible factor-1α (HIF-1α) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. CONCLUSIONS: We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.

A novel corporoplasty technique with a urethral plate flap in hypospadias repair.

OBJECTIVES: To report a novel corporoplasty technique with a urethral plate flap in hypospadias repair and evaluate its safety and efficacy for ventral lengthening. METHODS: Data were retrospectively collected from consecutive patients with hypospadias who underwent urethral plate flap corporoplasty between July 2021 and March 2022. All patients underwent hypospadias repair using the Duckett technique. The corporoplasty procedure involved the following key steps: the half-spongiosum of the urethral plate was harvested as a flap (with a pedicle attached to the corpus cavernosum); a transverse incision of the tunica albuginea was made adjacent to the pedicle; and the flap was patched onto the corporal defect. RESULTS: The study included 10 patients, with a median age of 20 months. The initial meatal location was penile in two patients, penoscrotal in four patients, and scrotal in four patients. The median ventral curvature was 45° after degloving and urethral plate transection. The median ventral lengthening distance proportional to penis length was 0.21. During the median follow-up of 13.8 months, complications occurred in three cases, including two cases of fistula and one case of urethral stricture with secondary diverticulum. No cases of recurrent ventral curvature, meatal stenosis, or urethral dehiscence were noted. Postoperative ultrasonography showed a good continuation of the tunica albuginea and integrity of the stratum spongiosum at the corporoplasty site. CONCLUSIONS: Urethral plate flap corporoplasty is a simple and effective ventral lengthening procedure. The novel corporoplasty technique allows for anatomical and architectural repair of corporal disproportion.

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice.

BACKGROUND: Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). METHODS: A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. RESULTS: Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). CONCLUSIONS: Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

COVID-19 Stressors and Poor Sleep Quality: The Mediating Role of Rumination and the Moderating Role of Emotion Regulation Strategies.

BACKGROUND: The global spread of COVID-19 has brought immense psychological distress and sleep problems to those affected. This study examined the mediating role of rumination in the direct association between COVID-19 stressors and poor sleep quality and the moderating roles of emotion regulation strategies. METHOD: A cross-sectional online survey study was conducted in China during the early outbreak of the pandemic. A total of 1106 Chinese college students (Mage = 19.58, SD = 1.61) completed measures of COVID-19 stressors, rumination, emotion regulation strategies (i.e., cognitive reappraisal and expressive suppression), and poor sleep quality. RESULTS: COVID-19 stressors were positively associated with poor sleep quality (ß = .431, p < .001), and rumination partially mediated this association. The mediation effect accounted for 70.93% of the total effect of COVID-19 stressors on poor sleep quality. Moreover, cognitive reappraisal moderated the relation between COVID-19 stressors and rumination, and expressive suppression moderated the association between rumination and poor sleep quality. CONCLUSION: Rumination could be a mechanism by which COVID-19 stressors are linked with poor sleep quality. Cognitive reappraisal might provide desired benefits to improving sleep quality while expressive suppression may do the opposite. Implications for future steps and health interventions are discussed.

Epstein-Barr virus (EBV) encoded microRNA BART8-3p drives radioresistance-associated metastasis in nasopharyngeal carcinoma.

Radiotherapy plays an important role in the treatment of nasopharyngeal carcinoma (NPC), however, 20% of patients with NPC exhibit unusual radioresistance. Patients with radioresistance are at risk of recurrence, so it is imperative to explore the mechanism of resistance to radiotherapy. In the past, studies on the mechanism of radioresistance have been restricted to DNA damage and related cell cycle remodeling or apoptosis. So far, no studies have explored the relationship between radioresistance and metastasis. Through the analysis of clinical samples, we observed that the metastasis rate of recurrent NPC was much higher than that of primary patients. In vitro and in vivo experiments showed that NPC cells with acquired radioresistance exhibited a stronger ability for invasion and metastasis. Mechanistically, we found that the Epstein-Barr virus (EBV)-encoded miRNA BART8-3p was increased in patients with NPC, and its expression was positively correlated with adverse prognostic factors, such as radioresistance. Besides this, miR-BART8-3p promoted the epithelial-mesenchymal transition, invasion, and metastasis of radioresistant NPC cells by targeting and inhibiting their PAG1 host gene. These findings suggested a novel role for EBV-miR-BART8-3p in promoting NPC radioresistance-associated metastasis and highlighted its potential value as a prognostic indicator or therapeutic target.

Profiles of immune infiltration in lung adenocarcinoma and their clinical significant: A gene-expression-based retrospective study.

Lung cancer is one of the fatal tumors. The tumor microenvironment plays a key role in regulating tumor progression. To figure out the role of tumor microenvironment in lung adenocarcinoma (LUAD), ESTIMATE algorithm was used to evaluate the immune scores in LUAD. Patients with low immune scores had a worse overall survival (OS) compared with high immune scores. Using RNA-Seq data of 489 patients in The Cancer Genome Atlas (TCGA), differentially expressed genes (DEGs) were identified between high- and low-immune score groups. Based on the DEGs, nine-gene signature was constructed by the least absolute shrinkage and selection operator Cox regression model in TCGA set. The signature demonstrated significant prognostic value in both TCGA and Gene Expression Omnibus database. Multivariate Cox regression analyses indicated that nine-genes signature was an independent prognostic factor. Subgroup analysis also revealed a robust prognostic ability of nine-gene signature. A nomogram with a C-index of 0.722 had a favorable power for predicting 3-, 5-, and 10-year survival for clinical use by integrating nine-gene signature and other clinical features. Co-expression and functional enrichment analysis showed that nine-gene signature was significantly associated with immune response and provided potential profound molecules for revealing the mechanism of tumor initiation and progression. In conclusion, we revealed the significance of immune infiltration and built a novel nine-gene signature as a reliable prognostic factor for patients with LUAD.

Influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters in petrochemical workers: a cross-sectional study.

BACKGROUND: Ubiquitously distributed benzene is a known hematotoxin. Increasing evidence has suggested that erythroid-related hematologic parameters may be sensitive to benzene exposure. Fat content, which is also closely associated with erythroid-related hematologic parameters, may affect the distribution and/or metabolism of benzene, and eventually benzene-induced toxicity. METHODS: To explore the influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters, we recruited 1669 petrochemical workers and measured their urinary S-phenylmercapturic acid (SPMA) concentration and erythroid-related hematological parameters. Indices for fat content included body fat percentage (BF%), plasma total cholesterol (TC) and triglycerides (TG), and occurrence of fatty liver. RESULTS: The dose-response curve revealed U-shaped nonlinear relationships of SPMA with hematocrit (HCT) and mean corpuscular hemoglobin concentration (MCHC) (P-overall < 0.001, and P-nonlinear < 0.015), as well as positive linear associations and r-shaped nonlinear relationships of continuous fat content indices with erythroid-related hematological parameters (P-overall ≤0.005). We also observed modification effects of fat content on the associations between benzene exposure and erythroid-related hematological parameters, with workers of lower or higher BF% and TG more sensitive to benzene-induced elevation of MCHC (Pinteraction = 0.021) and benzene-induced decrease of HCT (Pinteraction = 0.050), respectively. We also found that some erythroid-related hematologic parameters differed between subgroups of workers with different SPMA levels and fat content combination. CONCLUSIONS: Our study suggested that benzene exposure, fat content, and their interactions may affect erythroid-related hematological parameters in petrochemical workers in a complex manner that are worthy of further investigation.

Stressors of COVID-19 and stress consequences: The mediating role of rumination and the moderating role of psychological support.

BACKGROUNDS AND AIMS: As COVID-19 spreads rapidly, this global pandemic has not only brought the risk of death but also spread unbearable psychological pressure to people around the world. The aim of this study was to explore (a) the mediating role of rumination in the association between stressors of COVID-19 and stress consequences of college students, and (b) the moderating role of psychological support in the indirect relationship between stressors of COVID-19 and stress consequences of college students. METHODS: Eight hundred and forty-one Chinese college students (Mage = 19.50 years, SD = 1.580) completed the measures of stressors of COVID-19, stress consequences, rumination, and psychological support. RESULTS: Stressors of COVID-19 were significantly positively associated with stress consequences, and mediation analyses indicated that rumination partially mediated this association. Moderated mediation analysis further revealed that psychological support buffered the relation between stressors of COVID-19 and rumination, as well as the relation between rumination and stress consequences. DISCUSSION AND CONCLUSION: Findings of this study demonstrated that stressors associated with COVID-19 is positively related to rumination, which in turn, is related to stress consequences in college students. However, psychological support buffered this effect at both indirect mediation paths, suggesting that college students with greater psychological support may be better equipped to prevent negative stress consequences.

Postoperative Myocardial Injury in Middle-Aged and Elderly Patients Following Curative Resection of Esophageal Cancer With Aggressive or Standard Body Temperature Management: A Randomized Controlled Trial.

BACKGROUND: Risk of intraoperative hypothermia is relatively high in middle-aged and elderly patients undergoing curative resection of esophageal cancer, which may cause myocardial ischemia during the early postoperative period. The objective of this study was to compare aggressive or standard body temperature management for lowering the incidence of postoperative myocardial injury that was assessed by troponin levels collected at a priori defined set times in these patients. METHODS: Seventy patients undergoing elective curative resection of esophageal cancer were randomly assigned to undergo aggressive body temperature management (nasopharyngeal temperature ≥36°C) or standard body temperature management (n = 35 in each arm). The primary outcome was myocardial injury, defined as the occurrence of elevated troponin I (>0.06 µg/L) or elevated high-sensitivity troponin T (≥0.065, or 0.02 µg/L≤ high-sensitivity troponin T <0.065 µg/L, but with an absolute change of at least 0.005 µg/L) or both during 2 days after surgery. Secondary outcomes included (1) severe arrhythmia, including atrial fibrillation, supraventricular tachycardia, frequent premature ventricular contractions intraoperatively or during 3 days postoperatively; (2) hypoxemia or metabolic acidosis during the first 12 h postoperatively; and (3) deep vein thrombosis or pulmonary embolism during 3 days postoperatively. RESULTS: Incidence of postoperative 2-day myocardial injury was 8.6% (3/35) among patients receiving aggressive body temperature management and 31.4% (11/35) among patients receiving standard body temperature management (P = .017, χ). Relative risk of myocardial injury in the aggressive body temperature management group was 0.27 (95% CI, 0.08-0.89). Incidence of intra- and postoperative 3-day severe cardiac arrhythmia was 2.9% (1/35) among patients receiving aggressive body temperature management and 28.6% (10/35) among patients receiving standard body temperature management. Incidence of postoperative 12-h hypoxia was 17.1% (6/35) with aggressive body temperature management and 40.0% (14/35) with standard body temperature management. Incidence of postoperative 12-h metabolic acidosis was 20% (7/35) among patients receiving aggressive body temperature management and 48.6% (17/35) among patients receiving standard body temperature management. Incidence of postoperative 3-day deep vein thrombosis or pulmonary embolism was 0% (0/35) with aggressive body temperature management and 2.9% (1/35) with standard body temperature management. CONCLUSIONS: Aggressive body temperature management may be associated with a lower incidence of postoperative myocardial injury.

miR-142-3p inhibits aerobic glycolysis and cell proliferation in hepatocellular carcinoma via targeting LDHA.

Cancer cells are addictively dependent on glycolysis even in an oxygen-rich condition. However, the mechanism underlying micro (mi)RNA regulation of aerobic glycolysis in cancer cells has not been fully understood. Here, we demonstrated that the expression of miR-142-3p was lower in hepatocellular carcinoma (HCC) as compared to adjacent non-tumor samples, which was confirmed in The Cancer Genome Atlas (TCGA) HCC cohorts and Gene Expression Omnibus (GEO) datasets. Function and pathway analysis showed that miR-142-3p was most relevent with metabolism. As predicted, the overexpression of miR-142-3p inhibited aerobic glycolysis and thus proliferation of HCC cells. Mechanistically, we identified lactate dehydrogenase A (LDHA), one of the important catalyticase for aerobic glycolysis, as the target of miR-142-3p. Exogenous expression of miR-142-3p reduced the protein levels of LDHA in both SK-Hep-1 and Huh7 cells. Dual luciferase report assays showed the expression of LDHA was directly modulated by miR-142-3p. miR-142-3p-induced deduction of aerobic glycolysis and proliferation were reversed by LDHA overexpression. Taken together, these results indicate that miR-142-3p could act as a tumor suppressor in HCC by targeting LDHA, suggesting new therapeutic targets for HCC treatment.

Width proportion of the urethral plate to the glans can serve as an appraisal index of the urethral plate in hypospadias repair.

OBJECTIVES: To find a new appropriate evaluation for urethral plate quality in hypospadias repair, with particular interest in the width proportion of the urethral plate to the glans, serving as an appraisal index. METHODS: Data were prospectively collected from prepubertal boys who underwent primary tubularized incised plate hypospadias repair between January 2014 and April 2016 in one center. Intrinsic parameters of the penis (meatal location, glans width, urethral plate width and curvature degree) were measured during the operation. Urethroplasty complications were recorded during follow up. The correlation between width proportion of the urethral plate to the glans and urethroplasty complications was analyzed. RESULTS: Primary tubularized incised plate repair was carried out in 442 patients (mean age 2.8 years, range 0.5-12 years). At mean follow up of 26 months (range 12-38 months), urethroplasty complications occurred in 59 (13.3%) patients. The width proportion of the urethral plate to the glans was weakly correlated to both the glans width and meatal location. The width proportion of the urethral plate to the glans ranged from 0.18 to 0.73, with a mean of 0.39. The cut-off value of width proportion of the urethral plate to the glans was determined to be 0.36 by the receiver operating characteristic curve. Urethroplasty complications occurred in 17 out of 254 patients (6.7%) with width proportion of the urethral plate to the glans >0.36, and 42 out of 188 patients (22.3%) with width proportion of the urethral plate to the glans ≤0.36. The width proportion of the urethral plate to the glans ≤0.36 showed an increased odds of 4.819-fold (95% confidence interval 2.548-9.112, P < 0.001) risk of urethroplasty complications compared with width proportion of the urethral plate to the glans >0.36. Midshaft and proximal meatal location also increased the risk of urethroplasty complications. CONCLUSIONS: The present study highlights the value of the width proportion of the urethral plate to the glans for objectivity and accuracy in urethral plate evaluation, which in turn serves as an independent factor influencing outcomes in tubularized incised plate repair.

Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway.

Talin1 is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrins and focal adhesion signaling. Several studies have found that Talin1 is overexpressed in several tumor types and promotes tumor progression. However, the explicit role of Talin1 in hepatocellular carcinoma (HCC) progression is still unclear and its functional mechanism remains largely unknown. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non-tumor, primary HCC, and eventually metastatic foci, indicating that Talin1 may correlate with HCC initiation to progression. Talin1 was significantly downregulated in HCC tissues compared with adjacent non-tumor tissues and low Talin1 expression was associated with HCC progression and poor prognosis. Furthermore, Talin1 knockdown induced epithelial-mesenchymal transition and promoted migration and invasion in SK-Hep-1 cells and HepG2 cells. Mechanistically, we found that the ERK pathway was responsible for these promoting effects of Talin1 knockdown in HCC cells. The promoting effects of Talin1 knockdown on epithelial-mesenchymal transition, migration, and invasion were reversed by U0126, a specific ERK1/2 inhibitor. Taken together, our results suggested that Talin1 might serve as a tumor suppressor in HCC and a potential prognostic biomarker for HCC patients.

The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of ß-catenin in HCC cells.

BACKGROUND & AIMS: Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development. We investigated the mechanisms by which the long intergenic noncoding RNA UFC1 (lincRNA-UFC1) promotes progression of hepatocellular carcinoma (HCC), using human tissues and cell lines. METHODS: We used microarrays to compare expression profiles of lncRNAs in HCC samples and adjacent nontumor tissues (controls) from 7 patients. HCC and nontumor tissues were collected from 2006 through 2012 from patients in Guangzhou, China. We used quantitative real-time polymerase chain reaction to measure levels of lincRNA-UFC1 in tissues from 49 patients, and in situ hybridization to measure levels in samples from 131 patients; clinical data were collected from patients for up to 5 years. The lincRNA-UFC1 was expressed transgenically, or knocked down with short hairpin RNAs, in BEL-7402, SK-Hep1, Huh7, and MHCC-97H HCC cell lines; luciferase reporter and RNA immunoprecipitation and pull-down assays were performed. We also analyzed growth of xenograft tumors from these cells in BALB/c nude mice. RESULTS: Levels of the lincRNA-UFC1 were increased in HCC tissues compared with controls, and associated with tumor size, Barcelona Clinic Liver Cancer stage, and patient outcomes. Transgenic expression of the lincRNA-UFC1 in HCC cells promoted their proliferation and cell-cycle progression and inhibited apoptosis, whereas short hairpin RNA knockdown of lincRNA-UFC1 had opposite effects. Xenograft tumors grown from cells overexpressing lincRNA-UFC1 had larger mean volumes and weights, and formed more rapidly, than tumors grown from control cells. Tumors grown from lincRNA-UFC1 knockdown were smaller than controls. The lincRNA-UFC1 interacted directly with the messenger RNA (mRNA) stabilizing protein HuR (encoded by ELAVL1) to increase levels of ß-catenin mRNA (encoded by CTNNB1) and protein. Levels of lincRNA-UFC1 correlated with those of ß-catenin in HCC tissues. In contrast, there was a negative correlation between levels of microRNA 34a and lincRNA-UFC1 in HCC tissues; microRNA 34a reduced the stability of lincRNA-UFC1. CONCLUSIONS: The lincRNA-UFC1, a target of microRNA 34a, promotes proliferation and reduces apoptosis in HCC cells to promote growth of xenograft tumors in mice. It interacts directly with the mRNA stabilizing protein HuR to regulate levels of ß-catenin in HCC cells.