Research trends in ferroptosis since the origin of the concept: A bibliometric analysis.

Ferroptosis is a newly characterized form of regulated cell death. This bibliometric analysis identified the scientific output, leading institutions and research teams, current research hotspots and trends in research on ferroptosis since the origin of the concept. We searched the Science Citation Index Expanded of Web of Science Core Collection for papers on ferroptosis up to 3 June 2022. The acquired data were analysed and visualized by Bibliometrix package and VOSviewer. The study ultimately included 3511 relevant papers, and annual production in this field has grown rapidly in recent years. Institutions and scholars from China contributed the most work, but the impact of their research was much less than that of the United States. Prof. Brent R. Stockwell's team from Columbia University in the United States has a very strong academic influence in the field. Front Cell Dev Biol published the most papers in the field of ferroptosis. As the keywords of the papers in this field changed from the most numerous 'oxidative stress', 'cell-death', 'iron', 'expression', and 'lipid-peroxidation', to 'prognosis', 'immunotherapy', 'progression', 'tumour microenvironment', and 'colorectal cancer', the hotspot of ferroptosis research is gradually shifting from basic research to clinical translational research. The mechanism of tumour formation and treatment will become the frontier in the field of ferroptosis research in the future.

Predictive value of lymphocyte-to-monocyte ratio in critically Ill patients with atrial fibrillation: A propensity score matching analysis.

BACKGROUND: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). Lymphocyte-to-monocyte ratio (LMR) has been proved to be a reliable predictor of many inflammation-associated diseases, but little data are available on the relationship between LMR and AF. We aimed to evaluate the predictive value of LMR in predicting all-cause mortality among AF patients. METHODS: Data of patients diagnosed with AF were retrieved from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. X-tile analysis was used to calculate the optimal cutoff value for LMR. The Cox regression model was used to assess the association of LMR and 28-day, 90-day, and 1-year mortality. Additionally, a propensity score matching (PSM) method was performed to minimize the impact of potential confounders. RESULTS: A total of 3567 patients hospitalized with AF were enrolled in this study. The X-tile software indicated that the optimal cutoff value of LMR was 2.67. A total of 1127 pairs were generated, and all the covariates were well balanced after PSM. The Cox proportional-hazards model showed that patients with the low LMR (≤2.67) had a higher 1-year all-cause mortality than those with the high LMR (>2.67) in the study cohort before PSM (HR = 1.640, 95% CI: 1.437-1.872, p < 0.001) and after PSM (HR = 1.279, 95% CI: 1.094-1.495, p = 0.002). The multivariable Cox regression analysis for 28-day and 90-day mortality yielded similar results. CONCLUSIONS: The lower LMR (≤2.67) was associated with a higher risk of 28-day, 90-day, and 1-year all-cause mortality, which might serve as an independent predictor in AF patients.

Dynamic nomograms combining N classification with ratio-based nodal classifications to predict long-term survival for patients with lung adenocarcinoma after surgery: a SEER population-based study.

BACKGROUND: The prognostic roles of three lymph node classifications, number of positive lymph nodes (NPLN), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) in lung adenocarcinoma are unclear. We aim to find the classification with the strongest predictive power and combine it with the American Joint Committee on Cancer (AJCC) 8th TNM stage to establish an optimal prognostic nomogram. METHODS: 25,005 patients with T1-4N0-2M0 lung adenocarcinoma after surgery between 2004 to 2016 from the Surveillance, Epidemiology, and End Results database were included. The study cohort was divided into training cohort (13,551 patients) and external validation cohort (11,454 patients) according to different geographic region. Univariate and multivariate Cox regression analyses were performed on the training cohort to evaluate the predictive performance of NPLN (Model 1), LODDS (Model 2), LNR (Model 3) or LODDS+LNR (Model 4) respectively for cancer-specific survival and overall survival. Likelihood-ratio χ2 test, Akaike Information Criterion, Harrell concordance index, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to evaluate the predictive performance of the models. Nomograms were established according to the optimal models. They're put into internal validation using bootstrapping technique and external validation using calibration curves. Nomograms were compared with AJCC 8th TNM stage using decision curve analysis. RESULTS: NPLN, LODDS and LNR were independent prognostic factors for cancer-specific survival and overall survival. LODDS+LNR (Model 4) demonstrated the highest Likelihood-ratio χ2 test, highest Harrell concordance index, and lowest Akaike Information Criterion, and IDI and NRI values suggested Model 4 had better prediction accuracy than other models. Internal and external validations showed that the nomograms combining TNM stage with LODDS+LNR were convincingly precise. Decision curve analysis suggested the nomograms performed better than AJCC 8th TNM stage in clinical practicability. CONCLUSIONS: We constructed online nomograms for cancer-specific survival and overall survival of lung adenocarcinoma patients after surgery, which may facilitate doctors to provide highly individualized therapy.

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia.

BACKGROUND: Neuroinflammation plays a vital role in the development and maintenance of neuropathic pain. Recent evidence has proved that bone marrow mesenchymal stem cells (BMSCs) can inhibit neuropathic pain and possess potent immunomodulatory and immunosuppressive properties via secreting a variety of bioactive molecules, such as TNF-α-stimulated gene 6 protein (TSG-6). However, it is unknown whether BMSCs exert their analgesic effect against neuropathic pain by secreting TSG-6. Therefore, the present study aimed to evaluate the analgesic effects of TSG-6 released from BMSCs on neuropathic pain induced by chronic constriction injury (CCI) in rats and explored the possible underlying mechanisms in vitro and in vivo. METHODS: BMSCs were isolated from rat bone marrow and characterized by flow cytometry and functional differentiation. One day after CCI surgery, about 5 × 106 BMSCs were intrathecally injected into spinal cerebrospinal fluid. Behavioral tests, including mechanical allodynia, thermal hyperalgesia, and motor function, were carried out at 1, 3, 5, 7, 14 days after CCI surgery. Spinal cords were processed for immunohistochemical analysis of the microglial marker Iba-1. The mRNA and protein levels of pro-inflammatory cytokines (IL-1ß, TNFα, IL-6) were detected by real-time RT-PCR and ELISA. The activation of the TLR2/MyD88/NF-κB signaling pathway was evaluated by Western blot and immunofluorescence staining. The analgesic effect of exogenous recombinant TSG-6 on CCI-induced mechanical allodynia and heat hyperalgesia was observed by behavioral tests. In the in vitro experiments, primary cultured microglia were stimulated with the TLR2 agonist Pam3CSK4, and then co-cultured with BMSCs or recombinant TSG-6. The protein expression of TLR2, MyD88, p-p65 was evaluated by Western blot. The mRNA and protein levels of IL-1ß, TNFα, IL-6 were detected by real-time RT-PCR and ELISA. BMSCs were transfected with the TSG-6-specific shRNA and then intrathecally injected into spinal cerebrospinal fluid in vivo or co-cultured with Pam3CSK4-treated primary microglia in vitro to investigate whether TSG-6 participated in the therapeutic effect of BMSCs on CCI-induced neuropathic pain and neuroinflammation. RESULTS: We found that CCI-induced mechanical allodynia and heat hyperalgesia were ameliorated by intrathecal injection of BMSCs. Moreover, intrathecal administration of BMSCs inhibited CCI-induced neuroinflammation in spinal cord tissues. The analgesic effect and anti-inflammatory property of BMSCs were attenuated when TSG-6 expression was silenced. We also found that BMSCs inhibited the activation of the TLR2/MyD88/NF-κB pathway in the ipsilateral spinal cord dorsal horn by secreting TSG-6. Meanwhile, we proved that intrathecal injection of exogenous recombinant TSG-6 effectively attenuated CCI-induced neuropathic pain. Furthermore, in vitro experiments showed that BMSCs and TSG-6 downregulated the TLR2/MyD88/NF-κB signaling and reduced the production of pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in primary microglia treated with the specific TLR2 agonist Pam3CSK4. CONCLUSIONS: The present study demonstrated a paracrine mechanism by which intrathecal injection of BMSCs targets the TLR2/MyD88/NF-κB pathway in spinal cord dorsal horn microglia to elicit neuroprotection and sustained neuropathic pain relief via TSG-6 secretion.

Positive End-Expiratory Pressure During Anesthesia for Prevention of Postoperative Pulmonary Complications: A Meta-analysis With Trial Sequential Analysis of Randomized Controlled Trials.

BACKGROUND: Whether intraoperative positive end-expiratory pressure (PEEP) can reduce the risk of postoperative pulmonary complications remains controversial. We performed a systematic review of currently available literature to investigate whether intraoperative PEEP decreases pulmonary complications in anesthetized patients undergoing surgery. METHODS: We searched PubMed, Embase, and the Cochrane Library to identify randomized controlled trials (RCTs) that compared intraoperative PEEP versus zero PEEP (ZEEP) for postoperative pulmonary complications in adults. The prespecified primary outcome was postoperative pulmonary atelectasis. RESULTS: Fourteen RCTs enrolling 1238 patients met the inclusion criteria. Meta-analysis using a random-effects model showed a decrease in postoperative atelectasis (relative risk [RR], 0.51; 95% confidence interval [CI], 0.35-0.76; trial sequential analyses [TSA]-adjusted CI, 0.10-2.55) and postoperative pneumonia (RR, 0.48; 95% CI, 0.27-0.84; TSA-adjusted CI, 0.05-4.86) in patients receiving PEEP ventilation. However, TSA showed that the cumulative Z-curve of 2 outcomes crossed the conventional boundary but did not cross the trial sequential monitoring boundary, indicating a possible false-positive result. We observed no effect of PEEP versus ZEEP ventilation on postoperative mortality (RR, 1.78; 95% CI, 0.55-5.70). CONCLUSIONS: The evidence that intraoperative PEEP reduces postoperative pulmonary complications is suggestive but too unreliable to allow definitive conclusions to be drawn.

Nrf2 activation protects against intratracheal LPS induced mouse/murine acute respiratory distress syndrome by regulating macrophage polarization.

The transcription factor nuclear factor E2-related factor 2 (Nrf2) is known to control the expression of antioxidant response elements and cytoprotective genes and modulate inflammatory response, helping to ameliorate damage in many diseases. Exactly how Nrf2 regulates innate inflammatory homeostasis remains unclear. In this study, we provide in vitro and in vivo evidence that Nrf2 plays a crucial role in macrophage polarization and acute respiratory distress syndrome (ARDS). We conducted in vitro experiments using a mouse alveolar macrophage cell line as well as primary cultures of macrophages in which cells were exposed to lipopolysaccharide (LPS) or interferon-γ in order to mimic ARDS, in the presence or absence of the Nrf2 activator tert-butylhydroquinone (tBHQ). Using siRNA-mediated Nrf2 knockdown, we showed that Nrf2 inhibited the inflammatory response by promoting M2 macrophage polarization and inhibiting M1 macrophage polarization. At the same time, tBHQ activated Nrf2-mediated inhibition of the p65 nuclear factor-κB pathway and activation of peroxisome proliferator-activated receptor-γ, which play important roles in regulating macrophage polarization. We also conducted in vivo experiments in which mice were given tBHQ with or without intratracheal LPS, then their survival was monitored, lung injury was assessed using histology, and levels of pro- and anti-inflammatory cytokines were assayed in the lungs and serum. Activation of Nrf2 with tBHQ dramatically reduced LPS-induced mortality and lung injury, down-regulated pro-inflammatory mediators and up-regulated anti-inflammatory mediators. These results suggest that Nrf2 can help prevent ARDS progression by promoting M2 polarization of macrophages. Interfering with Nrf2 may be an effective strategy for reprogramming macrophage polarization in order to treat ARDS.

[Research progress in obesity-induced low fertility in males].

The prevalence of obesity in men of reproductive age is globally increasing. Obesity alters the ratio of testosterone to estradiol and the homeostasis of leptin and other hormone levels by interfering with the hypothalamus-pituitary-gonadal axis. In addition, it may change epigenetic modifications and intergenerational transmission, which would affect the health of the offspring. Both of the pathways reduce male fertility, which may be associated with the obesity-induced change in the levels of some hormones and consequently the alteration of epigenetic modifications. This review focuses on the adverse effects of obesity on male fertility by influencing endocrine hormones and epigenetic modifications, and further discusses the effects of endocrine hormones on male fertility by epigenetic modification, aiming to provide some basic data for the prevention and treatment of obesity-related male fertility in clinical practice.

Clinical evaluation of laparoscopic surgery combined with triptorelin acetate in patients with endometriosis and infertility.

OBJECTIVE: To investigate the effects of laparoscopic surgery combined with triptorelin acetate, gestrinone and mifepristone on pregnancy rate, pregnancy outcome, long-term recurrence and adverse reactions in patients with endometriosis (EMT) complicated with infertility. METHODS: In this study, 150 patients with EMT and infertility were selected and randomly divided into triptorelin group (group A), gestrinone group (group B) and mifepristone group (group C), with 50 people in each group. Treatment was with gonadotropin-releasing hormone (GnRH-a) after laparoscopic surgery. RESULTS: The success rate of pregnancy in group A was higher than that in group B and C. The incidence of adverse pregnancy outcome was lower than that in group B and C. Kupperman score and subjective symptom score were lower than those in group B and C before treatment. Sex hormone level and CA125 level were significantly better. In the B and C groups and before treatment; the long-term recurrence rate was significantly lower than the B and C groups; the incidence of adverse reactions was similar. CONCLUSION: Laparoscopic surgery combined with GnRH-a can improve the success and good rate of pregnancy in EMT patients, reduce clinical symptoms, avoid long-term recurrence, and increase the risk of adverse reactions. Triptorelin acetate is superior to gestrinone and mifepristone.

Therapeutic effects of mifepristone combined with Gestrinone on patients with endometriosis.

OBJECTIVE: To evaluate the clinical therapeutic effects of mifepristone combined with gestrinone on patients with endometriosis. METHODS: A total of 150 endometriotic patients treated in our hospital between January 2014 and December 2015 were randomly divided into a control group and a treatment group (n=75). The control group began to orally take gestrinone capsules on the second day after menstruation started (2.5 mg/time, twice/week). The treatment group orally took mifepristone tablets (12.5 mg/time, once/day), and the dosage and administration of gestrinone capsules were the same as those of the control group. After 24 weeks of consecutive treatment, the clinical therapeutic effects of the two groups were assessed, and the pelvic symptom score, clinical sign score, serum sex hormone levels and pregnancy outcomes were compared. RESULTS: The total effective rates of control and treatment groups were 77.3% and 90.7% respectively, between which the difference was statistically significant (P<0.05). After treatment, the scores of pelvic symptoms (dysmenorrhea, dyspareunia, pelvic pain) and clinical signs (pelvic tenderness, induration) significantly reduced (P<0.05). Each score of the treatment group decreased more significantly than that of the control group did (P<0.05). The serum follicle hormone, luteinizing hormone, estrogen and progesterone levels were significantly lower than those before treatment (P<0.05). Each level of the treatment group dropped more significantly than that of the control group did (P<0.05). The pregnancy rates in the 6th and 12th months of follow-up were 28.0% and 13.3% in the control group respectively, and 42.7% and 29.3% in the treatment group respectively. Such rates of the two groups were significantly different at each follow-up time point (P<0.05). CONCLUSION: Mifepristone combined with gestrinone had satisfactory clinical therapeutic effects on endometriosis by reducing hormone levels and improving pregnancy outcomes. Therefore, this regimen is worthy of promotion and application in clinical practice.

Comparation between novel online models and the AJCC 8th TNM staging system in predicting cancer-specific and overall survival of small cell lung cancer.

Background: Most of previous studies on predictive models for patients with small cell lung cancer (SCLC) were single institutional studies or showed relatively low Harrell concordance index (C-index) values. To build an optimal nomogram, we collected clinicopathological characteristics of SCLC patients from Surveillance, Epidemiology, and End Results (SEER) database. Methods: 24,055 samples with SCLC from 2010 to 2016 in the SEER database were analyzed. The samples were grouped into derivation cohort (n=20,075) and external validation cohort (n=3,980) based on America's different geographic regions. Cox regression analyses were used to construct nomograms predicting cancer-specific survival (CSS) and overall survival (OS) using derivation cohort. The nomograms were internally validated by bootstrapping technique and externally validated by calibration plots. C-index was computed to compare the accuracy and discrimination power of our nomograms with the 8th of version AJCC TNM staging system and nomograms built in previous studies. Decision curve analysis (DCA) was applied to explore whether the nomograms had better clinical efficiency than the 8th version of AJCC TNM staging system. Results: Age, sex, race, marital status, primary site, differentiation, T classification, N classification, M classification, surgical type, lymph node ratio, radiotherapy, and chemotherapy were chosen as predictors of CSS and OS for SCLC by stepwise multivariable regression and were put into the nomograms. Internal and external validations confirmed the nomograms were accurate in prediction. C-indexes of the nomograms were relatively satisfactory in derivation cohort (CSS: 0.761, OS: 0.761) and external validation cohort (CSS: 0.764, OS: 0.764). The accuracy of the nomograms was superior to that of nomograms built in previous studies. DCA showed the nomograms conferred better clinical efficiency than 8th version of TNM staging system. Conclusions: We developed practical nomograms for CSS (https://guowei2020.shinyapps.io/DynNom-CSS-SCLC/) and OS (https://drboidedwater.shinyapps.io/DynNom-OS-SCLC/) prediction of SCLC patients which may facilitate clinicians in individualized therapeutics.

Ultrasound-guided serratus anterior plane block to prevent neurocognitive impairment in elderly patients after thoracoscopic lobectomy: protocol for a single-centre, double-blind, randomised controlled trial.

INTRODUCTION: Postoperative neurocognitive dysfunction (PND), including postoperative delirium (POD), is a common complication in elderly patients after major surgeries, often leading to poor postoperative recovery. Although the pathological mechanism underlying PND is still unclear, postoperative pain is strongly associated with the development of PND. The ultrasound-guided serratus anterior plane block (SAPB) has been reported to relieve postoperative pain in thoracic surgery. Therefore, this prospective trial hypothesises that SAPB may reduce the incidence of PND in the elderly undergoing thoracoscopic lobectomy. METHODS AND ANALYSIS: This study is designed as a single-centre, double-blind, randomised controlled clinical trial. A total of 256 elderly patients scheduled to undergo thoracoscopic lobectomy at Shanghai Pulmonary Hospital will be randomly assigned to general anaesthesia group or SAPB group. The primary outcome is the incidence of PND 7 days postoperatively or before discharge from hospital. The secondary outcomes include the occurrence of POD, the postoperative pain scores, Quality of Recovery at 1-2 days postoperatively and incidence of PND at 3 months postoperatively. The levels of fasting blood glucose in peripheral blood will be examined before and 1-2 days postoperatively. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital (identifier: K20-290). All participants will be required to provide written informed consent before any protocol-specific procedures. Findings will be disseminated in a peer-reviewed journal and in national and/or international meetings to guide future practice. TRIAL REGISTRATION NUMBER: ChiCTR2100052633.

A Randomized Study of Rigid Video Stylet versus Macintosh Laryngoscope for Double-Lumen Endobronchial Tube Intubation Assistance in Thoracoscopic Pulmonary Surgery.

Double-lumen endobronchial tube (DLT) intubation is more challenging than single-lumen tube intubation is, and the rigid video stylet (RVS) is one of the tools that has emerged to deal with this demanding intubation procedure. We evaluated whether the UE® RVS can shorten the DLT intubation time and improve the first-attempt intubation success rate compared with that of Macintosh laryngoscope (ML). A total of 130 participants scheduled to undergo thoracoscopic pulmonary surgeries were enrolled. They were randomized to receive either ML- or RVS-assisted DLT intubation. The primary outcomes were the intubation time and first-attempt intubation success rate. The secondary outcomes were the overall intubation success rate, mean arterial pressure, postoperative sore throat (POST), and postoperative hoarseness at 1 h and 24 h. Compared with the ML group, the intubation time was significantly shorter in the RVS group (p < 0.001; 30.82 ± 10.61 vs. 39.62 ± 6.54 s), however, the first-attempt success rate was significantly lower (p = 0.048; 83.08% vs. 95.16%). The POST at 1 h was less severe in the RVS group (p = 0.021). No significant differences were found for the other indicators. Among the patients with normal airways, the UE® RVS can achieve faster DLT intubation and decrease the severity of a POST at 1 h, although it was associated with a lower first-attempt intubation success rate.

Compatibility Study of Peptide and Glycerol Using Chromatographic and Spectroscopic Techniques: Application to a Novel Antimicrobial Peptide Cbf-14 Gel.

The interactions between active pharmaceutical ingredients (APIs) and excipients may lead to API degradation, thereby affecting the safety and efficacy of drug products. Cbf-14 is a synthetic peptide derived from Cathelicidin-BF, showing potential for bacterial and fungal infections. In order to assess impurities in Cbf-14 gel, we developed a two-dimensional liquid chromatography coupled with quadrupole/time-of-flight mass spectrometric method. A total of eleven peptide degradation impurities were identified and characterized. Furthermore, the compatibility tests were conducted to evaluate the interactions of Cbf-14 with glycerol and methylcellulose, respectively. The results revealed that the impurities originated from condensation reactions between Cbf-14 and aldehydes caused by glycerol degradation. Several aldehydes were employed to validate this hypothesis. The formation mechanisms were elucidated as Maillard reactions between primary amino groups of Cbf-14 and aldehydes derived from glycerol degradation. Additionally, the compatibility of Cbf-14 with glycerol from different sources and with varying storage times was investigated. Notably, the interaction products in the gel increased with extended storage time, even when fresh glycerol for injection was added. This study offers unique insights into the compatibility study of peptides and glycerol, contributing to the ongoing quality study of Cbf-14 gel. It also serves as a reference for the design of other peptide preparations and excipients selections.

4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway.

Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1ß release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly downregulated cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Study on the Effect and Mechanism of Huaji Jianpi Decoction on Simple Obesity.

Background: As the major type of obesity in clinical, simple obesity has gained increasing attention in recent years. Depending on the etiology and pathogenesis of simple obesity and combined with clinical practice experience, Huaji Jianpi decoction (HJJPD) was established to invigorate the spleen and eliminate dampness; however, the underlying molecular mechanism is yet unclear. Materials and Methods: A simple obesity mouse model was established by feeding a high-fat diet to the animals, and the related indexes were analyzed. The mice were divided into the normal, positive control (orlistat), and HJJPD high-dose, medium-dose, and low-dose groups. After 6 weeks of administration, the curative effect of HJJPD was observed. Simple obesity is associated with leptin resistance. The leptin signal transduction pathways mainly include the JAK2-STAT3, AMPK-ACC, LepRb-IRS-PI3K-PDE3B-cAMP, and LepRb-SHP2-MAPKs (ERK1/2) pathways. Therefore, the networks of HJJPD acting on these four pathway-related targets were constructed using the network pharmacology method, and the key nodes were identified. Results: After 6 weeks of drug intervention, we found a good therapeutic effect of HJJPD on simple obesity in the mouse model. The biological network analysis showed that HJJPD plays a role in treating leptin resistance in simple obesity by acting on multiple targets in the JAK2-STAT3 pathway via various components. Also, HJJPD can improve leptin resistance in mice by enhancing the binding force of LEP and LEPRB and activating the LEP-mediated JAK2-STAT3 signaling pathway. Conclusion: In this study, animal experiments, network pharmacology, and molecular biology were combined to establish a mouse model of simple obesity, confirm the role of HJJPD in the treatment of simple obesity, and preliminarily reveal the related mechanism. Relevant research results will provide a basis for the treatment of simple obesity and the drug discovery.

A Novel Strategy for Predicting 72-h Mortality After Admission in Patients With Polytrauma: A Study on the Development and Validation of a Web-Based Calculator.

Background: Early and accessible screening of patients with polytrauma at a high risk of hospital death is essential. The purpose of this research was to seek an accurate and convenient solution to predict deaths occurring within 72 h after admission of these patients. Methods: A secondary analysis was conducted on 3,075 patients with polytrauma from the Dryad database. We imputed missing values in eligible individuals with the k-nearest neighbor algorithm and then randomly stratified them into the training group (n = 2,461) and the validation group (n = 614) based on a proportion of 8:2. The restricted cubic spline, univariate, backward stepwise, and multivariate logistic regression methods were employed to determine the suitable predictors. Calibration and receiver operating characteristic (ROC) curves were applied to assess the calibration and discrimination of the obtained model. The decision curve analysis was then chosen as the measure to examine the clinical usage. Results: Age, the Glasgow Coma Scale score, the Injury Severity Score, base excess, and the initial lactate level were inferred as independent prognostic factors related to mortality. These factors were then integrated and applied to construct a model. The performance of calibration plots, ROC curves, and decision curve analysis indicated that the model had satisfactory predictive power for 72-h mortality after admission of patients with polytrauma. Moreover, we developed a nomogram for visualization and a web-based calculator for convenient application (https://songandwen.shinyapps.io/DynNomapp/). Conclusions: A convenient web-based calculator was constructed to robustly estimate the risk of death in patients with polytrauma within 72 h after admission, which may aid in further rationalization of clinical decision-making and accurate individual treatment.

Role of Pneumonectomy in T1-4N2M0 Non-Small Cell Lung Cancer: A Propensity Score Matching Analysis.

Background: N2 stage disease constitutes approximately 20%-30% of all non-small cell lung cancer (NSCLC). Concurrently, surgery remains the first-choice treatment for patients with N2 NSCLC if feasible. However, the role of pneumonectomy in N2 NSCLC has rarely been investigated and remains controversial. Methods: We enrolled 26,798 patients with T1-4N2M0 NSCLC (stage IIIA/IIIB) from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. We compared the overall survival (OS) and cancer-specific survival (CSS) between patients who received pneumonectomy and those who did not receive surgery. The Kaplan-Meier method, Cox regression analyses, and propensity score matching (PSM) were applied to demonstrate the effect of pneumonectomy. Results: Patients receiving pneumonectomy had a significantly better OS and CSS than those without pneumonectomy both before [adjusted-HR (95% CI): 0.461 (0.425-0.501) for OS, 0.444 (0.406-0.485) for CSS] and after PSM [adjusted-HR (95% CI): 0.499 (0.445-0.560) for OS, 0.457 (0.405-0.517) for CSS] with all p-values <0.001. Subgroup analysis demonstrated concordant results stratified by demographic or clinicopathological variables. In sensitivity analysis, no significant difference was observed between patients receiving single pneumonectomy and chemoradiotherapy without surgery in OS and CSS both before [unadjusted-HR (95% CI): 1.016 (0.878-1.176) for OS, 0.934 (0.794-1.099) for CSS, p = 0.832] and after PSM [unadjusted-HR (95% CI): 0.988 (0.799-1.222) for OS, 0.938 (0.744-1.182) for CSS] with all p-values >0.4. Conclusion: For patients with T1-4N2M0 NSCLC (stage IIIA/IIIB), pneumonectomy is an independent protective factor of OS and should be considered when applicable.

Construction and validation of nomograms based on the log odds of positive lymph nodes to predict the prognosis of lung neuroendocrine tumors.

Background: This research aimed to investigate the predictive performance of log odds of positive lymph nodes (LODDS) for the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs). Methods: We collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The study cohort was split into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed based on the derivation cohort and validated using the external validation cohort to predict the 1-, 3-, and 5-year cancer-specific survival (CSS) and overall survival (OS) of patients with LNETs. The accuracy and clinical practicability of nomograms were tested by Harrell's concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses. Results: The Cox proportional-hazards model showed the high LODDS group (-0.79≤LODDS) had significantly higher mortality compared to those in the low LODDS group (LODDS<-0.79) for both CSS and OS. In addition, age at diagnosis, sex, histotype, type of surgery, radiotherapy, and chemotherapy were also chosen as predictors in Cox regression analyses using stepwise Akaike information criterion method and included in the nomograms. The values of C-index, NRI, and IDI proved that the established nomograms were better than the conventional eighth edition of the TNM staging system. The calibration plots for predictions of the 1-, 3-, and 5-year CSS/OS were in excellent agreement. Decision curve analyses showed that the nomograms had value in terms of clinical application. Conclusions: We created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to bring individually tailored risk assessment and therapy.

Characterization of Fatty Acid Metabolism in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Fatty acid metabolism takes part in malignancy progression. However, the roles fatty acid metabolism plays in LUAD are still unclear. Methods: The transcriptomic and clinical data of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were extracted. ssGSEA, WGCNA, univariable Cox regression, and LASSO Cox regression analyses were performed to identify the fatty acid metabolism-related genes which influenced the overall survival (OS) and build a fatty acid-related risk score (FARS) model. A nomogram was established based on the FARS and other clinicopathological features, and ROC and calibration plots were used to validate the prediction accuracy. The tumor microenvironment (TME) of patients with high and low FARS was compared. Results: A total of 38 genes were identified to be independently related to the survival outcome and put into a FARS model. High FARS patients exhibited significantly worse OS. The nomogram included the FARS and pathological stage, and the AUC of the nomogram predicting 1-, 2-, 3-, 4-, and 5-year OS was 0.789, 0.807, 0.798, 0.809, and 0.753, respectively. Calibration plots also indicated good accuracy. Moreover, the samples of the high FARS had higher expression of PDL1. Conclusion: We constructed a FARS model which could accurately predict the survival outcome of the LUAD patients. The genes of the FARS are related to the tumor microenvironment and patients with high FARS can potentially benefit more from anti-PD1/PDL1 immunotherapy. In addition, the mechanisms of the genes in the FARS affecting prognosis are worthy of further research to develop new gene-targeted drugs.

Magnesium Hydride Ameliorates Endotoxin-Induced Acute Respiratory Distress Syndrome by Inhibiting Inflammation, Oxidative Stress, and Cell Apoptosis.

Acute respiratory distress syndrome (ARDS) causes uncontrolled pulmonary inflammation, resulting in high morbidity and mortality in severe cases. Given the antioxidative effect of molecular hydrogen, some recent studies suggest the potential use of molecular hydrogen as a biomedicine for the treatment of ARDS. In this study, we aimed to explore the protective effects of magnesium hydride (MgH2) on two types of ARDS models and its underlying mechanism in a lipopolysaccharide (LPS)-induced ARDS model of the A549 cell line. The results showed that LPS successfully induced oxidative stress, inflammatory reaction, apoptosis, and barrier breakdown in alveolar epithelial cells (AEC). MgH2 can exert an anti-inflammatory effect by down-regulating the expressions of inflammatory cytokines (IL-1ß, IL-6, and TNF-α). In addition, MgH2 decreased oxidative stress by eliminating intracellular ROS, inhibited apoptosis by regulating the expressions of cytochrome c, Bax, and Bcl-2, and suppressed barrier breakdown by up-regulating the expression of ZO-1 and occludin. Mechanistically, the expressions of p-AKT, p-mTOR, p-P65, NLRP3, and cleaved-caspase-1 were decreased after MgH2 treatment, indicating that AKT/mTOR and NF-κB/NLRP3/IL-1ß pathways participated in the protective effects of MgH2. Furthermore, the in vivo study also demonstrated that MgH2-treated mice had a better survival rate and weaker pathological damage. All these findings demonstrated that MgH2 could exert an ARDS-protective effect by regulating the AKT/mTOR and NF-κB/NLRP3/IL-1ß pathways to suppress LPS-induced inflammatory reaction, oxidative stress injury, apoptosis, and barrier breakdown, which may provide a potential strategy for the prevention and treatment of ARDS.