Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.

SUMMARY: Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P = 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P = 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P =0.048) was associated with a higher risk of CIP.

Distributed adaptive control for nonlinear multi-agent systems with nonlinear parametric uncertainties.

This paper considers the distributed tracking control problem for a class of nonlinear multi-agent systems with nonlinearly parameterized control coefficients and inherent nonlinearities. The essential of multi-agent systems makes it difficult to directly generalize the existing works for single nonlinearly parameterized systems with uncontrollable unstable linearization to the case in this paper. To dominate the inherent nonlinearities and nonlinear parametric uncertainties, a powerful distributed adaptive tracking control is presented by combing the algebra graph theory with the distributed backstepping method, which guarantees that all the closed-loop system signals are global bounded while the range of the tracking error between the follower's output and the leader's output can be tuned arbitrarily small. Finally, a numerical example is provided to verify the validity of the developed methods.

The effects and mechanism of LncRNA NORAD on doxorubicin-induced cardiotoxicity.

In recent years, the role and mechanism of long non-coding RNA (LncRNA) in cardiovascular diseases have received increasing attention. The chemotherapy agent, doxorubicin (DOX), is one of the most effective drugs for various cancers, but its efficacy is limited by its cardiotoxicity. Therefore, further exploration is required for the molecular mechanism of DOX-induced cardiotoxicity. This study intended to investigate the role of LncRNA Non-coding RNA activated by DNA damage (NORAD) in DOX-induced cardiotoxicity, for which we adopted the AC16 human cardiomyocyte cell line for the exploration. The results showed that LncRNA NORAD knockdown could increase DOX-induced cardiomyocyte apoptosis and mitochondrial ROS level. LncRNA NORAD overexpression obtained reverse results, which further validated its role in DOX-induced cardiomyocyte apoptosis and mitochondrial ROS level. Moreover, cardiotoxicity was induced in both LncRNA NORAD-knockout and wild-type mice with DOX, showing that gene knockout aggravated pathologic lesions in the myocardial tissues of mice. Taken together, LncRNA NORAD affected DOX-induced cardiotoxicity via mitochondrial apoptosis, fission (PUM-MFF), and autophagy (p53-Parkin) pathways both in vivo and in vitro.

Cuproptosis-related gene identification and immune infiltration analysis in systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self-antigen, autoantibody production, and abnormal immune response. Cuproptosis is a recently reported cell death form correlated with the initiation and development of multiple diseases. This study intended to probe cuproptosis-related molecular clusters in SLE and constructed a predictive model. Methods: We analyzed the expression profile and immune features of cuproptosis-related genes (CRGs) in SLE based on GSE61635 and GSE50772 datasets and identified core module genes associated with SLE occurrence using the weighted correlation network analysis (WGCNA). We selected the optimal machine-learning model by comparing the random forest (RF) model, support vector machine (SVM) model, generalized linear model (GLM), and the extreme gradient boosting (XGB) model. The predictive performance of the model was validated by nomogram, calibration curve, decision curve analysis (DCA), and external dataset GSE72326. Subsequently, a CeRNA network based on 5 core diagnostic markers was established. Drugs targeting core diagnostic markers were acquired using the CTD database, and Autodock vina software was employed to perform molecular docking. Results: Blue module genes identified using WGCNA were highly related to SLE initiation. Among the four machine-learning models, the SVM model presented the best discriminative performance with relatively low residual and root-mean-square error (RMSE) and high area under the curve (AUC = 0.998). An SVM model was constructed based on 5 genes and performed favorably in the GSE72326 dataset for validation (AUC = 0.943). The nomogram, calibration curve, and DCA validated the predictive accuracy of the model for SLE as well. The CeRNA regulatory network includes 166 nodes (5 core diagnostic markers, 61 miRNAs, and 100 lncRNAs) and 175 lines. Drug detection showed that D00156 (Benzo (a) pyrene), D016604 (Aflatoxin B1), D014212 (Tretinoin), and D009532 (Nickel) could simultaneously act on the 5 core diagnostic markers. Conclusion: We revealed the correlation between CRGs and immune cell infiltration in SLE patients. The SVM model using 5 genes was selected as the optimal machine learning model to accurately evaluate SLE patients. A CeRNA network based on 5 core diagnostic markers was constructed. Drugs targeting core diagnostic markers were retrieved with molecular docking performed.

The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetin[in vivo/in vitro, C57BL/6 mice, AC16 and hiPSC-CMs].

Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect.

Roles of non-coding RNA in megakaryocytopoiesis and thrombopoiesis: new target therapies in ITP.

Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot encode proteins, and a better understanding of the complex interaction networks coordinated by ncRNAs will provide a theoretical basis for the development of therapeutics targeting the regulatory effects of ncRNAs. Platelets are produced upon the differentiation of hematopoietic stem cells into megakaryocytes, 1011 per day, and are renewed every 8-9 days. The process of thrombopoiesis is affected by multiple factors, in which ncRNAs also exert a significant regulatory role. This article reviewed the regulatory roles of ncRNAs, mainly microRNAs (miRNAs), circRNAs (circular RNAs), and long non-coding RNAs (lncRNAs), in thrombopoiesis in recent years as well as their roles in primary immune thrombocytopenia (ITP).

What is the context? Platelets are produced from progenitor cells named megakaryocytes (MKs) differentiated from bone marrow-derived hematopoietic stem cells (HSCs).Thrombopoiesis refers to the process by which platelet-producing MKs release platelet granules into peripheral blood under the shear force of blood flow for further development and maturation.The process of megakaryocytopoiesis and thrombopoiesis is affected by multiple factors, wherein some ncRNAs also exert a significant regulatory role.miRNAs/lncRNAs play a promising role in t primary immune thrombocytopenia (ITP).What is new? This article reviewed the regulatory roles of ncRNAs, mainly microRNAs (miRNAs), circRNAs (circular RNAs), and long non-coding RNAs (lncRNAs), in thrombopoiesis.This article also reviewed the roles of ncRNAs in ITP.What is the impact?Changes in ncRNA expression are associated with changes in the production of MKs, thrombopoiesis, and platelet function, which allows a new understanding of the pathogenesis of many congenital or acquired platelet-related diseases.

Identification of key genes related to skin burns based on bioinformatics analysis.

To further understand the regulatory network and molecular mechanisms of gene expression after skin burns, we performed bioinformatics analysis of gene expression profiles of skin burn samples and identified key genes associated with skin burns. The GSE8056 dataset and GSE139028 dataset was downloaded from the Gene Expression Omnibus (GEO) database for analysis and validation. The limma package was used to screen for differentially expressed genes (DEGs). Gene ontology (GO) and pathway enrichment analyses (KEGG) were then performed. Subsequently, LASSO regression analysis was performed on DEGs and a regulatory network map of skin burn-related genes was constructed. Finally, the infiltration of immune cells was calculated and co-expression network maps of immune-related key genes and skin regeneration genes were constructed. Analysis of the GSE8056 dataset showed that 432 genes were upregulated and 351 genes were downregulated. The DEGs were mainly focused on immune response and skin regeneration. Meanwhile, these two groups of pivotal genes were significantly associated with abnormal infiltration of 9 immune cells. GSE139028 validation revealed that 3 hub genes associated with skin burn immunity were differentially expressed, except for S100A8, while only the DPT gene was differentially expressed among the seven hub genes associated with skin regeneration. In short, the effect of skin burn on patients is to regulate the expression of immune-related genes UPP1, MMP1, MMP3 and skin regeneration-related gene DPT, which may be the key target for the treatment of skin burn.

Output-Feedback stabilization for stochastic nonlinear systems with Markovian switching and time-varying powers.

This paper investigates the output-feedback stabilization for stochastic nonlinear systems with both Markovian switching and time-varying powers. Specifically, by developing a novel dynamic gain method and using the Itô formula of Markovian switching systems, a reduced-order observer with a dynamic gain and an output-feedback controller are designed. By using advanced stochastic analysis methods, we show that the closed-loop system has an almost surely unique solution and the states are regulated to the origin almost surely. A distinct feature of this paper is that even though there is no Markovian switching, our design is also new since it can deal with nonlinear growth rate, while the existing results can only deal with constant growth rate. Finally, the effectiveness of the design method is verified by a simulation example.

Down-regulation of miR-let-7e attenuates LPS-induced acute lung injury in mice via inhibiting pulmonary inflammation by targeting SCOS1/NF-κB pathway.

Excessive pulmonary inflammatory response is critical in the development of acute lung injury (ALI). Previously, microRNAs (miRNAs) have been recognized as an important regulator of inflammation in various diseases. However, the effects and mechanisms of miRNAs on inflammatory response in ALI remain unclear. Herein, we tried to screen miRNAs in the processes of ALI and elucidate the potential mechanism. Using a microarray assay, microRNA let-7e (let-7e) was chose as our target for its reported suppressive roles in several inflammatory diseases. Down-regulation of let-7e by antagomiR-let-7e injection attenuated LPS-induced acute lung injury. We also found that antagomiR-let-7e could obviously improve the survival rate in ALI mice. Moreover, antagomiR-let-7e treatment reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-1ß and IL-6) in bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice. Luciferase reporter assays confirmed that suppressor of cytokine signaling 1 (SOCS1), a powerful attenuator of nuclear factor kappa B (NF-κB) signaling pathway, was directly targeted and suppressed by let-7e in RAW264.7 cells. In addition, it was further observed that SOCS1 was down-regulated, and inversely correlated with let-7e expression levels in lung tissues of ALI mice. Finally, down-regulation of let-7e suppressed the activation of NF-κB pathway, as evidenced by the reduction of p-IκBα, and nuclear p-p65 expressions in ALI mice. Collectively, our findings indicate that let-7e antagomir protects mice against LPS-induced lung injury via repressing the pulmonary inflammation though regulation of SOCS1/NF-κB pathway, and let-7e may act as a potential therapeutic target for ALI.

Cooperative Control of Multiple Nonlinear Benchmark Systems Perturbed by Second-Order Moment Processes.

This paper studies the cooperative control problem of multiple nonlinear benchmark systems perturbed by second-order moment processes. The nonlinear benchmark system consists of a moving car and a rolling ball in oscillating surroundings. When the leader is only accessible to a small part of the followers in a directed graph, a new vectorial backstepping method is proposed for the design of distributed cooperative control laws. By using stochastic analysis techniques and algebra graph theory, it is shown that the cooperative control problem under consideration is solvable. Specifically, the errors between the followers' outputs and the leader's output can be made arbitrarily small while keeping all states of the closed-loop system bounded in probability. Finally, the effectiveness of the proposed control scheme is demonstrated through a simulation example.

Associations of childhood maltreatment with subsequent illicit drug use among Chinese adolescents: The moderating role of the child's sex.

Adolescence is a critical period for the onset of illicit drug use. This study aimed to estimate the prevalence of illicit drug use among Chinese adolescents, to assess the associations between different forms of childhood maltreatment and subsequent illicit drug use and to test whether the child's sex plays a moderating role in the associations. A secondary analysis was made of cross-sectional data collected from 10th to 12th graders from China who were sampled in the 2015 School-based Chinese Adolescents Health Survey. A total of 59,518 questionnaires were included in the final analysis. The prevalence estimates and logistic regression analyses were weighted to account for the complex survey design. If the interaction term (between childhood maltreatment and sex) was significantly associated with illicit drug use, we would perform stratification analyses across sex. Of the total sample, 45.2% were boys, and the mean (SD) age was 17.0 (0.9) years. The results of stratification analyses demonstrated that among boys, physical abuse and sexual abuse were independently associated with an increased risk of use during their lifetime of MDMA, methamphetamine, ketamine, and mephedrone; among girls, only emotional abuse and sexual abuse were associated with MDMA use, methamphetamine use, ketamine use, and mephedrone use.

[Increased expression of HMGB1 and TLR4 in intestinal tissues and intestinal immune dysfunction in severely burned rats].

Objective To investigate the expressions of high mobility group box 1 (HMGB1) and Toll-like receptor 4 (TLR4) in the intestinal tract of severely burned rats and their relationship with intestinal immune function. Methods Forty male SD rats were randomly divided into control group (n=10) and severe burn group (n=30). 60% of the rats' body (the back and ventral side) was burned in the severe burn group, and only anesthesia was performed in normal control group. Rats were sacrificed at 6, 12 and 18 hours after injury in the burn group, while sacrificed immediately after anesthesia in control group. The protein levels of HMGB1 and TLR4 in the intestinal tissue were detected by Western blotting. The purity of total T cells (CD3+ T), as well as the ratio of Th1 to Th2 cell subsets, was measured by flow cytometry. ELISA was performed to detect the concentrations of IFN-γ, IL-4 and IL-10. Results Compared with the control group, the protein expressions of HMGB1 and TLR4 in the severe burn group were significantly higher than that in the control group at 6, 12 and 18 hours after injury, in a time-dependent manner. A positive correlation between HMGB1 and TLR4 protein expressions in the severe burn group was observed. The ratio of Th1 to total T cells was significantly raised at 6, 12 and 18 hours after burn injury, and the ratio of Th2 to total T cells decreased, and the ratio of Th1/Th2 significantly increased. Th1 cell percentage was positively correlated with HMGB1 and TLR4, while Th2 cell percentage was negatively correlated with HMGB1 and TLR4. Compared with the control group, the levels of IFN-γ and IL-4 in the intestinal tract were significantly elevated at 6, 12 and 18 hours after severe burn injury, while the level of IL-10 was significantly reduced. With the increase of postburn time, the levels of IFN-γ and IL-4 gradually increased, while the level of IL-10 gradually decreased. Conclusion HMGB1 was recruited in the intestinal tissues to activate TLR4 signaling pathway after severe burn, further activates the downstream signal transcripts and releases a series of inflammatory cytokines to induce inflammatory response, which is involved in Th1 and Th2 cell mediated immune function obstacle of rats.

miR-27a protects against acute lung injury in LPS-treated mice by inhibiting NF-κB-mediated inflammatory response.

Acute lung injury (ALI), which is an excessive uncontrolled inflammatory response in the lung, is mediated by several pro-inflammatory mediators. Recent evidence has implicated microRNAs (miRNAs) in regulation of inflammation in different diseases. However, the roles and underlying molecular mechanism of miRNAs in ALI have not been adequately elucidated. Thus, the aim of the present study was to investigate the possible regulatory mechanism of miRNAs in ALI. In this study, microRNA microarray analysis showed that 48 miRNAs were differentially expressed in lung tissues of an ALI model induced by LPS. Downregulation of miR-27a, played a key role in the regulation of the inflammatory response and protection from traumatic injury. Functional analyses indicated that overexpression of miR-27a using miR-27a agomir (agomiR-27a) protected the animals from LPS-induced ALI through decreased pulmonary inflammation, decreased wet-to-dry weight ratio, and ameliorated lung histopathological changes. In addition, agomiR-27a also decreased production of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in bronchoalveolar lavage fluid (BALF). Moreover, transforming growth factor ß-activated kinase 1 binding protein 3 (TAB3), as an activator of NF-κB, was confirmed as a direct target of miR-27a. Further study showed that the anti-inflammatory mechanism of miR-27a is exerted via suppression NF-κB signaling by inhibiting expression of TAB3 in LPS-induced ALI mice. Taken together, these data define the protective mechanism of miR-27a via inhibition of the inflammatory response through blocking NF-κB pathway. Therefore, miR-27a/TAB3/NF-κB axis may be therapeutically targeted to repress inflammation following ALI in the future.

Downregulation of miR-181a protects mice from LPS-induced acute lung injury by targeting Bcl-2.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a progressive syndrome with a high incidence and mortality rate. Apoptosis is a very important pathological feature of ALI. Recently, more and more researches on mircoRNAs are involved in the regulation of proliferation and apoptosis of cancer cells. However, the functions of microRNAs in ALI remain unknown. In this study, PCR array and qRT-PCR were used to investigate microRNA profiles and miR-181a regulates apoptosis induced by LPS. Then, we predict the potential target gene of miR-181a is BCL-2 by bioinformatics methods, and validate it using luciferase reporter gene assays. Finally, the effect of miR-181a on apoptosis was investigated in ALI animal model and cell model induced by LPS. Inhibition expression of miR-181a can significantly reduce LPS-induced acute lung injury in mice and A549 cells. Therefore, we suggest that MiR-181a inhibition protects mice from LPS-induced acute lung injury by targeting Bcl-2.

Ulinastatin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of AMPK/NF-κB pathway.

BACKGROUND: Ulinastatin (ULI), a serine protease inhibitor, had been widely used as a drug for patients with acute inflammatory disorders. However, evidence regarding the anti-inflammatory effect of ulinastatin was still lacking. In this study, we investigated the protective mechanisms of ULI in LPS-induced acute lung injury (ALI). METHODS: ALI was induced in mice by intratracheal instillation of LPS. The cells in the bronchoalveolar lavage fluid (BALF) were counted. The degree of animal lung edema was evaluated by measuring the wet/dry weight ratio and oxygenation index. The levels of inflammatory mediators, tumor necrosis factor-α, interleukin-1ß, and interleukin-6, were assayed by enzyme-linked immunosorbent assay. Pathological changes of lung tissues were observed by HE staining. The levels of NF-κB p65, AMPK, p-AMPK and IκBα expression were detected by Western blotting. Then, selective AMPK inhibitor Compound C was used to test whether AMPK activation was critical in protection process of ULI against LPS-induced ALI. RESULTS: Ulinastatin pretreatment at doses of 15, 30 and 45mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and oxygenation index. Expression of IL-6, IL-1ß, and TNF-α was suppressed by ULI at protein level in BALF. Additionally, the attenuation of inflammatory responses by ULI was closely associated with AMPK/NF-κB pathway and this effect was significantly inhibited by treatment with the AMPK inhibitor, Compound C. CONCLUSIONS: The results presented here indicated that ULI has a protective effect against LPS-induced ALI and this effect may be attributed partly to decreased production of proinflammatory cytokines through the regulation of AMPK/NF-κB signaling pathway.

The therapeutic efficacy of glutamine for rats with smoking inhalation injury.

Smoke inhalation injury represents a major cause of mortality in burn patients and is associated with a high incidence of pulmonary complications. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury. In our present work, rats were equally randomized into three groups: Sham group (ambient air inhalation plus GLN treatment), Control group (smoke inhalation plus physiological saline) and GLN treatment group (smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and Western blotting measurement. Our results exhibited that GLN attenuated the lung histopathological alterations, improved pulmonary oxygenation, and mitigated pulmonary edema. At 28days post-injury, GLN mitigated smoke inhalation-induced excessive collagen deposition as evidence by Masson-Goldner trichrome staining and hydroxyproline content. GLN mitigated smoke inhalation-induced lung inflammatory response, and further prevented the activity of NF-kappa-B. More importantly, results from Western blotting and Immunohistochemistry exhibited that GLN enhanced the expression of HSF-1, HSP-70 and HO-1 in lung tissues. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSP expression.

Hydrogen inhalation ameliorates lipopolysaccharide-induced acute lung injury in mice.

Acute lung injury (ALI) is a serious illness, the incidence and mortality of which are very high. Free radicals, such as hydroxyl radicals (OH) and peroxynitrite (ONOO(-)), are considered to be the final causative molecules in the pathogenesis of ALI. Hydrogen, a new antioxidant, can selectively reduce OH and ONOO(-). In the present study, we investigated the hypothesis that hydrogen inhalation could ameliorate ALI induced by intra-tracheal lipopolysaccharide (LPS, 5mg/kg body weight). Mice were randomized into three groups: sham group (physiological saline+2% hydrogen mixed gas), control group (LPS+normal air) and experiment group (LPS+2% hydrogen mixed gas). Bronchoalveolar lavage fluid (BALF) was performed to determine the total protein concentrations and pro-inflammatory cytokines. Lung tissues were assayed for oxidative stress variables, wet/dry (W/D) ratio, histological, immunohistochemistry and Western blotting examinations. Our experiments exhibited that hydrogen improved the survival rate of mice and induced a decrease in lung W/D ratio. In addition, hydrogen decreased malonaldehyde and nitrotyrosine content, inhibited myeloperoxidase and maintained superoxide dismutase activity in lung tissues and associated with a decrease in the expression of TNF-α, IL-1ß, IL-6 and total protein concentrations in the BALF. Hydrogen further attenuated histopathological alterations and mitigated lung cell apoptosis. Importantly, hydrogen inhibited the activation of P-JNK, and also reversed changes in Bax, Bcl-xl and caspase-3. In conclusion, our data demonstrated that hydrogen inhalation ameliorated LPS-induced ALI and it may be exerting its protective role by preventing the activation of ROS-JNK-caspase-3 pathway.