Analysis of Factors Contributing to the Injury Severity of Overloaded-Truck-Related Crashes on Mountainous Highways in China.

Overloaded transport can certainly improve transportation efficiency and reduce operating costs. Nevertheless, several negative consequences are associated with this illegal activity, including road subsidence, bridge collapse, and serious casualties caused by accidents. Given the complexity and variability of mountainous highways, this study examines 1862 overloaded-truck-related crashes that happened in Yunnan Province, China, and attempts to analyze the key factors contributing to the injury severity. This is the first time that the injury severity has been studied from the perspective of crashes involving overloaded trucks, and meanwhile in a scenario of mountainous highways. For in-depth analysis, three models are developed, including a binary logit model, a random parameter logit model, and a classification and regression tree, but the results show that the random parameter logit model outperforms the other two. In the best-performing model, a total of fifteen variables are found to be significant at the 99% confidence level, including random variables such as freeway, broadside hitting, impaired braking performance, spring, and evening. In regards to the fixed variables, it is likely that the single curve, rollover, autumn, and winter variables will increase the probability of fatalities, whereas the provincial highway, country road, urban road, cement, wet, and head-on variables will decrease the likelihood of death. Our findings are useful for industry-related departments in formulating and implementing corresponding countermeasures, such as strengthening the inspection of commercial trucks, increasing the penalties for overloaded trucks, and installing certain protective equipment and facilities on crash-prone sections.

IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue.

White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.

IL-33 in the basolateral amygdala integrates neuroinflammation into anxiogenic circuits via modulating BDNF expression.

Hyper-inflammatory reaction plays a crucial role in the pathophysiology of depression and anxiety disorders. However, the mechanisms underlying inflammation-induced anxiety changes remain poorly understood. Here, we showed that in the lipopolysaccharide (LPS)-induced anxiety model, Interleukin (IL)-33, a member of the IL-1 family, was up-regulated in the basolateral amygdala, and IL-33 deficiency prevent anxiety-like behavior. Overexpression of IL-33 in amygdalar astrocytes led to anxiety-like response via repressing brain-derived neurotrophic factor (BDNF) expression. Mechanically, IL-33 suppressed BDNF expression through NF-κB pathway to impair GABAergic transmission in the amygdala and NF-κB inhibitor abolished the effect of IL-33 on anxiety. Administration of an inverse GABAA receptor agonist increased the anxiety of IL-33- deficient mice. These results reveal that inflammatory response can activate anxiogenic circuits by suppressing BDNF and GABAergic neurons transmission, suggesting that IL-33 in basolateral amygdalar is a linker between inflammation and anxiety.

TNFAIP8L2/TIPE2 impairs autolysosome reformation via modulating the RAC1-MTORC1 axis.

Macroautophagy/autophagy is an evolutionarily conserved process that involves the selective degradation of cytoplasmic components within lysosomes in response to starvation. Autophagy is an ancient defense mechanism that has been closely integrated with the immune system and has multiple effects on innate and adaptive immunity. The pro-inflammatory and anti-inflammatory cytokines can activate and inhibit autophagy, respectively. TNFAIP8L2/TIPE2 (tumor necrosis factor, alpha-induced protein 8-like 2) is a newly identified immune negative regulator of innate and adaptive immunity that plays an important role in immune homeostasis. However, whether and how TNFAIP8L2 controls autophagy is still unknown. Murine TNFAIP8L2 can directly bind to and block the RAC1 GTPase activity to regulate innate immunity. RAC1 can also bind to MTOR and regulate MTORC1 cellular localization and activity. Here, we find that TNFAIP8L2 can compete with MTOR for binding to the GTP-bound state of RAC1 and negatively regulate MTORC1 activity. Interestingly, TNFAIP8L2 overexpression fails to induce autophagy flux by the suppression of the MTOR activity under glutamine and serum starvation. Instead, TNFAIP8L2 appears to impair autophagic lysosome reformation (ALR) during prolonged starvation. Finally, we demonstrate that TNFAIP8L2 overexpression leads to a defect in MTOR reactivation and disrupts autophagy flux, thereby leading to cell death. Furthermore, TNFAIP8L2 deficiency can exacerbate the inflammatory response and lung injury by controlling the MTOR activity in an LPS-induced mouse endotoxemia model. Our study reveals a novel role of TNFAIP8L2 in autophagy by regulating the RAC1-MTORC1 axis that supports its potential as a target for therapeutic treatment.Abbreviations: ALR: autophagic lysosome reformation; BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; Co-IP: Co-Immunoprecipitation; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; RAPA: rapamycin; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; Starv: Starvation; TNFAIP8L2/TIPE2: tumor necrosis factor-alpha-induced protein-8 like-2.

RNF180 mediates STAT3 activity by regulating the expression of RhoC via the proteasomal pathway in gastric cancer cells.

Ring finger protein 180 (RNF180) is an important member of the E3 ubiquitin ligase family. As a tumor suppressor gene, RNF180 is significantly associated with the prognosis of patients with gastric cancer (GC) and can inhibit the proliferation, invasion, and migration of GC cells. Signal transducer and activator of transcription 3 (STAT3) are considered one of the most common oncogenes in human cancers with a key role in GC progression. In this study, we explored the molecular signaling pathways by which RNF180 could potentially regulate STAT3 through transcriptomics and proteomics experiments. Here, we found RNF180 overexpression could suppress STAT3 phosphorylation in GC cells. Ubiquitin label-free experiments showed that the ubiquitination level of Ras homolog gene family member C (RhoC) is significantly increased in GC cells transfected with an RNF180 expression vector (RNF180-GFP vector) compared with cells transfected with an empty vector (vehicle vector). We subsequently demonstrated that RNF180 could directly combine with RhoC and promote the ubiquitination and degradation of RhoC protein in GC cells. The phosphorylation level of STAT3 significantly decreased in GC cells after RhoC knockdown using small hairpin RNA (shRNA). Together, these results reveal RNF180 could inhibit GC progression by reducing the phosphorylation of STAT3 via the ubiquitination and degradation of RhoC protein in GC cells. Thus, the protein may be considered a novel therapeutic target for patients with GC.

Extranodal soft tissue metastasis as an independent prognostic factor in gastric cancer patients aged under 70 years after curative gastrectomy.

BACKGROUND: Accumulating evidence confirms the potential prognostic value of extranodal soft tissue metastasis (ESTM) in patients with solid cancers. The aim of this study was to elucidate the potential relationship between ESTM and lymph node (LN) metastasis, demonstrate clinicopathological predictive prognostic factors for ESTM and LN metastasis, and identify the prognostic value of ESTM for gastric cancer (GC) patients aged under 70 years. METHODS: A total of 580 GC patients who underwent the curative resection between 2003 and 2011 were included to identify if ESTM is essential to improve the accuracy of prognostic evaluation of the GC patients postoperatively. Overall survival rates were tested by Kaplan-Meier analysis. Univariate and multivariate analyses were applied to clarify the independent prognostic factors. Logistic regression analysis was adopted to clarify the risk factors for evaluating the presence of ESTM and LN metastasis. After cut-point survival analysis, the GC patients were divided into three subgroups based on the number of ESTM and then incorporated into the pTNM stage of gastric carcinoma to identify the possibility and necessity of incorporating ESTM into staging. RESULTS: ESTM was associated with advanced pT, pN and pTNM categories, large tumour size and the presence of signet-ring cell (SRC) variants. Survival analyses revealed that ESTM was associated with the OS and was an independent prognostic predictor in this GC patient cohort. Logistic regression analysis proved that ESTM and pT stage are significantly correlated with LN metastasis. Additionally, the ESTM was incorporated into the eighth edition of the pTNM classification and the prognostic evaluation of pTNME classification were calculated directly, and the results indicated that ESTM can reduce the stage migration. CONCLUSIONS: ESTM is a significant independent predictor of survival in GC patients. To achieve R0 surgery, lymph nodes, soft tissues, fascia and adipose tissue should be resected en bloc at the same time as lymph node dissection. ESTM should be incorporated into pTNM staging according to the number retrieved from postoperative samples.

Prognostic impact of D2-plus lymphadenectomy and optimal extent of lymphadenectomy in advanced gastric antral carcinoma: Propensity score matching analysis.

OBJECTIVE: To investigate the prognostic impact of D2-plus lymphadenectomy including the posterior (No. 8p, No. 12b/p, No. 13, and No. 14v), and para-aortic (No. 16a2, and No. 16b1) lymph nodes (LNs) in subtotal gastrectomy for advanced gastric antral carcinoma. METHODS: A total of 203 patients with advanced gastric cancer (GC) located in the antrum, who underwent R0 gastrectomy with D2 or D2-plus lymphadenectomy between January 2003 and December 2011 were enrolled. Propensity score matching was used to reduce the strength of the confounding factors to accurately evaluate prognoses. The therapeutic value index (TVI) was calculate to evaluate the survival benefit of dissecting each LN station. RESULTS: Of 102 patients with D2-plus lymphadenectomy, 21 (20.59%) were pathologically identified as having LN metastases beyond the extent of D2 lymphadenectomy. After matching, the overall survival (OS) was significantly better in the D2-plus than the D2 group (P=0.030). In the multivariate survival analysis, D2-plus lymphadenectomy (hazard ratio, 0.516; P=0.006) was confirmed to significantly improve the survival rate. In the logistic regression analysis, pN stage [odds ratio (OR), 2.533; 95% confidence interval (95% CI), 1.368-4.691; P=0.003] and extent of LNs metastasis (OR, 5.965; 95% CI, 1.335-26.650; P=0.019) were identified as independent risk factors for LN metastases beyond the extent of D2 lymphadenectomy. The TVI of patient with metastasis to LNs station was 7.1 (No. 8p), 5.7 (No. 12p), 5.1 (No. 13), and 7.1 (both No. 16a2 and No. 16b1), respectively. CONCLUSIONS: D2-plus lymphadenectomy may improve the prognoses of some patients with advanced GC located in the antrum, especially for No. 8p, No. 12b, No. 13, and No. 16.