CT radiomics-based long-term survival prediction for locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy using features from tumor and tumor organismal environment.

BACKGROUND: Definitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LANSCLC) patients, but the treatment response and survival outcomes varied among these patients. We aimed to identify pretreatment computed tomography-based radiomics features extracted from tumor and tumor organismal environment (TOE) for long-term survival prediction in these patients treated with CCRT. METHODS: A total of 298 eligible patients were randomly assigned into the training cohort and validation cohort with a ratio 2:1. An integrated feature selection and model training approach using support vector machine combined with genetic algorithm was performed to predict 3-year overall survival (OS). Patients were stratified into the high-risk and low-risk group based on the predicted survival status. Pulmonary function test and blood gas analysis indicators were associated with radiomic features. Dynamic changes of peripheral blood lymphocytes counts before and after CCRT had been documented. RESULTS: Nine features including 5 tumor-related features and 4 pulmonary features were selected in the predictive model. The areas under the receiver operating characteristic curve for the training and validation cohort were 0.965 and 0.869, and were reduced by 0.179 and 0.223 when all pulmonary features were excluded. Based on radiomics-derived stratification, the low-risk group yielded better 3-year OS (68.4% vs. 3.3%, p < 0.001) than the high-risk group. Patients in the low-risk group had better baseline FEV1/FVC% (96.3% vs. 85.9%, p = 0.046), less Grade ≥ 3 lymphopenia during CCRT (63.2% vs. 83.3%, p = 0.031), better recovery of lymphopenia from CCRT (71.4% vs. 27.8%, p < 0.001), lower incidence of Grade ≥ 2 radiation-induced pneumonitis (31.6% vs. 53.3%, p = 0.040), superior tumor remission (84.2% vs. 66.7%, p = 0.003). CONCLUSION: Pretreatment radiomics features from tumor and TOE could boost the long-term survival forecast accuracy in LANSCLC patients, and the predictive results could be utilized as an effective indicator for survival risk stratification. Low-risk patients might benefit more from radical CCRT and further adjuvant immunotherapy. TRIAL REGISTRATION: retrospectively registered.

Activating transcription factor 3 involved in Pseudomonas aeruginosa PAO1-induced macrophage senescence.

Pseudomonas aeruginosa (PA) is one of the most prevalent pathogens that cause nosocomial infection in critical patients. Previously, we reported PA induced macrophage to senescence under the circumstance of infection. As an oxidative stress responsiveness element, activating transcription factor 3 (ATF3) might be involved in the macrophage senescence process. To test this presumption, we manipulated the expression of ATF3 in macrophage by using a PAO1 infection system. In the present study, ATF3 expression in macrophage was increased, following the duration and colony counts of PAO1 infection. Knockdown of ATF3 in macrophage resulted in increased percentage of senescent macrophage under PAO1 infection, while overexpressing ATF3 partly blocked PAO1-induced macrophage senescence. In accordance with the senescent phenotype, elevated reactive oxygen species (ROS) production was shown in ATF3 knockdown macrophages. Also, capacity of phagocytosis was also affected by manipulation of ATF3 expression in macrophages, and increased phagocytosed fluorescent beads was found in ATF3 knockdown macrophage. ATF3 might regulate the senescence process through influence on NF-κB translocation. During infection, the overexpression or downregulation of ATF3 in macrophage negatively modulated the translocation of NF-κB p65 and its phosphorylation at Ser-536. As a result, IL-6 and TNFα was elevated, while IL-10 decreased in case of ATF3 knockdown. In conclusion, ATF3 negatively regulates NF-κB translocation and activation, and participates in PA-induced macrophage senescence. As oxidative stress and inflammation induced element, ATF3 may modulate macrophage-related host defense.

Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection.

Pseudomonas aeruginosa (PA) is one of the most prevalent pathogens that cause nosocomial infection in critical patients. However, the mechanisms underlying macrophage growth status and functional changes during PA infection are yet unknown. In the present study, NADPH oxidase, gp91phox (NOX2) mediated macrophage to senescence in a PAO1 colony-dependent manner. gp91phox might regulate the senescence process through mutual interaction with the NF-κB pathway. During infection, the overexpression or downregulation of gp91phox in macrophage could affect the nuclear activity of NF-κB p65, while the downregulation of NF-κB p65 led to a suppressed expression of gp91phox. Reactive oxygen species (ROS) served as the second messenger between both molecules as the ROS inhibitor, N-acetylcysteine (NAC), could partially restore these changes. Consequently, the level of ROS and inflammatory cytokines, including IL-6 and TNFα, elevated during PAO1 infection, and their production altered as a result of the genetic manipulation of gp91phox and NF-κB p65, as well as NAC treatment. Also, the senescent phenotypes, SA-ß-gal staining and p16ink4a, changed after genetic manipulation with gp91phox and NF-κB p65 and NAC treatment. The capacity of phagocytosis in macrophages was decreased during senescence. In conclusion, PA directs the macrophage towards senescence, and senescent macrophages exhibit a decreased ability of phagocytosis. This process of senescence was regulated by the interactions between NADPH oxidase gp91phox and NF-κB p65 via ROS as a second messenger.

Activation of M1 macrophages plays a critical role in the initiation of acute lung injury.

The goal of the present study was to investigate the role of M1 macrophages in acute lung injury (ALI). To address this, we used lipopolysaccharide (LPS)-treated wild-type and CD11b-DTR mice, and examined their M1 macrophage levels, and the extent of their inflammation and pulmonary injuries. In addition, we evaluated pulmonary function by measuring the expressions of SP-A and SP-B in infiltrated M1 macrophages. Finally, we co-cultured the mouse type II-like alveolar epithelial cells (AT-II) and mouse pulmonary microvascular endothelial cells (PMECs) with M1 macrophages in the presence of TNF-α or H2O2 and assessed them for viability and apoptosis. After LPS treatment, we observed that the number of pulmonary M1/M2 macrophages and the serum levels of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and reactive oxygen species (ROS) significantly increased. Furthermore, the increase in cytokines was accompanied with the initiation of lung injury indicated by the decreased levels of SP-A and SP-B. In macrophage-depleted CD11b-DTR mice, ALI was attenuated, serum levels of IL-1ß, TNF-α and ROS were reduced, and lung levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were decreased. After administering TNF-α and H2O2, the proapoptotic effect of M1 macrophages on AT-II or PMECs significantly increased, the cell viabilities significantly decreased, and apoptosis significantly increased. Our results suggest that M1 macrophages are recruited to the lungs where they significantly contribute to an increase in TNF-α and ROS production, thus initiating ALI.

Multifunctional nanocomposite based on halloysite nanotubes for efficient luminescent bioimaging and magnetic resonance imaging.

A novel multifunctional halloysite nanotube (HNT)-based Fe3O4@HNT-polyethyleneimine-Tip-Eu(dibenzoylmethane)3 nanocomposite (Fe-HNT-Eu NC) with both photoluminescent and magnetic properties was fabricated by a simple one-step hydrothermal process combined with the coupling grafting method, which exhibited high suspension stability and excellent photophysical behavior. The as-prepared multifunctional Fe-HNT-Eu NC was characterized using various techniques. The results of cell viability assay, cell morphological observation, and in vivo toxicity assay indicated that the NC exhibited excellent biocompatibility over the studied concentration range, suggesting that the obtained Fe-HNT-Eu NC was a suitable material for bioimaging and biological applications in human hepatic adenocarcinoma cells. Furthermore, the biocompatible Fe-HNT-Eu NC displayed superparamagnetic behavior with high saturation magnetization and also functioned as a magnetic resonance imaging (MRI) contrast agent in vitro and in vivo. The results of the MRI tests indicated that the Fe-HNT-Eu NC can significantly decrease the T2 signal intensity values of the normal liver tissue and thus make the boundary between the normal liver and transplanted cancer more distinct, thus effectively improving the diagnosis effect of cancers.

Induction of GADD45α protects M17 neuroblastoma cells against MPP*.

Growth arrest and DNA-damage-inducible protein 45α (GADD45α) is an important member of the family of growth arrest and DNA damage-inducible (GADD) proteins. The expression patterns and possible roles of GADD45α in Parkinson's disease (PD) are so far less understood. In this study, we found that 1-methyl-4-phenylpyridinium (MPP+) treatment up-regulates the expression of GADD45α in both a time-dependent manner and a dose-dependent manner in human dopamine neuroblastoma M17 cells. The up-regulation of GADD45α was abolished by pretreatment with the c-Jun N-terminal kinases (JNK) inhibitor SP600125 but not the p38 specific inhibitor SB203580. Further study revealed that c-Jun silencing abolished the effects of MPP+ on the expression of GADD45α. Important, ChIP studies verified the ability of c-Jun to bind to the GADD45 promoter. In addition, we found that inhibition of GADD45α by small RNA interference exacerbates the impaired cell viability, LDH release, and apoptosis induced by MPP+. Correspondingly, silence of GADD45 exacerbated Caspase-3 activation induced by MPP+. These data suggested a neuroprotective effect of GADD45α against MPP+ neurotoxicity.

[Pathological analysis of heroin spongiform leukoencephalopathy].

OBJECTIVE: To investigate the pathological characteristics of heroin spongiform leukoencephalopathy (HSLE). METHODS: Cerebral tissue specimens were obtained from 15 patients with HSLE and the histological observations under optical and electron microscopes were carried out by HE, Bielschowsky's, and chromotrope 2R-brilliant green staining. RESULTS: HSLE was characterized primarily by spongiform vacuolar degeneration of the cerebral white matter. Neurons in the gray matter, Purkinje and granular cells in the cerebella remain intact in all the cases. Numerous vacuoles, which merged to form larger cavities, appeared in the damaged white matter, and the axons survived in the deep white matter. The myelin sheath in the cerebellar white matter sustained more severe damages than those in the cerebral white matter. No vacuoles or lymphocyte infiltration occurred in the small peripheral vessels. CONCLUSION: HSLE is pathologically characterized by vacuolar degeneration due to primary damage of the myelin, and the spongiform vacuolar degeneration is closely associated with the severity of demyelination in the white matter.

[Glucocortioid treatment for heroin-induced spongiform leucoencephalopathy: a clinical controlled study].

OBJECTIVE: To evaluate the therapeutic effects of the glucocorticoid on heroin-induced spongiform leucoencephalopathy. METHODS: Twenty cases of heroin-induced spongiform leucoencephalopathy were randomly divided into the control group and the treating group with equal number. In the control group, the treatment was constituted by oral administration of vitamin B and coenzyme Q10 in a course of 1 month. In glucocorticoid treatment group, glucocorticoid (20 mg/d) for 10 d were given in addition to vitamin B and coenzyme Q10, and the dose of the glucocorticoid was gradually decreased afterwards. General observation and statistical analysis of function scores were performed in both groups before and 1, 6, 12 months after the treatment respectively. RESULTS: No significant difference in function scores was observed between the 2 groups, while the results of observation before and after the treatment were significantly different (P<0.05). The most significant difference occurred when comparing the observations made 1 month and 6 months respectively after treatment (P<0.001). CONCLUSION: Glucocorticoid has no obvious therapeutic effect on heroin-induced spongiform leucoencephalopathy, and rapid clinical recovery occurs within the initial 6 months of the treatment.