CD24+LCN2+ liver progenitor cells in ductular reaction contributed to macrophage inflammatory responses in chronic liver injury.

BACKGROUND: CD24+CK19+/CD24+SOX9+ resident liver cells are activated and expanded after chronic liver injury in a ductular reaction. However, the sources and functions of these cells in liver damage remain disputed. RESULTS: The current study combined genetic lineage tracing with in vitro small-molecule-based reprogramming to define liver progenitor cells (LPCs) derived from hepatic parenchymal and non-parenchymal tissues. tdTom+ hepatocytes were isolated from ROSA26tdTomato mice following AAV8-Tbg-Cre-mediated recombination, EpCAM+ biliary epithelial cells (BECs) from wild-type intrahepatic bile ducts and ALB/GFP-EpCAM- cells were isolated from AlbCreERT/R26GFP mice. A cocktail of small molecules was used to convert the isolated cells into LPCs. These in vitro cultured LPCs with CD24 and SOX9 expression regained the ability to proliferate. Transcriptional profiling showed that the in-vitro cultured LPCs derived from the resident LPCs in non-parenchymal tissues expressed Lipocalin-2 (Lcn2) at high levels. Accordingly, endogenous Cd24a+Lcn2+ LPCs were identified by integration of sc-RNA-sequencing and pathological datasets of liver dysfunction which indicates that LPCs produced by ductular reactions might also originate from the resident LPCs. Transplantation of in-vitro cultured Cd24a+Lcn2+ LPCs into CCl4-induced fibrotic livers exacerbated liver damage and dysfunction, possibly due to LCN2-dependent macrophage inflammatory response. CONCLUSIONS: CD24+LCN2+ LPCs constituted the expanding ductular reaction and contributed to macrophage-mediated inflammation in chronic liver damage. The current findings highlight the roles of LPCs from distinct origins and expose the possibility of targeting LPCs in the treatment of chronic hepatic diseases.

Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells.

UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 µM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 µM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

Predictors of difficult endoscopic resection of submucosal tumors originating from the muscularis propria layer at the esophagogastric junction.

BACKGROUND: Endoscopic resection approaches, including endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR), have been widely used for the treatment of submucosal tumors (SMTs) located in the upper gastrointestinal tract. However, compared to SMTs located in the esophagus or stomach, endoscopic resection of SMTs from the esophagogastric junction (EGJ) is much more difficult because of the sharp angle and narrow lumen of the EGJ. SMTs originating from the muscularis propria (MP) in the EGJ, especially those that grow extraluminally and adhere closely to the serosa, make endoscopic resection even more difficult. AIM: To investigate the predictors of difficult endoscopic resection for SMTs from the MP layer at the EGJ. METHODS: A total of 90 patients with SMTs from the MP layer at the EGJ were included in the present study. The difficulty of endoscopic resection was defined as a long procedure time, failure of en bloc resection and intraoperative bleeding. Clinicopathological, endoscopic and follow-up data were collected and analyzed. Statistical analysis of independent risks for piecemeal resection, long operative time, and intraoperative bleeding were assessed using univariate and multivariate analyses. RESULTS: According to the location and growth pattern of the tumor, 44 patients underwent STER, 14 patients underwent EFTR, and the remaining 32 patients received a standard ESD procedure. The tumor size was 20.0 mm (range 5.0-100.0 mm). Fourty-seven out of 90 lesions (52.2%) were regularly shaped. The overall en bloc resection rate was 84.4%. The operation time was 43 min (range 16-126 min). The intraoperative bleeding rate was 18.9%. There were no adverse events that required therapeutic intervention during or after the procedures. The surgical approach had no significant correlation with en bloc resection, long operative time or intraoperative bleeding. Large tumor size (≥ 30 mm) and irregular tumor shape were independent predictors for piecemeal resection (OR: 7.346, P = 0.032 and OR: 18.004, P = 0.029, respectively), long operative time (≥ 60 min) (OR: 47.330, P = 0.000 and OR: 6.863, P = 0.034, respectively) and intraoperative bleeding (OR: 20.631, P = 0.002 and OR: 19.020, P = 0.021, respectively). CONCLUSION: Endoscopic resection is an effective treatment for SMTs in the MP layer at the EGJ. Tumors with large size and irregular shape were independent predictors for difficult endoscopic resection.

Establishment of Functional Liver Spheroids From Human Hepatocyte-Derived Liver Progenitor-Like Cells for Cell Therapy.

Globally, about two million people die from liver diseases every year. Liver transplantation is the only reliable therapy for severe end-stage liver disease, however, the shortage of organ donors is a huge limitation. Human hepatocytes derived liver progenitor-like cells (HepLPCs) have been reported as a novel source of liver cells for development of in vitro models, cell therapies, and tissue-engineering applications, but their functionality as transplantation donors is unclear. Here, a 3-dimensional (3D) co-culture system using HepLPCs and human umbilical vein endothelial cells (HUVECs) was developed. These HepLPC spheroids mimicked the cellular interactions and architecture of mature hepatocytes, as confirmed through ultrastructure morphology, gene expression profile and functional assays. HepLPCs encapsulated in alginate beads are able to mitigate liver injury in mice treated with carbon tetrachloride (CCL4), while alginate coating protects the cells from immune attack. We confirmed these phenomena due to HUVECs producing glial cell line-derived neurotrophic factor (GDNF) to promote HepLPCs maturation and enhance HepLPCs tight junction through MET phosphorylation. Our results display the efficacy and safety of the alginate microencapsulated spheroids in animal model with acute liver injury (ALF), which may suggest a new strategy for cell therapy.

Triple network hypothesis-related disrupted connections in schizophrenia: A spectral dynamic causal modeling analysis with functional magnetic resonance imaging.

OBJECTIVE: The symptom-related neurobiology characteristic of schizophrenia in the brain from a network perspective is still poorly understood, leading to a lack of potential biologically-based markers and difficulty identifying therapeutic targets. We aim to test the dysregulated cross-network interactions among the Salience Network (SN), Central Executive Network (CEN) and Default Mode Network (DMN) and how they contributed to different symptoms in schizophrenia patients. METHODS: We examined network interactions among the SN, CEN and DMN in 76 patients with schizophrenia vs. 80 well-matched controls using dynamic causal modeling (DCM). We further analyzed the relation between network dynamics and Positive and Negative Syndrome Scale (PANSS). RESULTS: We observed that the DMN, CEN and SN across healthy controls and schizophrenia patients showed several similarities within or between-network pattern in the resting state. Comparing schizophrenia to controls, SN-centered cross-network interactions were most significantly reduced. Crucially, the strength of connections from CEN subnetwork 1 to DMN subnetwork 1 was positively correlated with the Positive Score of PANSS. The connection from the DMN subnetwork 2 to CEN subnetwork 2 was negatively correlated with the Negative Score of PANSS. CONCLUSIONS: Our study provides strong evidence for the dysregulation among SN, CEN and DMN in a triple-network perspective in schizophrenia. The connection between DMN and CEN could be clinically-relevant neurobiological signature of schizophrenia symptoms. Our study indicated that the description of brain triple network hypothesis could be a novel and possible bio-marker for schizophrenia.

Clinical features and mortality-related factors of extensive burns among young adults: the Kunshan disaster experience.

BACKGROUND: The aim of the study was to identify the clinical features and the factors associated with burn induced mortality among young adults after exposure to indoor explosion and fire. METHODS: This is an observational study which included burn patients who were admitted to eighteen ICUs after a fire disaster. Epidemiologic and clinical characteristics, as well as therapy were recorded. The primary outcome was 90-day mortality. The mortality-related factors were also analyzed. RESULTS: There were 167 burn patients enrolled in the study, the median age was 38 years, 62 (37.1%) patients died within 90 days. Seventy-one percent of patients had a burn size ≥90% TBSA, and 73.7% of patients had a full-thickness burn area above 50% TBSA. The survivors had lower Baux scores, and received earlier escharectomy and autologous skin grafts. The 50% mortality rates (LA50s) for burn size and full-thickness burn area were 95.8% and 88.6% TBSA, respectively. The multivariate analysis showed that full-thickness burn area over 50% TBSA and residual burned surface area (RBSA)/TBSA at 28 days were strong predictors of mortality among burn patients (odds ratio 2.55; 95% CI, 1.01 to 6.44, P=0.047; odds ratio 1.07; 95% CI, 1.04 to 1.09, P<0.001). The ROC curve-based cut-off values of RBSA/TBSA at 28 days for predicting 90-day mortality were 62.5%. CONCLUSIONS: Burn size and full-thickness burn area were the main risk factors for poor outcome in patients with extensive burns. Earlier escharectomy and autologous skin grafts may improve outcomes.

[The role of syndecan-1 in the transformation of pulmonary epithelial stroma in rats with chronic obstructive pulmonary disease and its mechanism].

Objective: To explore the role and mechanism of polysaccharide-1 (syndecan-1) in the transformation of lung epithelial stroma (EMT) in rats with chronic obstructive pulmonary disease (COPD). Methods: Thirty male SD rats of clean grade were randomly divided into sham operation group (normal saline injection after tracheal exposure, n=10), COPD group (fumigation after injection of 1 mg/ml lipopolysaccharide, transfection of 100 µl empty virus, n=10) and syndecan-1 overexpression group (fumigation after injection of 1 mg/ml lipopolysaccharide, and transfection of 100 µl carrying rat syndecan-1 gene Ad-CMV-GFP-SDC1, n=10), once a day for two weeks. After the treatment, the lung function was detected and lung tissues were collected. HE staining was used to observe lung injury. The expression levels of syndecan-1, vimentin and E-cadherin in lung tissue of rats in each group were detected by immunohistochemistry. Western blot was used to detect the expressions of TGF-ß1, Smad2/3 and p-Smad2/3. The mRNA levels of vimentin, E-cadherin, TGF-ß1 and Smad2/3 were detected by qRT-PCR. Results: Compared with the sham operation group, the airway mucosa of COPD group was exfoliated, the lumen was narrow, the airway wall was more inflammatory cell infiltration, emphysema was serious, expiratory volume (VE), peak expiratory flow (PEF), Forced expiratory volume in 0.3 s (FEV0.3) and the expression of E-cadherin mRNA were significantly decreased (P＜0.05). While the expression of vimentin, TGF-ß1 and Smad2/3 mRNA were increased, and the expression levels of TGF-ß1, Smad2/3 and p-Smad2/3 protein were significantly increased (P＜0.05). Compared with COPD group, the number of airway mucosa exfoliation and inflammatory cell infiltration in airway wall were decreased, lumen stenosis and emphysema were improved, the levels of VE, PEF, FEV0.3 and the expression of E-cadherin mRNA were significantly increased (P＜0.05). And the expressions of vimentin, TGF-ß1 and Smad2/3 mRNA were decreased, and expression levels of TGF-ß1, Smad2/3 and p-Smad2/3 protein were significantly decreased (P＜0.05). Conclusion: In COPD rats, TGF-ß/Smad signal pathway activation induced the production of EMT; overexpression of syndecan-1 could inhibit the EMT mediated by TGF-ß/Smad signal pathway, and improve the lung tissue injury of COPD rats.

Gray matter volume changes following antipsychotic therapy in first-episode schizophrenia patients: A longitudinal voxel-based morphometric study.

Despite evidence of structural brain abnormalities in schizophrenia, the current study aimed to explore the effects of antipsychotic treatment on gray matter (GM) volume using structural magnetic resonance imaging (MRI) and investigate the relationship between brain structure and treatment response. The GM volumes of 33 patients with first-episode schizophrenia were calculated with voxel-based morphometry (VBM), with 33 matched healthy controls. Longitudinal volume changes within subjects after 4-month antipsychotic treatment were also evaluated. Correlation between volumetric changes and clinical symptoms derived from the Positive and Negative Syndrome Scale (PANSS) were further investigated. Compared with healthy controls, decreased GM volumes in the frontal gyrus were observed in schizophrenia patients. After 4-month treatment, patients showed significantly decreased GM volume primarily in the bilateral frontal, temporal and left parietal brain regions. In addition, the GM volume changes of the left postcentral gyrus was positively correlated with negative symptoms improvement, and the correlation analysis revealed the total PANSS scores changes were associated with GM volume changes in the right inferior frontal gyrus and the right superior temporal gyrus. Besides, non-responders had reduced GM volume in the bilateral middle frontal gyrus and the right superior frontal gyrus compared with responders and healthy controls. Our results suggest that the abnormality in the right frontal gyrus exists in the early stage of schizophrenia. Moreover, the relationship between antipsychotics and structural changes was identified. The GM volume might have the potential to reflect the symptom improvement in schizophrenia patients. And MRI may assist in predicting the antipsychotic treatment response in first-episode schizophrenia patients.

Effect of second-generation antipsychotics on brain network topology in first-episode schizophrenia: A longitudinal rs-fMRI study.

OBJECTIVE: We aimed to evaluate the functional network properties in first-episode schizophrenia (SZ) patients at baseline and after 4-months treatment with second-generation antipsychotic drugs. METHODS: Resting-state functional magnetic resonance imaging and graph theory approaches were utilized to evaluate the functional integration and segregation of brain networks in 36 first-episode patients (20 male/16 female) with SZ and 36 age and sex matched healthy controls (20 male/16 female). RESULTS: Compared with healthy controls, SZ at baseline showed lower clustering coefficient (Cp) and local network efficiency (Eloc), and this abnormal pattern was modulated with treatment of antipsychotic drugs at follow-up. Longitudinally, the increase of Cp was associated with the improvement of negative symptom. We found that the strength of functional connectivity between brain regions were significantly increased in three connections after treatment, mainly involving the frontal, parietal and occipital lobes. CONCLUSION: The current study suggested that antipsychotic drugs could modulate the faulty local clustering of the functional connectome in SZ. Furthermore, Cp, the parameter that reflects local clustering of topological organization, demonstrated the potential to be a connectome-based biomarker of treatment response to second-generation antipsychotics in patients with SZ.

Minimally invasive thalamic hematoma drainage can improve the six-month outcome of thalamic hemorrhage.

OBJECTIVE: To explore predictors of the 6-month clinical outcome of thalamic hemorrhage, and evaluate if minimally invasive thalamic hematoma drainage (THD) could improve its prognosis. METHODS: A total of 54 patients with spontaneous thalamic hemorrhage were evaluated retrospectively. Clinical data, including demographics, stroke risk factors, neuroimaging variables, Glasgow Coma Score (GCS) on admission, surgical strategy, and outcome, were collected. Clinical outcome was assessed using a modified Rankin Scale, six months after onset. Univariate analysis and multivariate logistic regression analysis were performed to determine predictors of a poor outcome. RESULTS: Conservative treatment was performed for five patients (9.3%), external ventricular drainage (EVD) for 20 patients (37.0%), THD for four patients (7.4%), and EVD combined with THD for 25 patients (46.3%). At six months after onset, 21 (38.9%) patients achieved a favorable outcome, while 33 (61.1%) had a poor outcome. In the univariate analysis, predictors of poor 6-month outcome were lower GCS on admission (P = 0.001), larger hematoma volume (P < 0.001), midline shift (P = 0.035), acute hydrocephalus (P = 0.039), and no THD (P = 0.037). The independent predictors of poor outcome, according to the multivariate logistic regression analysis, were no THD and larger hematoma volume. CONCLUSIONS: Minimally invasive THD, which removes most of the hematoma within a few days, with limited damage to perihematomal brain tissue, improved the 6-month outcome of thalamic hemorrhage. Thus, THD can be widely applied to treat patients with thalamic hemorrhage.

Positive feedback loop of IL-1ß/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1ß/Akt signaling activation, which suggested a positive feedback loop of IL-1ß/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

Cerebral blood flow and its connectivity features of auditory verbal hallucinations in schizophrenia: A perfusion study.

The goal of the study was to investigate cerebral blood flow (CBF) and its connectivity (an across-subject covariance measure) patterns of schizophrenia (SZ) patients with auditory verbal hallucinations (AVHs). A total of demographically matched 25 SZ patients with AVHs, 25 without AVHs, and 25 healthy controls (HCs) underwent resting state perfusion imaging using a pulsed arterial spin labeling sequence. CBF and its connectivity were analyzed and then CBF topological properties were calculated. AVHs patients exhibited decreased CBF in the bilateral superior and middle frontal gyri and postcentral gyri, and right supplementary motor area compared with SZ patients without AVHs. SZ patients without AVHs showed reduced CBF in the left middle frontal gyrus relative to HCs. Moreover, AVHs groups showed distinct connectivity pattern, an intermediate level between HCs and patients without AVHs in the global efficiency. Our study demonstrates aberrant CBF in the brain regions associated with inner speech monitoring and language processing in SZ patients with AVHs. The complex network measures showed by CBF-derived functional connectivity indicate dysconnectivity between different functional units within the network of AVHs in SZ. Our findings might shed light on the neural underpinnings behind AVHs in this devastating disease at the level of CBF and its connectivity.

The structural connectivity pathology of first-episode schizophrenia based on the cardinal symptom of auditory verbal hallucinations.

Heterogeneous findings across studies of structural abnormality in schizophrenia (SZ) have impeded the development a unified theory of white matter pathology. As a cardinal symptom of SZ, auditory verbal hallucination (AVH) has been suspected to be associated with improper communication among several brain regions, which might indicated white matter pathology. Participants comprised 25 first-episode (FE) patients with AVH, 25 patients without AVH and 25 healthy subjects. Diffusion tensor imaging (DTI) measures were calculated using the TBSS of FSL. Voxel-based ANOVA tests were performed among the three groups and threshold-free cluster enhancement (TFCE) method correction was used for multiple comparisons. Voxel-based one-way ANOVA showed significant group effects for fractional anisotropy (FA) and radial diffusivity (RD) values. Post-hoc t-tests indicated that schizophrenia patients had lower FA and higher RD values in the internal capsule and anterior corona radiata than control subjects. Post-hoc analyses exhibited more widespread fiber disruptions in AVH patients than non-AVH patients. These results hinted on the important role of projection fiber disruption in schizophrenia patients. In addition, the current study also suggested that direct comparison between studies using patients with different symptom profiles should be interpreted with caution.

Putamen-related regional and network functional deficits in first-episode schizophrenia with auditory verbal hallucinations.

OBJECTIVE: Auditory verbal hallucinations (AVHs) are one of the cardinal symptoms of schizophrenia (SZ). Cerebral dysfunction may represent pathophysiological underpinnings behind AVHs in SZ. However, regional and network functional deficits for AVHs in SZ remain to be identified. METHODS: Seventeen medication-naïve first-episode SZ patients with AVHs, 15 without AVHs, and 19 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging. We compared the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) among these subjects. Areas with both ALFF and ReHo alterations were used as seeds in functional connectivity (FC) analysis. Then we performed correlation analysis between image measures and symptoms and receiver operating characteristic analysis. RESULTS: One-way analysis of variance showed significant differences of ALFF and ReHo in the bilateral putamen, thereby being used as seeds. SZ patients with AVHs showed decreased ALFF in the left putamen, increased ReHo in the right dorsolateral prefrontal cortex (DLPFC), and increased right putamen-seeded FC with the left DLPFC and Broca's area relative to those without AVHs. Furthermore, the increased strength of the connectivity between the right putamen and left Broca's area correlated with the severity of SZ symptoms. Both patient groups demonstrated hypoconnectivity within frontal/parietal/temporal cortico-striatal-cerebellar networks compared with HCs. CONCLUSION: AVHs in SZ may be caused by abnormal regional function in the putamen and prefrontal cortex, as well as hyperconnectivity between them. The putamen-related regional and network functional deficits may reflect imbalance in neuromodulation of AVHs in SZ. Furthermore, dysconnectivity within cortico-striatal-cerebellar networks might subserve the pathogenesis of SZ.

Impact of the number of resected lymph nodes on survival after preoperative radiotherapy for esophageal cancer.

To assess the impact of the number of resected lymph nodes (RLNs) for survival in esophageal cancer (EC) patients treated with preoperative radiotherapy and cancer-directed surgery. The Surveillance Epidemiology and End Results (SEER) database was queried to identify EC patients treated from 1988 to 2012 who had complete data on the number of positive lymph nodes and number of RLNs. Kaplan-Meier survival analysis and Cox regression proportional hazard methods were used to determine factors that significantly impact cause-specific survival (CSS) and overall survival (OS). There were a total of 3,159 patients who received preoperative radiotherapy and cancer-directed surgery. The median number of RLNs was 10 in both patients who received and did not receive preoperative radiotherapy (P = 0.332). Cox regression univariate and multivariate analysis showed that RLN count was a significant prognostic factor for CSS and OS. Patients with 11-71 RLNs had better CSS (hazard ratio [HR] = 0.694, 95% confidence interval [CI]: 0.603-0.799, P < 0.001) and OS (HR = 0.724, 95% CI: 0.636-0.824, P < 0.001) than patients with 1-10 RLNs. The 5-year CSS rates were 39.1% and 44.8% in patients with 1-10 RLNs and 11-71 RLNs, respectively (P < 0.001). The 5-year OS rates were 33.7% and 39.9% in patients with 1-10 RLNs and 11-71 RLNs, respectively (P < 0.001). A higher number of RLNs was associated with better survival by tumor stage and nodal stage (all P < 0.05). RLN count is an independent prognostic factor in EC patients who undergo preoperative radiotherapy and cancer-directed surgery.

Effect of postoperative radiotherapy for squamous cell cancer of the breast in a surveillance epidemiology and end results population-based study.

The therapeutic value of postoperative radiotherapy (RT) for squamous cell cancer of the breast (SCCB) is unclear. This retrospective study used a population-based national registry to determine the impact of postoperative RT on survival of women with SCCB. The Surveillance Epidemiology and End Results (SEER) database was used to identify females with SCCB who underwent primary surgical resection from 1973 to 2012. Kaplan-Meier survival analysis and Cox regression proportional hazard methods were used to determine the impact of RT following resection associated with cause-specific survival (CSS) and overall survival (OS). A total of 523 patients met the eligibility criteria. The median follow-up time was 55 months, the 10-year CSS and OS rates were 65.6%, and 46.0%, respectively. A total of 167 patients (31.9%) received postoperative RT. Multivariate analysis indicated that advanced pT and pN stage, and no postoperative RT were independently associated with poor OS; advanced pT and pN stage were independently associated with poor CSS. Postoperative RT was significantly associated with improved 10-year OS (54.5% vs. 42.0%, P =.001), but had no effect on CSS (P =.217). Analysis of patients with different stages of SCCB indicated that RT was associated with improved CSS (P =.047) and OS (P <.001) in those with stage II cancer and improved OS in patients with stage pN0 cancer (P <.001). Postoperative RT improved the survival of SCCB patients, especially in those with stage II and stage pN0 cancer.

IL-1ß induced RXRα overexpression through activation of NF-κB signaling in gastric carcinoma.

BACKGROUND: Abnormal expression of Retinoid X Receptor α (RXRα) seems to be a frequent incident in a variety of cancers. However, the expression pattern and the mechanisms in gastric carcinoma (GC) remain unclear. METHODS: In GC tissues and cell lines, the expression levels of RXRα mRNA and protein were detected by Q-PCR and Western blot, respectively; the localization of RXRα was evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC). The effect of IL-1ß on RXRα expression and localization was detected by Western blot and ICC. Nuclear factor-κB (NF-κB) pathway was assessed via Western blot. RESULTS: RXRα expression was markedly elevated at both mRNA and protein levels in GC tissues and cell lines (all P<0.05). The abnormal overexpression of RXRα was predominantly visualized in cytoplasm. IL-1ß significantly induced cytoplasmic expression of RXRα in a time-dependent manner. Co-incubation with IL-1ß enhanced phospho-IKKα (p-IKKα) expression and this effect could be inhibited by the specific inhibitor for NF-κB (all P<0.01). CONCLUSIONS: IL-1ß upregulated RXRα through activation of NF-κB signaling and these suggested a possible clinic significance of retinoid receptor expression in the diagnosis and treatment of GC.

Anterior cingulate cortex-related connectivity in first-episode schizophrenia: a spectral dynamic causal modeling study with functional magnetic resonance imaging.

Understanding the neural basis of schizophrenia (SZ) is important for shedding light on the neurobiological mechanisms underlying this mental disorder. Structural and functional alterations in the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, and medial prefrontal cortex (MPFC) have been implicated in the neurobiology of SZ. However, the effective connectivity among them in SZ remains unclear. The current study investigated how neuronal pathways involving these regions were affected in first-episode SZ using functional magnetic resonance imaging (fMRI). Forty-nine patients with a first-episode of psychosis and diagnosis of SZ-according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-were studied. Fifty healthy controls (HCs) were included for comparison. All subjects underwent resting state fMRI. We used spectral dynamic causal modeling (DCM) to estimate directed connections among the bilateral ACC, DLPFC, hippocampus, and MPFC. We characterized the differences using Bayesian parameter averaging (BPA) in addition to classical inference (t-test). In addition to common effective connectivity in these two groups, HCs displayed widespread significant connections predominantly involved in ACC not detected in SZ patients, but SZ showed few connections. Based on BPA results, SZ patients exhibited anterior cingulate cortico-prefrontal-hippocampal hyperconnectivity, as well as ACC-related and hippocampal-dorsolateral prefrontal-medial prefrontal hypoconnectivity. In summary, spectral DCM revealed the pattern of effective connectivity involving ACC in patients with first-episode SZ. This study provides a potential link between SZ and dysfunction of ACC, creating an ideal situation to associate mechanisms behind SZ with aberrant connectivity among these cognition and emotion-related regions.

Poly(amidoamine)s with pendant primary amines and flexible backbone for enhanced nonviral gene delivery: transfection and intracellular trafficking.

We synthesized poly(amidoamine)s with pendant primary amines and flexible backbone (polymers 1-3) by Michael polyaddition of N-tert-butyloxycarbonyl (N-Boc) protected diamine to 1,6-Bis(acrylamido)hexane, followed by the deprotection of N-Boc under acidic conditions. The physicochemical properties of polymers 1-3, including buffer capacity, DNA-binding capacity, cytotoxicity, particle sizes, and zeta potentials of polycation/DNA complexes, were explored. All the three polymers possess high buffer capacity and excellent DNA-binding capacity. In vitro MTT assay revealed that these synthesized poly(amidoamine)s were less cytotoxic than commercial branched PEI (25 kDa). These poly(amidoamine)s with pendant primary amines and flexible backbone were evaluated as in vitro nonviral gene delivery vectors for 293T and COS-7 cells. All the three polymers exhibited high transfection efficiencies, which were even higher than branched PEI (25 kDa) at optimized conditions. Further evidences from confocal laser scanning microscope (CLSM) demonstrated that the high transfection efficiencies of polymers 1-3 were due to the efficient uptake and intracellular trafficking of plasmid DNA in the cells during the transfection.