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The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages, and plays a critical role in regulating inflammatory response. Our previous work has shown its role in promoting the progression of non-small cell lung cancer (NSCLC), yet the mechanism remains unclear. Here, using Tgr5-knockout mice, we show that TGR5 is required for M2 polarization of tumor-associated macrophages (TAMs) and suppresses antitumor immunity in NSCLC via involving TAMs-mediated CD8+ T cell suppression. Mechanistically, we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating cAMP-STAT3/STAT6 signaling. Induction of cAMP production restores M2-like phenotypes in TGR5-deficient macrophages. In NSCLC tissues from human patients, the expression of TGR5 is associated with the infiltration of TAMs. The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients. Together, this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC, highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.

The characteristics of fermented apple juice ‘Jiaosu’ as a traditional folk beverage were determined. Sequential alcoholic, acetic and malolactic fermentation was mediated either by intrinsic or inoculated microbiota over six months at room temperature under static conditions. The fermentation mixture was composed of fruits of Malus pumila Mill., var. Fuji (Rosaceae) and fruit of Citrus limon Burm. f., var. Eureka (Rutaceae), acacia honey of Robinia pseudoacacia L. (Fabaceae) and spring water at a weight ratio of 3:1:10. Product anti-oxidative features, antimicrobial capacities and the metabolic byproducts were determined at the end of fermentation. Our results showed an elevation of antioxidant activity, good antimicrobial ability and enrichment of bioactive compounds in the directed fermentation inoculated with Saccharomyces cerevisiae, Acetobacter pasteurianus and a mixture of Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus paracasei compared to the spontaneous fermentation. Prebiotic fermentation tended to preserve and even improve the antioxidant capacity throughout the fermentation process and generated valuable substances. Though it may reduce the amounts of some other bioactive compounds, the final product quality of directed fermentation was reliable. This study provides valuable information for understanding tradition functional beverages based on fermented fruits.

The regulation mechanism of the hybrid yellow catfish "Huangyou-1" was assessed under conditions of hypoxia and reoxygenation by examination of oxygen sensors and by monitoring respiratory metabolism, oxidative stress, and apoptosis. The expressions of genes related to oxygen sensors (HIF-1α, HIF-2α, VHL, HIF-1β, PHD2, and FIH-1) were upregulated in the brain and liver during hypoxia, and recovered compared with control upon reoxygenation. The expressions of genes related to glycolysis (HK1, PGK1, PGAM2, PFK, and LDH) were increased during hypoxia and then recovered compared with control upon reoxygenation. The mRNA levels of CS did not change during hypoxia in the brain and liver, but increased during reoxygenation. The mRNA levels of SDH decreased significantly only in the liver during hypoxia, but later increased compared with control upon reoxygenation in both tissues. Under hypoxic conditions, the expressions of genes related to oxidative stress (SOD1, SOD2, GSH-Px, and CAT) and the activity of antioxidant enzymes (SOD, CAT, and GSH-Px) and MDA were upregulated compared with control. The expressions of genes related to apoptosis (Apaf-1, Bax, Caspase 3, Caspase 9, and p53) were higher than those in control during hypoxic exposure, while the expressions of Bcl-2 and Cyt C were decreased. The findings of the transcriptional analyses will provide insights into the molecular mechanisms of hybrid yellow catfish "Huangyou-1" under conditions of hypoxia and reoxygenation. Overall, these findings showed that oxygen sensors of "Huangyou-1" are potentially useful biomarkers of environmental hypoxic exposure. Together with genes related to respiratory metabolism, oxidative stress and apoptosis occupy a quite high position in enhancing hypoxia tolerance. Our findings provided new insights into the molecular regulatory mechanism of hypoxia in "Huangyou-1."

PURPOSE To evaluate the impact of respiratory motion on radiomics features in 18 F-fluoro-2-deoxy-D-glucose three dimensional positron emission tomography (18 F-FDG 3D PET) imaging and optimize feature stability by combining preprocessing configurations and aggregation strategies. METHODS An in-house developed respiratory motion phantom was imaged in 3D PET scanner under nine respiratory patterns including one reference pattern. In total, 487 radiomics features were extracted for each respiratory pattern. Feature stability to respiratory motion was first evaluated by metrics of coefficient of variation (COV) and relative difference (RD) in a fixed preprocessing configuration. Further, one-way ANOVA and trend analysis were performed to evaluate the impact of preprocessing configuration (voxel size, discretization scheme) and aggregation strategy on feature stability. Finally, an optimization framework was proposed by selected feature-specific configurations with minimum COV value, and the diagnostic performance was validated in stable versus unstable features and fixed versus optimal features by a set of 46 patients with lung disease. RESULTS PET radiomics features were sensitive to respiratory motion, only 79/487 (16%) features were identified to be very stable in the fixed configuration. Preprocessing configuration and aggregation strategy had an impact on feature stability. For different voxel size, bin number, bin size and aggregation strategy, 188/487 (39%), 70/487 (15%), 148/487 (30%), and 38/95 (29%) features appeared significant changes in feature stability. The optimized configuration had the potential to improve feature stability compared to fixed configuration, with the COV decreased from 22% ±24% to 16% ±20%. Regarding the diagnostic performance, the stable and optimal configuration features outperformed the unstable and fixed configuration features, respectively (AUC 0.88, 0.87 vs. 0.83, 0.85). CONCLUSIONS Respiratory motion shows considerable impact on feature stability in 3D PET imaging, while optimizing preprocessing configuration may improve feature stability and diagnostic performance.

Babesia orientalis, belonging to the phylum Apicomplexa, is mainly accountable for water buffalo babesiosis, which adversely affected the livestock industry in China. Variant erythrocyte surface antigen-1 (VESA1), an antigen that helps infected erythrocytes to escape from host immune responses, was first reported in Babesia bovis. Various VESA1 proteins have also been characterized in other Babesia species. Nevertheless, there is no research on the identification and characterization of VESA1 proteins in Babesia orientalis. In this study, the BoVESA1 gene was amplified from both gDNA and cDNA. The results revealed that it is an intronless gene with a full length of 753 bp, encoding a protein of 250 amino acids with a predicted molecular weight of 28 kDa. The coding sequence (CDS) was cloned into the pGEX-6p-1 vector using a homologous recombination kit and expressed as a glutathione-S-transferase (GST)-fusion protein with a molecular weight of 53 kDa. The tertiary structure of BoVESA1 was predicted using the I-TASSER software. The recombinant protein was subjected to western blotting; the immunogenicity of recombinant BoVESA1 (rBoVESA1) was identified by incubating it with B. orientalis-positive serum. The native BoVESA1 was identified using the lysates of B. orientalis-infected water buffalo erythrocytes incubated with the anti-rBoVESA1 mouse serum. The results showed a band of ~ 28 kDa, which is similar to the predicted size. Immunofluorescence assay (IFA) using anti-rBoVESA1 serum probed indicated a strong signal in the infected RBCs, while the negative control showed no signal. In conclusion, the VESA1 protein was first identified in B. orientalis. This study facilitated further investigation of B. orientalis, and the results indicated that BoVESA1 may serve as a potential candidate antigen for diagnosis and detection of B. orientalis infection.

Background: The 2019 coronavirus disease (COVID-19) pandemic has impacted the mental health and well-being of medical personnel, including nursing students. Network analysis provides a deeper characterization of symptom-symptom interactions in mental disorders. The aim of this study was to elucidate characteristics of anxiety and depressive symptom networks of Chinese nursing students during the COVID-19 pandemic. Method: A total of 932 nursing students were included. Anxiety and depressive symptom were measured using the seven-item Generalized Anxiety Disorder Scale (GAD-7) and two-item Patient Health Questionnaire (PHQ-2), respectively. Central symptoms and bridge symptoms were identified via centrality indices and bridge centrality indices, respectively. Network stability was examined using the case-dropping procedure. Results: Irritability, Uncontrollable worry, Trouble relaxing, and Depressed mood had the highest centrality values. Three bridge symptoms (Depressed mood, Nervousness, and Anhedonia) were also identified. Neither gender nor region of residence was associated with network global strength, distribution of edge weights or individual edge weights. Limitations: Data were collected in a cross-sectional study design, therefore, causal relations and dynamic changes between anxiety and depressive symptoms over time could not be inferred. Generalizability of findings may be limited to Chinese nursing students during a particular phase of the current pandemic. Conclusions: Irritability, Uncontrollable worry, Trouble relaxing, and Depressed mood constituted central symptoms maintaining the anxiety-depression network structure of Chinese nursing students during the pandemic. Timely, systemic multi-level interventions targeting central symptoms and bridge symptoms may be effective in alleviating co-occurring experiences of anxiety and depression in this population.

Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor in various cancer types, including non-small cell lung cancer (NSCLC). Circular RNA (circRNA) has recently been proven to be strongly linked with cancer progression. Here, we aimed to investigate the biological relevance and clinical significance of circRNA derived from PTEN in NSCLC. We found that circ-PTEN (hsa_circ_0094342) was significantly decreased in NSCLC tissues and serum, which was attributed to the upregulation of RNA-binding protein DHX9. Low circ-PTEN was linked with malignant clinical features and poor outcome. Exogenous expression of circ-PTEN markedly inhibited NSCLC cell proliferation in vitro as well as retarded tumor growth in vivo. Circ-PTEN increased the expression of its host gene PTEN via acting as a sponge for miR-155 and miR-330-3p, leading to the inactivation of the carcinogenic PI3K/AKT signaling pathway. The xenograft tumor model also indicated the existence of circ-PTEN/miR-155/miR-330-3p/PTEN regulatory axis in vivo. Our data for the first time demonstrate that circ-PTEN functions as a tumor-inhibiting circRNA in NSCLC through post-transcriptionally regulating PTEN, hinting a promising diagnostic/prognostic biomarker as well as therapeutic target for NSCLC patients.

Background: Mastitis results in great economic loss to the dairy goat industry. Many approaches have attempted to decrease the morbidity associated with this disease, and among these, transgenic strategy have been recognized as a potential approach. A previous mammalian study reports that interferon-gamma (IFN-γ) has potential anti-bacterial bioactivity against infection in vitro; however, its capacity in vivo is ambiguous. Results: In this study, we first constructed targeting and homologous recombination vectors (containing the IFN-γ gene) and then transferred the vectors into goat mammary gland epithelial cells (GMECs). Enzyme digestion and sequencing analysis indicated that the vectors used in this study were built correctly. Subsequently, monoclonal cells were selected using puromycin and the polymerase chain reaction (PCR) test indicated that IFN-γ was correctly inserted downstream of the casein promoter. Monoclonal cells were then assessed for reducible expression, and reverse transcriptase-PCR (RT-PCR) and Western blot tests confirmed that monoclonal cells could express IFN-γ. Finally, anti-bacterial capacity was evaluated using bacterial counts and flow cytometry analysis. Decreased bacterial counts and cell apoptosis rates in transgenic GMECs demonstrated that the secretion of IFN-γ could inhibit bacterial proliferation and reduce the risk of mammary infection in goats. Conclusions: IFN-γ gene transfection in goat mammary epithelial cells could inhibit bacterial proliferation and reduce the risk of mammary infection in goats.

Glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is a key enzyme associated with glucose metabolism and uridine diphosphate-N-acetylglucosamine biosynthesis. Abnormal GNPNAT1 expression might be associated with carcinogenesis. We analyzed multiple lung adenocarcinoma (LUAD) gene expression databases and verified GNPNAT1 higher expression in LUAD tumor tissues than in normal tissues. Moreover, we analyzed the survival relationship between LUAD patients’ clinical status and GNPNAT1 expression, and found higher GNPNAT1 expression in LUAD patients with unfavorable prognosis. We built GNPNAT1 gene co-expression networks and further annotated the co-expressed genes’ Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and various associated regulatory factors. These co-expression genes’ functional networks mainly participate in chromosome segregation, RNA metabolic process, and RNA transport. We analyzed GNPNAT1 genetic alterations and co-occurrence networks, and the functional networks of these genes showed that GNPNAT1 participates in multiple steps of cell cycle transition and in the development of some cancers. We assessed the correlation between GNPNAT1 expression and cancer immune infiltrates and showed that GNPNAT1 expression is correlated with several immune cells, chemokines, and immunomodulators in LUAD. We found that GNPNAT1 correlates with LUAD development and prognosis, laying a foundation for further research, especially in immunotherapy.

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody-drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.

The disposal of large quantities of tobacco stalks and animal manures generated annually is among the serious challenges faced in China, especially the former, as its toxic composition (nicotine) can induce the risk of healthy impairment during tradition treatment process. Anaerobic digestion (AD) may be an efficient technique for tobacco stalks. Nevertheless, the impact of nicotine in tobacco stalks upon AD is still unclear so far. Thus, a simulated AD experiment using glucose with different nicotine concentrations was implemented, suggesting a nicotine concentration of more than 4% (w/w) could inhibit AD. The nicotine component in tobacco stalks would not be an inhibitor on AD because its content was far below 4%. Meanwhile, in order to efficiently treat abundant tobacco stalks and manure wastes at the same time, untreated and alkaline hydrogen peroxide (AHP)-pretreated tobacco stalks were co-digested with three typical manures, including pig manure (PM), chicken manure (CM), and dairy manure (DM), to investigate their digestion performance. Co-digestion of pretreated tobacco stalks and PM at 1:4 ratio exhibited the highest methane production of 397.2 mL/g VS and had a synergistic effect. This study provides valuable guidance for simultaneously converting these two wastes in future AD applications.

Heptaphylline, a carbazole alkaloid, has been shown to exert anticancer effects against different human cancers. The study was designed to evaluate the anticancer effects of heptaphylline against t...

The quantitative accuracy of positron emission tomography (PET) is affected by several factors, including the intrinsic resolution of the imaging system and inherently noisy data, which result in a low signal-to-noise ratio (SNR) of PET image. To address this problem, in this paper, we proposed a novel deep learning denoising framework aiming to enhance the quantitative accuracy of dynamic PET images via introduction of deep image prior (DIP) combined with Regularization by Denoising (RED), as such the method is labeled as DeepRED denoising. The network structure is based on encoder-decoder architecture and uses skip connections to combine hierarchical features to generate the estimated image. The network input can be random noise or other prior images (such as the patient’s own static PET image), avoiding the need of high quality noiseless images, which is limited in PET clinical practice due to high radiation dose. Based on simulated data and real patient data, the quantitative performance of the proposed method was compared with conventional Gaussian filtering (GF), non-local mean (NLM), block-matching and 3D filtering (BM3D), DIP and stochastic gradient Langevin dynamics (SGLD) method. Overall, the proposed method can outperform other conventional methods in substantial visual as well as quantitative accuracy improvements (in terms of noise versus bias performance) with and without prior images.

Although p21 activated kinase 5 (PAK5) is related to the progression of multiple cancers, its biological function in breast cancer remains unclear. Apoptosis-inducing factor (AIF) is a vital apoptosis factor in mitochondria, which can be released from mitochondria and enter the nucleus, causing caspase-independent apoptosis. In this study, we reveal that PAK5 inhibits apoptosis by preventing the nuclear translocation of AIF. PAK5 inhibits the release of AIF from mitochondria in breast cancer cells by decreasing the mitochondria membrane permeability and increasing the membrane potential. Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin α3 complex, leading to decrease AIF nuclear translocation. Functionally, we demonstrate that PAK5-mediated AIF phosphorylation promotes the proliferation of breast cancer cells and accelerates the growth of breast cancer in vivo. Significantly, PAK5 and AIF expression in breast cancer are positively correlated with poor patient prognosis. PAK5 expression is negatively correlated with AIF nuclear translocation. These results suggest that PAK5-AIF signaling pathway may play an essential role in mammary tumorigenesis, providing a new therapeutic target for the treatment of breast cancer.

Dynamic positron emission tomography (PET) image reconstruction is challenging due to the low-count statistics of individual frames. This study proposes a novel reconstruction framework aiming to enhance the quantitative accuracy of individual dynamic frames via the introduction of priors based on multiscale superpixel clusters. The clusters are derived from pre-reconstruction composite images using superpixel clustering followed by fuzzy c-means (FCM) clustering. A multiscale aggregation is exploited during the superpixel clustering to generate multiscale superpixel clusters. Then, maximum a posteriori (MAP) PET reconstruction with different-scale clusters is separately applied to individual frame and fused to generate the final result. Using realistic simulated dynamic brain PET data, the quantitative performance of the proposed method is investigated and compared with the maximum-likelihood expectation-maximization (MLEM), Bowsher method, and kernelized expectation-maximization (the kernel method). The proposed method achieves substantial improvements in both visual and quantitative accuracy (in terms of the signal-to-noise ratio and contrast versus noise performances). The method is also tested with a 60 min 18F-FDG rat study performed with an Inveon small animal PET scanner. The proposed method is shown to outperform the other methods via improvements in visual and quantitative accuracy (in terms of noise versus the mean intensity of the region of interest).

BACKGROUND & AIMS: Ustekinumab induces and maintains histologic improvement in patients with ulcerative colitis (UC). The clinical relevance of this endpoint alone, and in combination with endoscopic improvement, is unknown. METHODS: Histologic disease activity was evaluated in 2630 colonic biopsy samples from patients with UC treated in the UNIFI phase 3 UC clinical studies of ustekinumab. We evaluated associations between histologic improvement (defined as the composite of neutrophil infiltration in less than 5% of crypts and no crypt destruction, erosions, ulcerations, or granulation tissue) and clinical endpoints at the end of induction (week 8 and 16) and maintenance (week 44) periods. We assessed the validity of a combined histologic and endoscopic (Mayo endoscopy subscore, 0 or 1) improvement endpoint, which we called histo-endoscopic mucosal healing (or histo-endoscopic mucosal improvement). RESULTS: Histologic improvement was significantly (P < .0001) associated with clinical remission, lower mean disease activity scores, and greater improvement in disease activity at the end of induction and maintenance studies. Ustekinumab induced and maintained significantly higher rates of histologic improvement at induction week 8 and maintenance week 44 than placebo when more stringent definitions of histologic improvement were used. Histologic improvement and endoscopic improvement following induction were associated with 10% to 20% higher rates of histo-endoscopic mucosal healing, clinical remission, and corticosteroid-free remission at week 44 (all P < .05) in patients who received ustekinumab maintenance therapy. At week 44, 61% of patients (56/92) with histo-endoscopic mucosal healing after induction therapy achieved clinical remission, versus 39% of patients (9/23, P = .0983) and 34% of patients (24/71, P = .0009) with endoscopic or histologic improvement alone after induction, respectively. CONCLUSION: Data from the UNIFI program of ustekinumab in patients with UC treated with ustekinumab indicated the achievement of histo-endoscopic mucosal healing after induction therapy is associated with lower disease activity at the end of maintenance therapy than either histologic or endoscopic improvement alone. ClinicalTrials.gov number: NCT02407236. ispartof: GASTROENTEROLOGY vol:159 issue:6 ispartof: location:United States status: published

Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.

PURPOSE Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively ( P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.

Purpose Temporal lobe epilepsy (TLE) is a common neurological disorder, which is characterized by recurrent spontaneous seizures. Exploring the mechanisms of epileptogenesis has been considered as a priority. The aim of this study is to investigate the effects of LncRNA MEG3 in spontaneous recurrent epileptiform discharges (SREDs) and rats with TLE. Methods Rat model of TLE was produced by intraperitoneal injection of lithium chloride and pilocarpine. Rat hippocampal neuronal model of SREDs was established by Mg2+-free treatment. MEG3 was overexpressed by transfection of AAV-MEG3 in TLE and SREDs model. The expression of MEG3, interleukin-1β (IL-1β), interleukin-6 (IL-6) and recombinant human tumor necrosis factor-alpha (TNF-α) was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected by corresponding kit. The apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase transfer‑mediated dUTP nick end‑labeling (TUNEL) assay and flow cytometry. The expression of proteins related to apoptosis (Caspase-3, Bax, and Bcl-2) and the PI3K/AKT/mTOR pathway was detected by Western blot. Results MEG3 expression was downregulated in SREDs and rats with TLE. Overexpression of MEG3 reduced the expression of IL-1β, IL-6, and TNF-α, MDA content, apoptosis rate of hippocampal neuron, increased SOD activity, and inhibited the PI3K/AKT/mTOR pathway in rats with TLE. In addition, overexpression of MEG3 enhanced cell viability and inhibited apoptosis through the activation of the PI3K/AKT/mTOR pathway in SREDs. Conclusion MEG3 reduced proinflammatory cytokines, oxidative stress, and apoptosis rate of hippocampal neuron and enhanced cell viability through the activation of the PI3K/AKT/mTOR pathway in SREDs and rats with TLE. Our findings may contribute to find a new therapeutic target for the treatment of epilepsy.

Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

BackgroundTo report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC).MethodsPatients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy.ResultsA total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74;P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75;P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib.ConclusionsConcurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC.Clinical trial registrationTrial registration: NCT00686114.

The relationship between pain and mortality risk has not been well established.This study aimed to assess the possible association between a chief complaint of pain and in-hospital mortality.Retrospective cohort study using 11-year hospital administrative data.Southwest Hospital of Third Military Medical University (Chongqing, China).A total of 645,998 adult inpatients admitted without department limitation between January 1, 2003, and December 31, 2013.Information on the chief complaint at admission was obtained, and the main outcome measure was in-hospital mortality.The crude overall in-hospital mortality rate for patients admitted with chief complaint of pain was 958 (3.9%), which was significantly lower than that of patients without pain (1,970, 4.9%). The risk of hospital death for inpatients admitted with pain was 21% lower compared to inpatients admitted without pain (p .001). Female patients with a chief complaint of pain had a lower risk of in-hospital mortality (p .001) compared with male patients (p .001). When stratified by location of pain, patients with chest pain had a significantly higher risk of in-hospital mortality compared with those without complaint of pain (p .001), whereas for patients with a chief complaint of waist, abdominal, limb, or joint pain, the risk of hospital death was lower compared with cases without pain.The present study suggested that inpatients admitted with a chief complaint of pain might have a significantly lower risk of in-hospital mortality compared with those admitted without a chief complaint of pain.

BACKGROUND: The occurrence and development of atherosclerosis (AS) are closely related to the abnormality of vascular smooth muscle cells (VSMCs), and multiple microRNAs (miRNAs) have been reported to participate in the pathogenesis of AS. This study explored the expression and clinical value of miR-374 in the serum of AS patients, and analyzed its effect on the proliferation and migration of VSMCs. METHODS: The expression levels of miR-374 in the serum of 102 asymptomatic patients with AS and 89 healthy patients were detected by fluorescence quantitative PCR. The diagnostic value of miR-374 was evaluated through the receiver operating characteristic (ROC) curve. What’s more, CCK-8 and Transwell assays were used to analyze the effects of miR-374 on the proliferation and migration of VSMCs. RESULTS: The expression level of miR-374 in the serum of AS patients was significantly higher than that of the control group. At the same time, the expression of miR-374 in AS patients was positively correlated with carotid intima-media thickness (CIMT). The area under the ROC curve is 0.824. Furthermore, overexpression of miR-374 significantly promoted the proliferation and migration of VSMCs, whereas reducing miR-374 inhibited the proliferation and migration of VSMCs. CONCLUSIONS: The high expression of miR-374 may be a potential diagnostic marker for AS, and overexpression of miR-374 may play a role in AS by promoting the proliferation and migration of VSMCs.

The influence of polyvinylpyrrolidone (PVP) and monoethanolamine (MEA) as surfactants on photoluminescence (PL) of Eu-doped ZnO (ZnO:Eu) has been studied. X-ray diffraction (XRD) results show that there are more Eu3+ ions to replace Zn2+ ions into ZnO lattice for ZnO:Eu in the presence of surfactant MEA. From the spectral analysis for ZnO:Eu with different surfactants by Gaussian deconvolution, it can be seen that the use of MEA as a surfactant affects the energy transfer from ZnO host to Eu3+ ions and leads to three new emission peaks, including UV emission (389 nm), violet emission (411 nm) and green emission (506 nm).

Lin-Wei Wang,* Li Li,* Hong-Yan Zhang, Yuan-Yuan Chen, Ya-Hua Zhong Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ya-Hua Zhong Email doctorzyh73@163.comPurpose: Radiotherapy is a powerful strategy to prevent chest wall recurrence (CWR) of postmastectomy breast cancer (BC). This retrospective study aims at analyzing patterns of CWR to explore the delineation of clinical target volume.Patients and Methods: Detailed clinicopathological information of postmastectomy BC patients with CWR was collected from our single cancer center based on clear criteria. To describe recurrent positions more accurately, the chest wall was divided into three layers: skin layer (skin and subcutaneous tissues), pectoralis layer (pectoralis major and minor), and rib layer (rib and intercostal muscle). The frequency distribution of recurrence location and its association with clinical pathological factors were analyzed.Results: A total of 121 postmastectomy BC with CWR were included in this study. The percentages of breast tumor located in the upper outer quadrant, upper inner quadrant, lower inner quadrant, lower outer quadrant, overlapping quadrant, and areola area were 31.0% (35/113), 26.5% (30/113), 12.4% (14/113), 5.3% (6/113), 21.1% (25/113), and 2.7% (3/113), respectively. HER2-positive BC (51/113, 45.1%) is the most common BC subtype. Analysis on the patterns of CWR showed that recurrences locating in the skin layer, pectoralis layer, rib layer, mixed layers, and incision periphery accounted for 58.6% (68/116), 9.5% (11/116), 1.7% (2/116), 30.2% (35/116), and 60.5% (46/76), respectively. Rates of recurrences located in the skin and/or pectoralis layers for all BC patients, patients with concomitant distance metastasis, and patients without concomitant distance metastasis were 82.8% (96/116), 85.9% (49/57), and 81.0% (47/58), respectively.Conclusion: For BC patients receiving mastectomy, skin, subcutaneous tissues, pectoralis, and area around incision have a high risk of recurrence, which should be paid more attention in chest wall radiotherapy.Keywords: breast cancer, radiotherapy, chest wall recurrence, clinical target volume