Search

Abstract Objective This study aimed to investigate the associations between physical activity (PA) intensity, occupational PA engagement, and sarcopenia in younger adults. Methods Data from the National Health and Nutrition Examination Survey (NHANES) (from 2011 to 2018) were used for the study. PA data were extracted for the Global Physical Activity Questionnaire, and the ratio of limb muscle mass (ALM) to body mass index (BMI) was used to determine sarcopenia. Multiple logistic regression was performed, and dose-response curves were drawn to evaluate the associations. Results Of the 8802 adults aged 20 to 59 years, 770 (8.7%) were identified as having sarcopenia. Compared to those in the reference group, the participants in the “low”, “moderate”, and “high” total METs groups had lower risks of sarcopenia (low: OR = 0.730, 95% CI = 0.583; 0.915; moderate: OR = 0.643, 95% CI = 0.485; 0.853; high: OR = 0.560, 95% CI = 0.457; 0.687). The risk of sarcopenia decreased in the high-intensity recreational PA group; however, such a significant association was observed only in the high-intensity occupational PA group. The relationship between total METs and sarcopenia showed a nonlinear U-shaped trend. Conclusions A greater intensity of PA is associated with a lower risk of sarcopenia among younger adults, regardless of whether moderate or vigorous PA is performed. Moreover, recreational PA may particularly advantageously contrast with occupational PA in lowering the risk of sarcopenia.

ABSTRACTThe gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A−/−mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

Applying unmanned aerial vehicles (UAVs) and vision-based analysis methods to detect bridge surface damage significantly improves inspection efficiency, but the existing techniques have difficulty in accurately locating damage, making it difficult to use the results to assess a bridge’s degree of deterioration. Therefore, this study proposes a method to generate panoramic bridge surface images using multi-view images captured by UAVs, in order to automatically identify and locate damage. The main contributions are as follows: (1) We propose a UAV-based image-capturing method for various bridge sections to collect close-range, multi-angle, and overlapping images of the surface; (2) we propose a 3D reconstruction method based on multi-view images to reconstruct a textured bridge model, through which an ultra-high resolution panoramic unfolded image of the bridge surface can be obtained by projecting from multiple angles; (3) we applied the Swin Transformer to optimize the YOLOv8 network and improve the detection accuracy of small-scale damages based on the established bridge damage dataset and employed sliding window segmentation to detect damage in the ultra-high resolution panoramic image. The proposed method was applied to detect surface damage on a three-span concrete bridge. The results indicate that this method automatically generates panoramic images of the bridge bottom, deck, and sides with hundreds of millions of pixels and recognizes damage in the panoramas. In addition, the damage detection accuracy reached 98.7%, which is improved by 13.6% when compared with the original network.

Summary: Pancreatic cancer (PC) is a lethal disease and associated with metabolism dysregulation. Nogo-B is related to multiple metabolic related diseases and types of cancers. However, the role of Nogo-B in PC remains unknown. In vitro, we showed that cell viability and migration was largely reduced in Nogo-B knockout or knockdown cells, while enhanced by Nogo-B overexpression. Consistently, orthotopic tumor and metastasis was reduced in global Nogo knockout mice. Furthermore, we indicated that glucose enhanced cell proliferation was associated to the elevation expression of Nogo-B and nuclear factor κB (NF-κB). While, NF-κB, glucose transporter type 1 (GLUT1) and sterol regulatory element-binding protein 1 (SREBP1) expression was reduced in Nogo-B deficiency cells. In addition, we showed that GLUT1 and SREBP1 was downstream target of NF-κB. Therefore, we demonstrated that Nogo deficiency inhibited PC progression is regulated by the NF-κB/GLUT1 and SREBP1 pathways, and suggested that Nogo-B may be a target for PC therapy.

Abstract Background Resistance to immune checkpoint inhibitor (ICI) therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB is a promising drug target as a costimulatory molecule of immune cells, no 4-1BB agonist has been given clinical approval because of severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods HK010 was generated by antibody engineering, and the Fab/antigen complex structure was analyzed using crystallography. The affinity and activity of HK010 were detected by multiple in vitro bioassays, including enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry, and luciferase-reporter assays. Humanized mice bearing human PD-L1-expressing MC38 (MC38/hPDL1) or CT26 (CT26/hPDL1) tumor transplants were established to assess the in vivo antitumor activity of HK010. The pharmacokinetics (PK) and toxicity of HK010 were evaluated in cynomolgus monkeys. Results HK010 was generated as an Fc-muted immunoglobulin (Ig)G4 PD-L1x4-1BB bispecific antibody (BsAb) with a distinguished Fab/antigen complex structure, and maintained a high affinity for human PD-L1 (KD: 2.27 nM) and low affinity for human 4-1BB (KD: 493 nM) to achieve potent PD-1/PD-L1 blockade and appropriate 4-1BB agonism. HK010 exhibited synergistic antitumor activity by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously, and being strictly dependent on the PD-L1 receptor in vitro and in vivo. In particular, when the dose was decreased to 0.3 mg/kg, HK010 still showed a strong antitumor effect in a humanized mouse model bearing MC38/hPDL1 tumors. Strikingly, HK010 treatment enhanced antitumor immunity and induced durable antigen-specific immune memory to prevent rechallenged tumor growth by recruiting CD8+ T cells and other lymphocytes into tumor tissue and activating tumor-infiltrating lymphocytes. Moreover, HK010 not only did not induce nonspecific production of proinflammatory cytokines but was also observed to be well tolerated in cynomolgus monkeys in 5 week repeated-dose (5, 15, or 50 mg/kg) and single-dose (75 or 150 mg/kg) toxicity studies. Conclusion We generated an Fc-muted anti-PD-L1x4-1BB BsAb, HK010, with a distinguished structural interaction with PD-L1 and 4-1BB that exhibits a synergistic antitumor effect by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously. It is strictly dependent on the PD-L1 receptor with no systemic toxicity, which may offer a new option for cancer immunotherapy.

Abstract Purpose Choosing a suitable surgical approach is crucial and challenging for type C pilon fractures. This article aims to explore the clinical efficacy of the medial malleolar window approach for varus-type tibial pilon fractures. Methods A retrospective analysis was conducted on 38 patients with type C varus-type pilon fractures treated between May 2018 and June 2021. In total, 16 cases underwent surgical treatment through the medial malleolar window approach and 22 cases were treated with the traditional anteromedial approach combined with a posterior approach. The operation time, hospitalization time, fracture healing time, the American Orthopedic Foot and Ankle score, Visual Analogue Scale, and complications were recorded to comprehensively evaluate the clinical efficacy of the technique. Fracture reduction quality was evaluated using the criteria proposed by Burwell and Charnley. Results All patients were followed up. No patients presented delayed union or nonunion. Compared with the conventional approach, the medial malleolar window approach had the advantage of better clinical effect recovery and better fracture reduction (P

Abstract Background There is no gold standard for the operative treatment of patients with Müller-Weiss disease (MWD). This study reports the mid-term follow-up results for at least 5 years following talonavicular-cuneiform (TNC) arthrodesis for Müller-Weiss disease. Methods A total of 15 patients undergoing TNC arthrodesis for MWD were retrospectively reviewed between January 2015 and August 2017. Two senior doctors assessed the radiographic results twice at each visit (preoperative, three months after the operation, and final follow-up). The clinical results and complications from preoperative and final follow-up were recorded. Results The mean follow up period was 74.0 (range 64 to 90) months. The calcaneal pitch angle, lateral Meary's angle, anteroposterior (AP) Meary's angle, AP talocalcaneal angle, and talonavicular coverage were significantly different before and three months after the operation (p 0.05). The radiological measurements of the two senior doctors were calculated and found to be moderate to strong (ICC:0.899–0.995). The AOFAS, VAS, and SF-12 scores significantly improved at the last follow-up compared to those before the operation (p

Abstract Background Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety. Methods The antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. Results HuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity. Conclusions This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

Summary: Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFβ1 expression and activates the TGFβ1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

The oxidation of benzyl alcohols is an important reaction in organic synthesis. Traditional methods for benzyl alcohol oxidation have not been widely utilized due to the use of significant amounts of precious metals and environmentally unfriendly reagents. In recent years, electrocatalytic oxidation has gained significant attention, particularly electrochemical anodic oxidation, which offers a sustainable alternative for oxidation without the need for external oxidants or reducing agents. Here, a copper monosubstituted phosphotungstate-based polyacrylate resins (Cu-LPOMs@PPAR) catalyst has been fabricated with immobilization and recyclability using 3D printing technology that can be successfully applied in the electrocatalytic oxidation of benzyl alcohol to benzaldehyde, achieving atom economy and reducing pollution. In this protocol, we obtain benzaldehyde in good yields with excellent functional group toleration under metal-free and oxidant-free conditions. This strategy could provide a new avenue for heterogeneous catalysts in application for enhancing the efficiency and selectivity of electrocatalytic oxidation processes.

Abstract Background Long noncoding RNAs (lncRNAs) are important regulators in tumor progression. However, their biological functions and underlying mechanisms in hypoxia adaptation remain largely unclear. Results Here, we established a correlation between a Chr3q29-derived lncRNA gene and tongue squamous carcinoma (TSCC) by genome-wide analyses. Using RACE, we determined that two novel variants of this lncRNA gene are generated in TSCC, namely LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). RNA-sequencing in 887S or 887L loss-of-function cells identified their common downstream target as Carbonic Anhydrase IX (CA9), a gene known to be upregulated by hypoxia during tumor progression. Mechanistically, our results showed that the hypoxia-augmented 887S and constitutively expressed 887L functioned in opposite directions on tumor progression through the common target CA9. Upon normoxia, 887S and 887L interacted. Upon hypoxia, the two variants were separated. Each RNA recognized and bound to their responsive DNA cis-acting elements on CA9 promoter: 887L activated CA9’s transcription through recruiting HIF1α, while 887S suppressed CA9 through DNMT1-mediated DNA methylation. Conclusions We provided hypoxia-permitted functions of two antagonistic lncRNA variants to fine control the hypoxia adaptation through CA9.

The innovation of structural forms and the increase in the energy-saving requirements of buildings have led to higher requirements regarding the application conditions of steel slag foam concrete (SSFC) to ensure that the SSFC has a lower thermal conductivity and sufficient compressive strength, which has become the primary research object. Through a comprehensive consideration of 7 d compressive strength and thermal conductivity, the recommend mix ratio of SSFC was as follows: maximum SS size = 1.18 mm, water–cement ratio = 0.45, replacement rate of SS = 20–30%. Moreover, a theoretical formula was derived to determine thermal conductivity versus porosity based on fractal theory. The measured values of the foam concrete found elsewhere corroborate the fractal relationship regarding thermal conductivity versus porosity. This fractal relationship offers a straightforward and scientifically sound way to forecast the thermal conductivity of SSFC.

BackgroundDepressive symptoms and mild cognitive impairment (MCI) are highly prevalent in rural China. The study aimed to investigate the longitudinal associations between changes in depressive symptoms and cognitive decline and MCI incidence among Chinese rural elderly individuals.MethodsA 2-year follow-up study was conducted among 1,477 participants from the Anhui Healthy Longevity Survey (AHLS). Depressive symptoms were assessed by the 9-item Patient Health Questionnaire (PHQ-9), and cognitive status was evaluated by the Mini Mental State Examination (MMSE). Multivariable linear regression and logistic regression were employed.ResultsEvery 1-unit PHQ-9 score increase was significantly associated with more cognitive decline (β = 0.157, 95% CI: 0.092, 0.221, p < 0.001) and a higher risk of MCI incidence (OR = 1.063, 95% CI: 1.025, 1.103, p = 0.001). The participants who experienced worsening of depression symptoms had a larger decline in the 2-year MMSE score (β = 0.650, 95% CI: 0.039, 1.261, p = 0.037) and elevated risks of incident MCI (OR = 1.573, 95% CI: 1.113, 2.223, p = 0.010).LimitationsScreening tools rather than standard diagnostic procedures were used in the study. Moreover, the long-term associations still need further exploration since the follow-up time was short.ConclusionsIncreased depressive symptoms were associated with more cognitive decline and higher risks of incident MCI among Chinese rural residents.

Abstract Background Paclitaxel (PTX) has been suggested to be a promising front-line drug for gastric cancer (GC), while P-glycoprotein (P-gp) could lead to drug resistance by pumping PTX out of GC cells. Consequently, it might be a hopeful way to combat drug resistance by inhibiting the out-pumping function of P-gp. Results In this study, we developed a drug delivery system incorporating PTX onto polyethylene glycol (PEG)-modified and oxidized sodium alginate (OSA)-functionalized graphene oxide (GO) nanosheets (NSs), called PTX@GO-PEG-OSA. Owing to pH/thermal-sensitive drug release properties, PTX@GO-PEG-OSA could induced more obvious antitumor effects on GC, compared to free PTX. With near infrared (NIR)-irradiation, PTX@GO-PEG-OSA could generate excessive reactive oxygen species (ROS), attack mitochondrial respiratory chain complex enzyme, reduce adenosine-triphosphate (ATP) supplement for P-gp, and effectively inhibit P-gp’s efflux pump function. Since that, PTX@GO-PEG-OSA achieved better therapeutic effect on PTX-resistant GC without evident toxicity. Conclusions In conclusion, PTX@GO-PEG-OSA could serve as a desirable strategy to reverse PTX’s resistance, combined with chemo/photothermal/photodynamic therapy. Graphic Abstract

Abstract Background CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells’ apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells’ mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). Results HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, l-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43–45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. Conclusion HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

The efficient “One-pot” CuCl2-catalyzed C–S bond coupling reactions were developed for the synthesis of dibenzo[b,f][1,4]thiazepines and 11-methy-ldibenzo[b,f][1,4]thiazepines via 2-iodobenzaldehydes/2-iodoacetophenones with 2-aminobenzenethiols/2,2′-disulfanediyldianilines by using bifunctional-reagent N, N′-dimethylethane-1,2-diamine (DMEDA), which worked as ligand and reductant. The reactions were compatible with a range of substrates to give the corresponding products in moderate to excellent yields.

The cancer stem cells (CSC) are the roots of cancer. The CSC hypothesis may provide a model to explain the tumor cell heterogeneity. Understand the biological mechanism of CSC will help the early detection and cure of cancer. The discovery of the dynamic changes in CSC will be possible by the using of bio-engineering techniques-lineage tracing. However, it is difficult to obtain real-time, continuous, and dynamic live-imaging information using the traditional approaches that take snapshots of time points from different animals. The goal of molecular imaging is to monitor the in situ, continuous molecular changes of cells in vivo. Therefore, the most advanced bioengineering lineage tracing approach, while using a variety of molecular detection methods, will maximize the presentation of CSC. In this review, we first introduce the method of lineage tracing, and then introduce the various components of molecular images to dynamic detect the CSC. Finally, we analyze the current situation and look forward the future of CSC detection.

Rubber-based conductive composites are widely used in sensors, wearable electronic devices and electromagnetic fields. In this work, by using the two-roll milling and hot-pressing process, chopped glass fiber (CGF) and graphene (Gr) as additives, and acrtlinitrile-brtadiene rubber (NBR) as the matrix, a series of anisotropic flexible rubber-based composites were prepared. Using this preparation method, both CGF and Gr additives were directly arranged in the material. When the content of CGF was 1 wt.%, the tensile strength in both the T and W directions of the material reached 27 MPa and 28 MPa, respectively. When the content of CGF was fixed at 1 wt.% and Gr was 1.5 wt.% and the elongation at break in both directions reached 328% and 347%. By focusing on the comparison of the dielectric differences in the T and W directions in the X band, it was found that the directional arrangement of the additives led to differences in the dielectric properties.

Abstract Background Drug resistance prevents the effective treatment of cancers. DNA methylation has been found to participate in the development of cancer drug resistance. Methods We performed the wound-healing and invasion assays to test the effect of the paraoxonase gene PON3 on esophageal cancer (EC) cells. In addition, in vivo EC-derived tumor xenografts in nude mice were generated to test the effect of PON3 on the chemoresistance of EC cells. Results We found that PON3 is hypermethylated in drug-resistant EC cell line K150, which in-return down-regulates its expression. The following experiments by the forced changes of PON3 level in vitro and in vivo demonstrated that the PON3 expression negatively correlates with drug resistance in EC cells. Further wound-healing and invasion assays showed that PON3 suppresses the migration and invasion of EC cells. Conclusion Our data established that PON3 is associated with the EC drug resistance, which may serve as a biomarker for the potential therapeutic treatment of EC.

Abstract Microbiota maintains host tissue homeostasis and influences tissue-resident macrophages. However, the mechanisms by which commensal bacteria in regulating the alveolar macrophages remain unclear. Here, by using an antibiotic-treated (Abt) mouse model, we found commensal bacteria depletion induced lower frequencies and numbers of alveolar macrophages. This effect was accompanied by the altered levels of genes involved in several biological pathways, including M2 macrophage polarization, as determined by gene expression analysis. Alveolar macrophages from the Abt mice had higher protein and gene levels of Arg1, CCL24, IL-13, IL-10, IL-6 and IL-1β, which could be recovered to normal levels by reconstructing commensal bacteria in the upper respiratory of Abt mice. Moreover, alveolar macrophages performed significant enhancement of M2 functions, especially CCL24 secretion, in the Abt mice challenged with B16/F10 melanoma. Adoptive transfer of normal alveolar macrophages or antibody neutralization of CCL24 significantly recovered the decrease of γδT17 cells and rescued the defect anti-tumor response of Abt mice, indicating the elevated amount of alveolar macrophage-derived CCL24 inhibited γδT cell mediated anti-tumor response. In conclusion, we demonstrated the ability of commensal bacteria to maintain alveolar macrophages with a low level of CCL24 production, which was necessary for the normal anti-tumor response in the lung.

Abstract Pd/C was found to be an efficient and convenient metal catalyst for intramolecular C–H arylation reactions in the synthesis of phenanthridinones and dibenzo-α-pyrones. A variety of phenanthridinones and dibenzo-α-pyrones were synthesized under the highly active catalytic system of Pd/C-KOAc-DMA in moderate to excellent yields. The high catalytic activity, high recyclability, low costs, and ease of removal of Pd/C, combined with its commercial availability, render this protocol attractive for both synthetic and industrial applications.

The epithelial cell adhesion molecule (EpCAM) is one of the most commonly used markers of cancer stem cells (CSCs), but the clinical and prognostic significance of EpCAM in gastric cancer (GC) remains disputable. Motivated by heterogeneous and inconclusive results, we conducted a systematic review and meta-analysis to systematically summarize and elucidate the association between EpCAM overexpression and GC patients.The PubMed, Cochrane Library, Medline, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) databases were searched to identify relevant studies. The RevMan 5.3 software was used for the meta-analysis. Fixed-effects or random-effects models were applied depending on the presence of heterogeneity. The pooled odds ratio (ORs) and 95% confidence intervals (CIs) were applied to estimate the associations between EpCAM and gastric cancer. For the significant heterogeneity studies, sensitivity analyses were applied based on the population to test the robustness of the pooled results and identify possible sources of heterogeneity.A total of 11 studies including 1960 GC patients met our inclusion criteria. The results of the meta-analyses revealed that there were significant differences in EpCAM overexpression and tumour size (OR = 2.97, 95% CI: 2.13~4.13, P < 0.00001), the nature of the tissue (OR = 80.30, 95% CI: 29.21~220.81, P < 0.00001), lymph node metastasis (OR = 2.78, 95% CI: 1.23~6.27, P = 0.01), and the cumulative 5-year overall survival rate (OR = 0.54, 95% CI:0.29~0.99, P = 0.05). No significant associations were identified between EpCAM overexpression and gender (OR = 0.89, 95% CI: 0.66~1.19, P = 0.43), age (OR = 1.13, 95% CI: 0.58~2.20, P = 0.73), tumour stage (OR = 2.26, 95% CI: 0.79~6.45, P = 0.13), distant metastasis (OR = 2.15, 95% CI: 0.20~22.69, P = 0.52), TNM stage (OR = 5.14, 95% CI: 0.77~34.37, P = 0.09), Lauren type (OR = 1.18, 95% CI: 0.08~16.45, P = 0.9), differentiation (OR = 1.88, 95% CI: 0.65~5.41, P = 0.24). However, due to significant heterogeneity in tumor stage, lymph node metastasis, TNM stage, differentiation and Lauren type, these results should be taken carefully.The meta-analysis demonstrated that the expression of EpCAM in the gastric cancer group was greater than that in the control group. Moreover, EpCAM overexpression was associated with larger tumour size, lymphnode metastasis and worse prognosis in gastric cancer. Due to significant heterogeneity, the sensitivity analysis suggests that population factor may be an important source of heterogeneity, and these results should be treated with caution. EpCAM may be useful as a novel prognostic factor, and large-scale and well-designed studies are needed to validate our results in the future.

Background: CD4+CD25+ regulatory T (Treg) cells and T-helper 17 (Th17) cells play important roles in acute cerebral infarction (ACI). Our previous findings have suggested that oxidized low-density lipoprotein (Ox-LDL) could influence Treg/Th17 ratio in ACI patients. However, the mechanisms are still not clear. Methods and Results: We evaluated the effects of ox-LDL on Th17/Treg cell apoptosis and proliferation in vitro. Our results demonstrated that with increased ox-LDL concentrations, the frequency and suppressive function of Treg cells was decreased while the frequency of Th17 cells was elevated in control subjects. In addition, AnnexinV+ apoptotic rate, Fas/Fas ligand (FasL) expression, and Caspase-3 activity were escalated in Treg cells while were no significant changes in Th17 cells. Simultaneously, 5-Bromo-29-Deoxyuridine (BrdU) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl Tetrazolium Bromide (MTT) incorporation of Th17 cells was elevated accompanied by upregulated nuclear factor-κB (NF-κB) activity. However, Th17 proliferation was decreased when pre-incubated with Pyrrolidine dithiocarbamate (PDTC, inhibitor of NF-κB activation). Furthermore, there were significant changes induced by ox-LDL in Treg apoptosis, Fas/FasL/Caspase-3 expression of Treg cells, and Th17 proliferation, NF-κB activation of Th17 in ACI patients than in patients with transient ischemic attack (TIA) and control subjects (PPConclusion: These data support that ox-LDL may influence the Th17/Treg balance by modulating Fasmediated Treg apoptosis and NF-κB-associated Th17 proliferation. Ox-LDL also induced a more significant alteration of Treg and Th17 in ACI patients than in TIA and control groups, suggesting a novel role in the pathogenesis of ACI.

A novel banana-shaped molecule using 2,8-Dimethyl-6H,12H-5,11-methanodibenzo [b,f] [1,5]diazocine (Tröger’s base) as bent-core was synthesized via double Carbon-Carbon cross-coupling reaction. The double Sonogashira cross-coupling reaction was optimized by using Pd(PPh3)2Cl2 as catalyst, CuI as cocatalyst and diisopropylamine as base in place of triethylamine. The structure of this compound was confirmed by 1H-NMR, 13C-NMR, Fourier transform infrared (FT-IR) spectroscopy and mass spectrometry.

A combination of electron cooling and rf system is an effective method to compress the beam bunch length in storage rings. A simulation code based on multiparticle tracking was developed to calculate the bunched ion beam cooling process, in which the electron cooling, intrabeam scattering (IBS), ion beam space-charge field, transverse and synchrotron motion are considered. Meanwhile, bunched ion beam cooling experiments have been carried out in the main cooling storage ring (CSRm) of the Heavy Ion Research Facility in Lanzhou, to investigate the minimum bunch length obtained by the cooling method, and study the dependence of the minimum bunch length on beam and machine parameters. The experiments show comparable results to those from simulation. Based on these simulations and experiments, we established an analytical model to describe the limitation of the bunch length of the cooled ion beam. It is observed that the IBS effect is dominant for low intensity beams, and the space-charge effect is much more important for high intensity beams. Moreover, the particles will not be bunched for much higher intensity beam. The experimental results in CSRm show a good agreement with the analytical model in the IBS dominated regime. The simulation work offers us comparable results to those from the analytical model both in IBS dominated and space-charge dominated regimes.

Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy.