Therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development through HSPA5/NFκB/CD55 pathway in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.

Is there a role for growth status in distinguishing gallbladder adenomas from cholesterol polyps? - A retrospective study based on 520 cholecystectomy patients.

INTRODUCTION: Gallbladder adenomas have cancerous potential and occur in 4-8.9% of gallbladder polyps. The growth status (size progression and growth rate during follow-up) of polyps and their effectiveness for predicting adenomas are poorly defined. Herein, we compared adenomas and cholesterol polyps based on the growth status and evaluated the reported risk factors in predicting neoplasm. METHODS: We enrolled 520 patients who underwent preoperative ultrasonic follow-up more than 6 months with post-cholecystectomy pathologically confirmed gallbladder polyps. The patients were classified into adenoma and cholesterol polyp groups. Growth status, clinical characteristics, laboratory data, ultrasonic findings were reviewed and compared between the groups. RESULTS: Seventy-nine adenomas and 441 cholesterol polyps were analyzed. The mean diameter of adenomas (cholesterol polyps) was 7.24 ± 4.36 mm (6.23 ± 2.88 mm) in the initial and 12.06 ± 4.61 mm (10.05 ± 2.95 mm) in the preoperative examination. The median size progression (range) of polyps in the cholesterol polyps [3 (0, 22)] mm was smaller than that in adenomas [4 (0, 21)] mm (p = .075). The mean growth rate of adenomas (1.07 ± 1.33 mm/6 months) was slightly faster than in cholesterol polyps (0.83 ± 1.04 mm/6 months) (p = .338). The indicators significantly associated with adenomas were age >49.5 years, lack of gallbladder polyps/cholelithiasis family history, polyp size >11.5 mm and solitary polyp (p = .005, p = .027, p = .001, and p = .021, respectively). CONCLUSION: Growth status was not a valuable modality to distinguishing gallbladder adenomas from cholesterol polyps. Risk factors such as age, polyp size, and solitary polyp were effective in predicting adenomas.

Whole-body hyperthermia combined with chemotherapy and intensity-modulated radiotherapy for treatment of advanced nasopharyngeal carcinoma: a retrospective study with propensity score matching.

BACKGROUND: Several studies have reported the combination of intracavity or cervical lymph node hyperthermia with chemoradiotherapy (CRT) to improve clinical outcomes in nasopharyngeal carcinoma (NPC), but the combination with whole-body hyperthermia (WBH) for treating NPC is unexplored. We aimed to assess the efficacy of the combination of radiotherapy, chemotherapy and WBH in patients with locoregionally advanced NPC. METHODS: Between July 2008 and November 2012, 239 newly diagnosed NPC patients were enrolled in a pre-propensity score-matched cohort, including 193 patients who received CRT (CRT group) and 46 who underwent CRT with WBH (HCRT group). The feasibility and clinical outcomes of both groups were evaluated and toxicities assessed. Survival rates were assessed using the Kaplan-Meier method, log-rank test and Cox regression. RESULTS: Following propensity score matching, 46 patients from each group were included. The 5-year overall survival (OS) rates were 65.2% in the CRT group and 80.3% in the HCRT group (p=.027). In contrast, the other survival outcomes at 5 years were similar between the groups: locoregional recurrence-free survival (LRRFS), 74.7% vs. 87.6% (p=.152); distant metastasis-free survival (DMFS), 67.4% vs. 77.9% (p=.125); and progression-free survival (PFS), 53.1% vs. 69.2% (p=.115). In the multivariate analyses, the only two independent predictors of OS were clinical stage and HCRT. CONCLUSIONS: These results suggest that WBH, when combined with CRT, can improve the OS of patients with advanced NPC.

Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia.

BACKGROUND: Microglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized. METHODS: We used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia. RESULTS: We found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR. CONCLUSIONS: Our findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.

A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma.

BACKGROUND: Lymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), is predictive of poor survival; however, the associated clinical characteristics and underlying molecular mechanisms remain largely unknown. METHODS: We performed weighted gene co-expression network analysis to construct gene co-expression networks and investigate the relationship between key modules and the LOI clinical phenotype. Functional enrichment and KEGG pathway analyses were performed with differentially expressed genes. A protein-protein interaction network was constructed using Cytoscape, and module analysis was performed using MCODE. Prognostic value, expression analysis, and survival analysis were conducted using hub genes; GEPIA and the Human Protein Atlas database were used to determine the mRNA and protein expression levels of hub genes, respectively. Multivariable Cox regression analysis was used to establish a prognostic risk formula and the areas under the receiver operating characteristic curve (AUCs) were used to evaluate prediction efficiency. Finally, potential small molecular agents that could target LOI were identified with DrugBank. RESULTS: Ten co-expression modules in two key modules (turquoise and pink) associated with LOI were identified. Functional enrichment and KEGG pathway analysis revealed that turquoise and pink modules played significant roles in HNSCC progression. Seven hub genes (CNFN, KIF18B, KIF23, PRC1, CCNA2, DEPDC1, and TTK) in the two modules were identified and validated by survival and expression analyses, and the following prognostic risk formula was established: [risk score = EXPDEPDC1 * 0.32636 + EXPCNFN * (- 0.07544)]. The low-risk group showed better overall survival than the high-risk group (P < 0.0001), and the AUCs for 1-, 3-, and 5-year overall survival were 0.582, 0.634, and 0.636, respectively. Eight small molecular agents, namely XL844, AT7519, AT9283, alvocidib, nelarabine, benzamidine, L-glutamine, and zinc, were identified as novel candidates for controlling LOI in HNSCC (P < 0.05). CONCLUSIONS: The two-mRNA signature (CNFN and DEPDC1) could serve as an independent biomarker to predict LOI risk and provide new insights into the mechanisms underlying LOI in HNSCC. In addition, the small molecular agents appear promising for LOI treatment.

miR-483-5p decreases the radiosensitivity of nasopharyngeal carcinoma cells by targeting DAPK1.

Recurrence or metastasis resulting from radioresistance are the main challenges for the treatment of nasopharyngeal carcinoma (NPC). A great deal of evidence supports the role of abnormal expression of miRNAs in radioresistance and malignancy. In some cancers, miR-483-5p is associated with inferior disease-specific survival. Therefore, we investigated the role of miR-483-5p in NPC radiosensitivity and the mechanism by which the miR-483-5p affects the radiosensitivity of NPC cells. In this study, we show that the overexpression of miR-483-5p decreases the radiosensitivity of NPC cells in vitro and in vivo. Mechanistically, miR-483-5p exerts these functions by decreasing radiation-induced apoptosis and DNA damage, and by increasing NPC cell colony formation, via targeting death-associated protein kinase 1 (DAPK1). Finally, our results confirm that the upregulation of miR-483-5p is correlated with advanced clinical stage and inferior overall survival of patients with NPC. These findings provide novel insights into our understanding of the molecular mechanisms underlying therapy failure in NPC. Modulation of miR-483-5p and DAPK1 levels may provide a new approach for increasing the radiosensitivity of these tumors.

Risk factors and prediction-score model for distant metastasis in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

The objective of this study is to identify the risk factors and construct a prediction-score model for distant metastasis (DM) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). A total of 520 nonmetastatic NPC patients were analysed retrospectively. The independent risk factors for DM were tested by multivariate Cox regression analysis. The prediction-score model was established according to the regression coefficient. The median follow-up was 88.4 months. The 5-year DM rate was 15.1%. N2-3, primary tumour volume of nasopharynx (GTVnx) >24.56 cm(3), haemoglobin change after treatment (ΔHGB) >25.8 g/L, albumin-globulin ratio (AGR) ≤1.34, pretreatment neutrophil-lymphocyte ratio (NLR) >2.81 and pretreatment serum lactate dehydrogenase (LDH) >245 U/L were significantly adverse independent predictive factors for DM. Three subgroups were defined based on the prediction-score model: low risk (0-2), intermediate risk (3-4) and high risk (5-8). The 5-year DM rates were 4.6, 21.8 and 50.8%, respectively (P < 0.001). The areas under the curve for DM in the prediction-score model and the UICC/AJCC staging system seventh edition were 0.748 and 0.627, respectively (P < 0.001). The scoring model is useful in evaluating the risk of DM in IMRT-treated NPC patients and guiding future therapeutic trials. Further prospective study is needed.

The effect of oxoguanine glycosylase 1 rs1052133 polymorphism on colorectal cancer risk in Caucasian population.

Human oxoguanine glycosylase 1 (OGG1) is an important part of the base excision repair pathway in the DNA repair. Numerous epidemiological studies have evaluated the association between OGG1 rs1052133 polymorphism and the risk of colorectal cancer, but the results of these studies from the Caucasian population were conflicting. To derive a more precise assessment on the association between OGG1 rs1052133 polymorphism and risk of colorectal cancer in Caucasian population, we performed a meta-analysis. The odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the association. Thirteen case-control studies with a total of 4,103 cases and 5,400 controls were finally included into the meta-analysis. Meta-analysis of all 13 studies showed that OGG1 rs1052133 polymorphism was significantly associated with the risk of colorectal cancer in Caucasian population (Cys versus Ser OR = 1.20, 95% CI = 1.03-1.39, P = 0.02; CysCys versus SerSer OR = 1.44, 95% CI = 1.04-2.00, P = 0.03; CysCys versus SerSer/SerCys OR = 1.39, 95% CI = 1.15-1.67, P = 0.0005). In the sensitivity analysis, omitting each study one at a time had no obvious influence on the pooled OR, which confirmed the stability of meta-analysis. The meta-analysis suggests that OGG1 rs1052133 polymorphism is significantly associated with the risk of colorectal cancer in Caucasian population.

Identifying the temporal contributors and their interactions during dynamic formation of black tea cream.

Tea cream formed in hot and strong tea infusion while cooling deteriorates quality and health benefits of tea. However, the interactions among temporal contributors during dynamic formation of tea cream are still elusive. Here, by deletional recombination experiments and molecular dynamics simulation, it was found that proteins, caffeine (CAF), and phenolics played a dominant role throughout the cream formation, and the contribution of amino acids was highlighted in the early stage. Furthermore, CAF was prominent due to its extensive binding capacity and the filling complex voids property, and caffeine-theaflavins (TFs) complexation may be the core skeleton of the growing particles in black tea infusion. In addition to TFs, the unidentified phenolic oxidation-derived products (PODP) were confirmed to contribute greatly to the cream formation.

Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay.

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

An integrated immunochromatographic device for C-reactive protein detection using hierarchical dendritic gold nanostructure films.

Immunochromatographic test strips typically consist of sample pad, conjugate pad, nitrocellulose membrane, and absorbent pad. Even minute variations in the assembly of these components can lead to inconsistent sample-reagent interactions, thereby reducing reproducibility. In addition, the nitrocellulose membrane is susceptible to damage during assembly and handling. To address this issue, we propose to replace the sample pad, conjugate pad, and nitrocellulose membrane with hierarchical dendritic gold nanostructure (HD-nanoAu) films to develop a compact integrated immunochromatographic strip. The strip uses quantum dots as a background fluorescence signal and employs fluorescence quenching to detect C-reactive protein (CRP) in human serum. A 5.9 µm thick HD-nanoAu film was electrodeposited on an ITO conductive glass by the constant potential method. The wicking kinetics of the HD-nanoAu film was thoroughly investigated, and the results indicated that the film exhibited favorable wicking properties, with a wicking coefficient of 0.72 µm ms-0.5. The immunochromatographic device was fabricated by etching three interconnected rings on HD-nanoAu/ITO to designate sample/conjugate (S/C), test (T), and control (C) regions. The S/C region was immobilized with mouse anti-human CRP antibody (Ab1) labeled with gold nanoparticles (AuNPs), while the T region was preloaded with polystyrene microspheres decorated with CdSe@ZnS quantum dots (QDs) as background fluorescent material, followed by mouse anti-human CRP antibody (Ab2). The C region was immobilized with goat anti-mouse IgG antibody. After the samples were added to the S/C region, the excellent wicking properties of the HD-nanoAu film facilitated the lateral flow of the CRP-containing sample toward the T and C regions after binding to AuNPs labeled with CRP Ab1. In the T region, CRP-AuNPs-Ab1 formed sandwich immunocomplexes with Ab2, and the fluorescence of QDs was quenched by AuNPs. The ratio of fluorescence intensity in the T region to that in the C region was used to quantify CRP. The T/C fluorescence intensity ratio was negatively correlated with the CRP concentration in the range of 26.67-853.33 ng mL-1 (corresponding to 300-fold diluted human serum), with a correlation coefficient (R2) of 0.98. The limit of detection was 15.0 ng mL-1 (corresponding to 300-fold diluted human serum), and the range of relative standard deviation: 4.48-5.31%, with a recovery rate of 98.22-108.33%. Common interfering substances did not cause significant interference, and the range of relative standard deviation: 1.96-5.51%. This device integrates multiple components of conventional immunochromatographic strips onto a single HD-nanoAu film, resulting in a more compact structure that improves the reproducibility and robustness of detection, making it promising for point-of-care testing applications.

Highly sensitive paper-based immunoassay: Combining nanomaterials modified cellulose with covalent and oriented immobilization of antibody.

Among the analytical tools, paper-based analytical devices (PADs) have become a leading alternative for point-of care testing (POCT). In this study, PADs were fabricated using an office laser printer. Then, the paper zone was modified with graphene oxide (GO) and pyrene derivatives, which provide a sufficient amount of carboxylic groups for conjugating antibodies. At an optimal pH, antibodies were covalently bound onto carboxylated cellulose surface in an oriented manner through a two-step strategy: electrostatic adsorption was followed by EDC/NHS coupling. α-fetoprotein (AFP) as a detection model, we compared with cellulose powder modified and unmodified paper zone. The results showed the color intensity and color uniformity on GO modified paper was improved. The activity of immobilized antibodies on GO/1-pyrenebutyric acid (GO/PBA) modified was three times higher than that of GO modified and about 1.8-fold higher than that of GO/1-pyrenecarboxylic acid (GO/PCA) modified. The GO/PBA modified paper-based immunoassay has enhanced sensitivity and low detection limit. A linear correlation between color intensity and concentration of AFP in the range of 0.01～16.5 ng mL-1 with a detection limit of 9.0 pg mL-1 were achieved, respectively. The obtained results point towards rapid, sensitive, and specific early diagnosis of liver cancer at the point of care and other low-resource settings.

Liubao tea extract ameliorates ovalbumin-induced allergic asthma by regulating gut microbiota in mice.

Asthma, a chronic airway inflammatory disease, has a complicated pathogenesis and limited therapeutic treatment. Evidence shows that the intestinal microbiota exhibits crucial functional interaction with asthma syndrome. Liubao tea (LBT), a type of postfermented tea in China, positively modulates gut microbiota. However, the potential benefits of LBT extract (LBTE) for allergic asthma are still not understood. Herein, the anti-inflammatory effects of LBTE and its modulation of the gut microbiota of asthmatic mice induced by ovalbumin were explored. The results demonstrate that LBTE significantly inhibited airway hyper-responsiveness and restrained the proliferation of proinflammatory cytokines and inflammatory cells associated with allergic asthma. Additionally, LBTE suppressed inflammatory infiltration, mucus secretion, and excessive goblet cell production by downregulating the gene expression of inflammatory indicators. Interestingly, fecal microbiota transplantation results further implied that the modulation of LBTE on gut microbiota played an essential role in alleviating airway inflammatory symptoms of allergic asthma.

Corrigendum: Epigenetic-mediated downregulation of zinc finger protein 671 (ZNF671) predicts poor prognosis in multiple solid tumors.

[This corrects the article DOI: 10.3389/fonc.2019.00342.].

Synergistic Phototherapy-Molecular Targeted Therapy Combined with Tumor Exosome Nanoparticles for Oral Squamous Cell Carcinoma Treatment.

Oral squamous cell carcinoma (OSCC) contributes to more than 90% of all oral malignancies, yet the performance of traditional treatments is impeded by limited therapeutic effects and substantial side effects. In this work, we report a combinational treatment strategy based on tumor exosome-based nanoparticles co-formulating a photosensitizer (Indocyanine green) and a tyrosine kinase inhibitor (Gefitinib) (IG@EXOs) for boosting antitumor efficiency against OSCC through synergistic phototherapy-molecular targeted therapy. The IG@EXOs generate distinct photothermal/photodynamic effects through enhanced photothermal conversion efficiency and ROS generation, respectively. In vivo, the IG@EXOs efficiently accumulate in the tumor and penetrate deeply to the center of the tumor due to passive and homologous targeting. The phototherapy effects of IG@EXOs not only directly induce potent cancer cell damage but also promote the release and cytoplasmic translocation of Gefitinib for achieving significant inhibition of cell proliferation and tumor angiogenesis, eventually resulting in efficient tumor ablation and lymphatic metastasis inhibition through the synergistic phototherapy-molecular targeted therapy. We envision that the encouraging performances of IG@EXOs against cancer pave a new avenue for their future application in clinical OSCC treatment.

A pH-Activatable Copper-Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo-Immunotherapy against Aggressive Cancers.

Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic-utilization efficiency, and undesired off-target toxicity. Herein, it is reported that peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2 O2 into hydroxyl radicals (·OH) in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.

Continental scale deciphering of microbiome networks untangles the phyllosphere homeostasis in tea plant.

INTRODUCTION: Assembly and co-occurrence of the host co-evolved microbiota are essential ecological and evolutionary processes, which is not only crucial for managing individual plant fitness but also ecological function. However, understanding of the microbiome assembly and co-occurrence in higher plants is not well understood. The tea plant was shown to contribute the forest fitness due to the microbiome assembled in the phyllosphere; the landscape of microbiome assembly in the tea plants and its potential implication on phyllosphere homestasis still remains untangled. OBJECTIVES: This study aimed to deciphering of the microbiome networks of the tea plants at a continental scale. It would provide fundamental insights into the factors driving the microbiome assembly, with an extended focus on the resilience towards the potential pathogen in the phyllosphere. METHODS: We collected 225 samples from 45 locations spanning approximately 2000-km tea growing regions across China. By integration of high-throughput sequencing data, physicochemical properties profiling and bioinformatics analyses, we investigated continental scale microbiome assembly and co-occurrence in the tea plants. Synthetic assemblages, interaction assay and RT-qPCR were further implemented to analyze the microbial interaction indexed in phyllosphere. RESULTS: A trade-off between stochastic and deterministic processes in microbiomes community assembly was highlighted. Assembly processes were dominated by deterministic processes in bulk and rhizosphere soils, and followed by stochastic processes in roots and leaves with amino acids as critical drivers for environmental selection. Sphingobacteria and Proteobacteria ascended from soils to leaves to sustain a core leaf taxa. The core taxa formed a close association with a prevalent foliar pathogen in the co-occurrence network and significantly attenuated the expression of a set of essential virulence genes in pathogen. CONCLUSION: Our study unveils the mechanism underpinning microbiome assembly in the tea plants, and a potential implication of the microbiome-mediated resilience framework on the phyllosphere homeostasis.

Efficacy of concurrent chemoradiotherapy alone for loco-regionally advanced nasopharyngeal carcinoma: long-term follow-up analysis.

BACKGROUND: To analysis the clinical outcomes of concurrent chemoradiotherapy (CCRT) alone based on 10-year results for loco-regionally advanced nasopharyngeal carcinoma (LANPC), so as to provide evidence for individualized treatment strategy and designing appropriate clinical trial for different risk LANPC patients. METHODS: Consecutive patients with stage III-IVa (AJCC/UICC 8th) were enrolled in this study. All patients received radical intensity-modulated radiotherapy (IMRT) and concurrent cisplatin chemotherapy (CDDP). The hazard ratios (HRs) of death risk in patients with T3N0 was used as baseline, relative HRs were calculated by a Cox proportional hazard model to classify different death risk patients. Survival curves for the time-to-event endpoints were analyzed by the Kaplan-Meier method and compared using the log-rank test. All statistical tests were conducted at a two-sided level of significance of 0.05. RESULTS: A total of 456 eligible patients were included. With 12-year median follow-up, 10-year overall survival (OS) was 76%. 10-year loco-regionally failure-free survival (LR-FFS), distant failure-free survival (D-FFS) and failure-free survival (FFS) were 72%, 73% and 70%, respectively. Based on the relative hazard ratios (HRs) of death risk, LANPC patients were classified into 3 subgroups, low-risk group (T1-2N2 and T3N0-1) contained 244 patients with HR < 2; medium-risk group (T3N2 and T4N0-1) contained 140 patients with HR of 2 - 5; high-risk group (T4N2 and T1-4N3) contained 72 patients with HR > 5. The 10-year OS for patients in low-, medium-, and high-risk group were 86%, 71% and 52%, respectively. Significantly differences of OS rates were found between each of the two groups (low-risk group vs. medium-risk group, P < 0.001; low-risk group vs. high-risk group, P < 0.001; and medium-risk group vs. high-risk group, P = 0.002, respectively). Grade 3-4 late toxicities included deafness/otitis (9%), xerostomia (4%), temporal lobe injury (5%), cranial neuropathy (4%), peripheral neuropathy (2%), soft tissue damage (2%) and trismus (1%). CONCLUSIONS: Our classification criteria demonstrated that significant heterogeneity in death risk among TN substages for LANPC patients. IMRT plus CDDP alone maybe suitable for low-risk LANPC (T1-2N2 or T3N0-1), but not for medium- and high-risk patients. These prognostic groupings provide a practicable anatomic foundation to guide individualized treatment and select optimal targeting in the future clinical trials.

Upregulated Long Non-coding RNA Lnc-MRPL39-2:1 Induces the Growth and Invasion of Nasopharyngeal Carcinoma by Binding to HuR and Stabilizing ß-Catenin mRNA.

Long non-coding RNAs (lncRNAs) have been to regulate tumor progression and therapy resistance through various molecular mechanisms. In this study, we investigated the role of lncRNAs in nasopharyngeal carcinoma (NPC) and the underlying mechanism. Using lncRNA arrays to analyze the lncRNA profiles of the NPC and para-tumor tissues, we detected the novel lnc-MRPL39-2:1, which was validated by in situ hybridization and by the 5' and 3' rapid amplification of the cDNA ends. Further, its role in NPC cell growth and metastasis was verified in vitro and in vivo. The researchers conducted the RNA pull-down assays, mass spectrometry (MS), dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and the MS2-RIP assays were then used to identify the lnc-MRPL39-2:1-interacting proteins and miRNAs. We found that lnc-MRPL39-2:1, which was highly expressed in in NPC tissues, was related to a poor prognosis in NPC patients. Furthermore, lnc-MRPL39-2:1 was shown to induce the growth and invasion of NPC by interacting directly with the Hu-antigen R (HuR) to upregulate ß-catenin expression both in vivo and in vitro. Lnc-MRPL39-2:1 expression was also suppressed by microRNA (miR)-329. Thus, these findings indicate that lnc-MRPL39-2:1 is essential in NPC tumorigenesis and metastasis and highlight its potential as a prognostic marker and therapeutic target for NPC.

Modeling and Robust Tracking Decoupling Control of a Coaxial Unmanned Helicopter Based on the Improved Alternating Direction Method of Multipliers.

In this paper, a robust tracking control strategy based on the dynamic feedback linearization method is proposed for the nonlinear and highly coupled dynamic characteristics of coaxial unmanned helicopter. The mathematical model of the coaxial unmanned helicopter is determined by fault analysis. Then the high-order state system is dynamically feedback linearized by extending the state variables, and the dynamic characteristics of the zeros are analyzed according to the expected tracking characteristics of the inner loop. The pole placement of the subsystem realizes robust monitoring of height and position commands by designing robust compensators. On this basis, an outer loop proportional derivative controller is designed for the horizontal positioning subsystem to realize position tracking. Loop tracking simulation ensures the good separation characteristics of feedback linearization method, and trajectory tracking simulation under fault conditions ensures the control ability and durability of the designed controller.