Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Soil microbial community characteristics and the influencing factors at different elevations on the eastern slope of Helan Mountain, Northwest China.

As an important bridge connecting aboveground communities and belowground biological processes, soil microorganisms play an important role in regulating belowground ecological processes. The altitudinal changes and driving factors of soil microbial community in mountain ecosystem in arid region are still unclear. We measured soil physicochemical properties at seven altitudes in the range of 1300-2800 m in Helan Mountains, and investigated the understory community composition, soil physicochemical properties, and soil microbial community. The driving factor for soil microbial community was explored by variance partitioning analysis and redundancy analysis. The results showed that the total amount of soil microorganisms and bacterial biomass first increased and then decreased with the increases of altitude, fungi, actinomyces, arbuscular mycorrhizal fungi, Gram-positive bacteria, and Gram-negative bacteria groups showed a gradual increase. The variation of fungal-to-bacterial ratio (F/B) along the altitude showed that the cumulative ability of soil bacteria was stronger than that of fungi at low altitudes, while the pattern is opposite at high altitudes. The ratio of Gram-positive bacteria to Gram-negative bacteria (GP/GN) showed an overall decreasing trend with the increases of altitude, indicating that soil bacteria and organic carbon availability changed from "oligotrophic" to "eutrophication" and from "low" to "high" transition as the altitude increased. Vegetation properties, soil physical and chemical properties jointly accounted for 95.7% of the variation in soil microbial community. Soil organic carbon (SOC), soil water content (SWC), and total nitrogen (TN) were significantly correlated with soil microbial community composition. Our results revealed the distribution pattern and driving factors of soil microbial communities at different elevations on the eastern slope of Helan Mountain, which would provide theoretical basis and data support for further understanding the interaction between plant-soil-microorganisms in arid areas.

Janus Interface Engineering Boosting Visibly Transparent Radiative Cooling for Energy Saving.

Visibly transparent radiative cooling (VTRC) shows great potential in energy-saving buildings or car glasses for lighting and cooling. How to balance the lighting and cooling performance is of significance to VTRC. In addition, the thermal radiative performance on the inner side should also be determined for cooling. Here, we designed a Janus VTRC coating consisting of a thermal emitter, PDMS, and a transparent near-infrared reflector, TiO2/Ag/TiO2. On the outer side, the visible transmittance T̅vis = 0.70, while the solar reflectance R̅solar = 0.40, and the thermal emittance in the atmospheric window ε̅LWIR = 0.94 can be achieved experimentally. On the inner side, the thermal emittance ε̅IR can be 0.90 or 0.01 depending on the substrate (glass or near-infrared reflector), which acts as the radiative conductor or barrier for energy saving in hot or cold internal situations. Compared with glass, the designed PDMS/NIR/glass achieves an average temperature drop of 14.6 °C experimentally. The energy-saving calculation based on seven cities in China shows that the VTRC coating can save 34-44% of the annual cooling energy consumption. This Janus visibly transparent radiative cooling technology with internal and external regulation provides a potential strategy for energy saving under the requirement of simultaneous lighting and cooling.

[Responses of soil microbial community structure to litter inputs.] / åœŸå£¤å¾®ç”Ÿç‰©ç¾¤è½å¯¹æž¯è½ç‰©è¾“å ¥çš„å“åº”.

Litter decomposition is one of the most important ecosystem processes, which plays a critical role in regu-lating nutrient cycling and energy flow in terrestrial ecosystems. The influence of litter inputs on soil microbial community is helpful for understanding the relationship between soil microbial diversity and terrestrial ecosystem function. We conducted a meta-analysis to examine how litter inputs affect soil microbial activity (fungi, bacteria, actinomycetes) and microbial biomass carbon, nitrogen in China. The results showed that compared with non-litter input, soil microbial biomass carbon and nitrogen were significantly increased by 3.9% and 4.4% respectively after litter inputs. Soil fungal PLFA, bacterial PLFA, and total microbial PLFA were increased by 4.0%, 3.1% and 2.4%, respectively. The effects of litter inputs differed significantly with climatic region, annual precipitation, vege-tation type, and soil pH. Under different climate conditions, the responses of soil microbe showed the trend of subtropical monsoon climatic region > temperate monsoon climatic region > temperate continental climatic region, which increased first and then decreased with increasing annual precipitation. Under different vegetation types, the responses of soil microbes showed the trend of broad-leaved forest > grassland ≈ mixed forest > coniferous forest.

Drug resistance characteristics and molecular typing of Escherichia coli isolates from neonates in class A tertiary hospitals: A multicentre study across China.

OBJECTIVES: Escherichia coli is a common pathogen causing invasive bacterial infections in neonates. In recent years, clinical antimicrobial susceptibility testing has demonstrated an increased rate of drug-resistant E. coli infections. This study aimed to analyse the resistance characteristics of E. coli against common antimicrobial agents, and perform multilocus sequence typing (MLST) in clinical strains of E. coli collected from Chinese neonates. METHODS: Culture-positive specimens of E. coli were collected from neonates in seven class A tertiary hospitals located in seven cities across different provinces in China between November 2019 and October 2020. E. coli isolated from these specimens were subjected to antimicrobial susceptibility testing (by broth microdilution method), extended-spectrum ß-lactamase (ESBL) detection, and MLST. RESULTS: A total of 223 E. coli strains were isolated, with an overall resistance rate of 87.4%, an ESBL-positive rate of 48.0%, and a multidrug resistance rate of 42.2%. Among the 20 antimicrobial agents tested, E. coli strains showed the highest resistance rates against cefotaxime (59.2%), trimethoprim/sulfamethoxazole (56.5%), doxycycline (39.9%), ciprofloxacin (36.8%), and aztreonam (31.0%). The resistance rates of E. coli strains isolated from children's hospitals against piperacillin/tazobactam, cefotaxime, ciprofloxacin, trimethoprim/sulfamethoxazole, and carbapenems, were significantly higher than those of strains isolated from maternity and child health hospitals. The primary E. coli multilocus sequence types were ST1193, ST95, ST73, ST410, and ST131. The ESBL production rates and multidrug resistance rates of ST1193, ST410, and ST131 were significantly higher than those of ST95 and ST73. Significantly, more strains of E. coli ST1193 and ST410 were isolated from children's hospitals than from maternity and child health hospitals. CONCLUSIONS: The rates of antimicrobial agent resistance in E. coli isolates from hospitalised neonates in China were high. The increased number of strains of E. coli ST1193 and ST410 was the reason for higher resistance rates to multiple antimicrobial agents in E. coli from children's hospitals compared with those from maternal and child health hospitals.

Highly solar reflectance and infrared transparent porous coating for non-contact heat dissipations.

Passive daytime radiative cooling (PDRC) can dissipate heat to outer space with high solar reflectance ( R ¯ solar ) and thermal emittance ( ε ¯ LWIR ) in the atmospheric transmission window. However, for the non-contact heat dissipation, besides the high R ¯ solar , a high infrared transmittance ( τ ¯ LWIR ) is needed to directly emit thermal radiation through the IR-transparent coating to outer space. In this work, An IR-transparent porous PE (P-PE) coating with R ¯ solar = 0.96 and τ ¯ LWIR = 0.88 was prepared for non-contact heat dissipations. Under the direct sunlight of 860 W m-2, the IR-transparent coating obtained a 4°C lower heater temperature than the normal PDRC coating under the same condition. In addition, the spectral reflectance of the P-PE coating after immersing in air or water changed little, which showed excellent durability for long-term outdoor applications. These results indicate the P-PE coating can be a potential IR-transparent coating for non-contact heat dissipations under direct sunlight.

Efficacy on rabbits with arrhythmia: needling acupoint of Neiguan (PC6) at shallow or deep depth, and retaining needles for 10, 20, or 30 min.

OBJECTIVE: To compare the effects of Neiguan (PC6) acupuncture at different depths and retention time on arrhythmia duration, myocardial tissue morphology, mRNA expression level of L-type calcium channel α1C subunit and Ca2 + -Mg2 + -AtPase activity in tachirrhythmia model of rabbits. METHODS: The tachyarrhythmia model was made by intravenous injection of barium chloride into the ears of rabbits. A total of 56 healthy adult male New Zealand big-eared white rabbits, apply the random number table method, divided into normal control group (group A), model group (group B), shallow needling Neiguan (PC6) 10 min group (group C), shallow needling Neiguan (PC6) 20 min group (group D), shallow needling Neiguan (PC6) 30 min group (group E), deep needling Neiguan (PC6) 10 min group (group F), deep needling Neiguan (PC6) 20 min group (group G), deep needling Neiguan (PC6) 30 min group (group H), 7 animals in each group. Electrocardiograms were used to collect the duration of arrhythmia; hematoxylin-eosin staining method was performed on myocardial tissue, RT-PCR tested the expression of α1C subunit mRNA, and the activity of Ca2 + -Mg2 + -ATPase were quantified by phosphorus determination method. RESULTS: The duration of arrhythmia in each acupuncture treatment group was shortened to varying degrees. Compare to the model group, the tissue damage from barium chloride inducing was improved in the acupuncture group. Compared to the model group, except for group E, most treatment groups had varying degrees of improvement with significantly down-regulated L-type calcium channel α1C subunit mRNA expressions level and increased Ca2+ -Mg2+ -ATPase activity. CONCLUSIONS: The effect of acupuncture at Neiguan (PC6) with different depths and retention time can reduce the duration of arrhythmia induced by barium chloride relatively, improve the induced pathological changes, down regulate L-type calcium channel α1C subunit mRNA expressions level and increase Ca2 + -Mg2 + -ATPase activity. Both the shallow and deep tissues of Neiguan (PC6) may be involved in transmitting acupuncture information. There is an optimal induction period for shallow needling at Neiguan (PC6) to reach the best therapeutic effect.

[Soil enzyme activities and their stoichiometry at different altitudes in Helan Mountains, Northwest China]. / è´ºå °å±±ä¸åŒæµ·æ‹”åœŸå£¤é ¶æ´»æ€§åŠå ¶åŒ–å­¦è®¡é‡ç‰¹å¾.

Understanding altitudinal variation characteristics and driving mechanism of soil enzyme activities and their stoichiometry is of great significance for studying nutrient cycling in fragile mountain forest ecosystems. In this study, we collected soil samples from different altitudes (1380-2438 m) in Helan Mountains to analyze the altitudinal changes in soil physicochemical properties, soil enzyme activities and their stoichiometry and its influencing factors. The results showed that the activities of ß-glucosidase (ßG) and ß-N-acetylglucosaminidase (NAG) and the enzyme activities ratios of soil C/N and soil C/P firstly increased and then decreased with increasing altitude, which all peaked at 2139 m. Alkaline phosphatase (AKP) activities increased with the increases of altitude, with the maximum being found at 2438 m. However, L-leucine aminopeptidase (LAP) activities and soil N/P enzyme activities ratios did not change with increasing altitude. Compared with the soil enzyme stoichiometry in other regions of the world, Helan Mountains showed a certain degree of N limitation. Except for LAP, the activities of the other three enzymes were significantly positively correlated with the ratios of soil organic carbon/total nitrogen, soil organic carbon/total phosphorus, and total nitrogen/total phosphorus, and negatively correlated with pH. The LAP, soil C/P enzyme activities ratios and soil N/P enzyme activities ratios showed significant negative correlation with TP. In addition, AKP was significantly negatively correlated with soil bulk density.

[Changes of the concentrations and stoichiometry of carbon, nitrogen and phosphorus in soil aggregates along different altitudes of Helan Mountains, Northwest China.] / è´ºå °å±±ä¸åŒæµ·æ‹”åœŸå£¤å›¢èšä½“ç¢³æ°®ç£·å«é‡åŠå ¶åŒ–å­¦è®¡é‡ç‰¹å¾å˜åŒ–.

Exploring the distribution patterns of soil nutrients in aggregates of forests along different altitudes in arid and semi-arid areas can provide a theoretical basis for understanding nutrient cycling in vulnerable mountain ecosystems. In this study, we analyzed the distribution and stability of aggregates in the 0-20 cm soil layer along different altitudes (1380-2438 m) of Helan Mountains and measured the storage and stoichiometric characteristics of organic carbon, total nitrogen, and total phosphorus in soil aggregates. Results showed that the main soil aggregates of Helan Mountains changed from micro-aggregates (0.25-0.053 mm) to macro-aggregates (>0.25 mm) with increa-sing elevation. The mean weight diameter (MWD) and geometric mean diameter (GMD) of soil aggregates in high altitude (2139-2248 m) were significantly higher than those in low altitude (1380-1650 m). The content and storage of organic carbon and total nitrogen in soil aggregates of different size fractions were positively correlated with altitude, while the content of total phosphorus fluctuated with the increase in elevation and distributed uniformly in aggregates. Macro-aggregates and micro-aggregates had more contribution to soil nutrient storage than the silt and clay fractions, indicating that the proportion of aggregates with different size fractions was the key factor affecting soil nutrient storage and that macro-aggregates and micro-aggregates were the main carriers of soil nutrients. Moreover, the C:N ratio in aggregates of different size fractions did not change across different altitudes, whereas the C:P and N:P ratio were higher at mid and high elevations than those at low elevations. Our results indicated that the mid and high elevations of Helan Mountains had higher nutrient storage in the surface soil layer, and that higher content of macro-aggregates and micro-aggregates would help to retain organic carbon and nutrients in the soil. Soil nitrogen limitation was strong at low altitude in our study, suggesting that the appropriate amount of nitrogen addition in low altitudes could improve total nitrogen status during forest cultivation.

Designing Mesoporous Photonic Structures for High-Performance Passive Daytime Radiative Cooling.

Passive daytime radiative cooling (PDRC) has drawn significant attention recently for electricity-free cooling. Porous polymers are attractive for PDRC since they have excellent performance and scalability. A fundamental question remaining is how PDRC performance depends on pore properties (e.g., radius, porosity), which is critical to guiding future structure designs. In this work, optical simulations are carried out to answer this question, and effects of pore size, porosity, and thickness are studied. We find that mixed nanopores (e.g., radii of 100 and 200 nm) have a much higher solar reflectance R̅solar (0.951) than the single-sized pores (0.811) at a thickness of 300 µm. With an Al substrate underneath, R̅solar, thermal emittance ε̅LWIR, and net cooling power Pcool reach 0.980, 0.984, and 72 W/m2, respectively, under a semihumid atmospheric condition. These simulation results provide a guide for designing high-performance porous coating for PDRC applications.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2.

Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.

RACO-1 modulates Hippo signalling in oesophageal squamous cell carcinoma.

Oesophageal cancer is one of the most lethal malignancies worldwide, whereas the 5-year survival is less than 20%. Although the detailed carcinogenic mechanisms are not totally clear, recent genomic sequencing data showed dysregulation of Hippo signalling could be a critical factor for oesophageal squamous cell carcinoma (ESCC) progression. Therefore, understanding of the molecular mechanisms that control Hippo signalling activity is of great importance to improve ESCC diagnostics and therapeutics. Our current study revealed RACO-1 as an inhibitory protein for YAP/TEAD axis. Depletion of RACO-1 increases the protein level of YAP and expression of YAP/TEAD target gene. Besides, RACO-1 silencing could promote ESCC cell invasion and migration, which effect could be rescued by YAP depletion in ESCC cells. Immunoprecipitation showed that RACO-1 associated with YAP and promote ubiquitination and degradation of YAP at k48 poly-ubiquitination site. Our research discovered a new regulator of Hippo signalling via modulating YAP stability. RACO-1 could be a promising factor, which serves cancer diagnostics and therapeutics in ESCC patients.

Expression Profile of Osteoclasts Following the Stimulation With Interleukin-23 in Mice.

OBJECTIVES: This study aims to analyze the expression profile of osteoclasts (OCs) following the stimulation with interleukin 23 (IL-23) in mice, which would imply the underlying effects of IL-23 on the function of OCs in inflammatory arthritis. MATERIALS AND METHODS: Mature OCs were induced from bone marrow mononuclear cells of 5 male mice (age 6 weeks; weighing 18-20 g) in the presence of macrophage-colony stimulating factor (50 ng/mL) and receptor activator of nuclear factor kappa B ligand (30 ng/mL) in vitro. The Agilent SurePrint G3 Mouse GE V2.0 Microarray was used to analyze the gene expression profile of OCs stimulated with IL-23 (30 ng/mL) or vehicle. The four major IL-23-modulated genes were validated by quantitative real-time polymerase chain reaction (qPCR) analysis. RESULTS: The expression levels of 23 genes were up-regulated and 32 genes were down-regulated by IL-23 stimulation (fold change ≥1.5 and p value <0.05). Among them, there were 37 genes with assigned gene symbols. Gene ontology analysis showed that the IL-23-regulated messenger ribonucleic acids (mRNAs) were related to positive regulation of leukocyte chemotaxis, chemokine-mediated signaling pathway and C-X-C chemokine receptors binding. The pathway analysis showed that the IL-23-regulated mRNAs were related to chemokine signaling pathway and cytokine-cytokine receptor interaction. The significant up-regulation of chemokine (C-X-C motif) ligand 1 and chemokine (C-X-C motif) ligand 2 induced by IL-23 was confirmed by qPCR. In addition, there were 18 long non-coding RNAs that were regulated by IL-23, while their function needs to be confirmed in the future. CONCLUSION: Expression levels of genes related to chemotaxis in OCs were up-regulated by IL-23 in mice, which imply that IL-23 may facilitate chemotaxis of OCs in inflammatory arthritis.

SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling.

Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion. Depletion SHARPIN increases YAP protein level and YAP/TEAD target genes, such as CTGF and CYR61 in ESCC. Immuno-precipitation assay shows that SHARPIN associates with YAP, promoting YAP degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Our study reveals a novel post-translational mechanism in modulating Hippo signaling in ESCC. Overexpression or activation of SHARPIN could be a promising strategy to target Hippo signaling for ESCC patients.

Non-steroidal Anti-inflammatory Drugs Are Unlikely to Inhibit Radiographic Progression of Ankylosing Spondylitis: A Systematic Review.

Objective: To clarify if non-steroidal anti-inflammatory drugs (NSAIDs) could retard the disease progression of ankylosing spondylitis (AS). Methods: A systematic search of Embase, Pubmed, and the Cochrane Central Register of Controlled Trials (CCRCT) databases was conducted. Structural damage of AS was evaluated using spinal radiographs to assess modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Results: Five full-text papers (from 2 prospective and 2 retrospective studies) were included. Of the 4 studies deemed relevant, 3 reported no significant inhibition of spinal progression in AS patients treated continuously with NSAIDs, as determined by radiograph over 2-3 years. Only the 1st prospective randomized trial demonstrated that 2-year continuous use of celecoxib reduced mean changes in mSASSS of AS patients compared with on-demand treatment. However, the dosage difference of celecoxib between the two groups in the study seemed to be too small to elicit such differences in radiographic progression, while the therapy did not elicit any differences in disease activity, C-reactive protein (CRP) levels or global pain. Of the 3 studies that reported radiographic progression in the subgroup with elevated CRP, only post-hoc analysis of the 1st randomized study revealed that the patients treated continuously with NSAIDs had less radiological progression than those using on-demand NSAIDs. In 2 studies that reported radiographic progression in the patient subgroup with baseline syndesmophytes, both reported that there was no significant inhibition of progression of mSASSS in patients who had received continuous NSAID treatment compared with patients given on-demand NSAIDs. Conclusion: The available evidence suggests that NSAIDs are unable to delay radiographic progression of AS even in patients with elevated CRP levels.

The SIS model with diffusion of virus in the environment.

In this paper, we propose an SIS-type reaction-diffusion equations, which contains both direct transmission and indirect transmission via free-living and spatially diffusive bacteria/virus in the contaminated environment, motivated by the dynamics of hospital infections. We establish the basic reproduction number R0 which can act as threshold level to determine whether the disease persists or not. In particular, if R0<1 then="" the="" disease-free="" equilibrium="" is="" globally="" asymptotically="" stable="" whereas="". For the spatially homogeneous system, we investigate the traveling wave solutions and obtain that there exists a critical wave speed, below which there has no traveling waves, above which the traveling wave solutions may exist for small diffusion coefficient by the geometric singular perturbation method. The finding implies that great spatial transmission leads to an increase in new infection, while large diffusion of bacteria/virus results in the new infection decline for spatially heterogeneous environment.

RNF168 facilitates proliferation and invasion of esophageal carcinoma, possibly via stabilizing STAT1.

Oesophageal cancer ranks as one of the most common malignancy in China and worldwide. Although genome-wide association studies and molecular biology studies aim to elucidate the driver molecules in oesophageal cancer progression, the detailed mechanisms remain to be identified. Interestingly, RNF168 (RING finger protein 168) shows a high frequency of gene amplification in oesophageal cancer from TCGA database. Here, we report an important function for RNF168 protein in supporting oesophageal cancer growth and invasion by stabilizing STAT1 protein. RNF168 gene is amplified in oesophageal cancer samples, which tends to correlate with poor prognosis. Depletion RNF168 causes decreased cell proliferation and invasion in oesophageal cancer cells. Through unbiased RNA sequencing in RNF168 depleted oesophageal cancer cell, we identifies JAK-STAT pathway is dramatically decreased. Depletion RNF168 reduced JAK-STAT target genes, such as IRF1, IRF9 and IFITM1. Immuno-precipitation reveals that RNF168 associates with STAT1 in the nucleus, stabilizing STAT1 protein and inhibiting its poly-ubiquitination and degradation. Our study provides a novel mechanism that RNF168 promoting JAK-STAT signalling in supporting oesophageal cancer progression. It could be a promising strategy to target RNF168 for oesophageal cancer treatment.

Circulating CD8+ T-cell repertoires reveal the biological characteristics of tumors and clinical responses to chemotherapy in breast cancer patients.

PURPOSE: CD8+ T cells are primarily cytotoxic cells that provide immunological protection against malignant cells. Considerable evidence suggests that the T-cell repertoire is closely associated with the host immune response and the development of cancer. In this study, we explored the characteristics of the circulating CD8+ T-cell repertoire and their potential value in predicting the clinical response of breast cancer patients to chemotherapy. EXPERIMENTAL DESIGN: We applied a high-throughput TCR ß-chain sequencing method to characterize the CD8+ T-cell repertoire of the peripheral blood from 26 breast cancer patients. In addition, changes in the circulating CD8+ T-cell repertoire during chemotherapy were analyzed. RESULTS: We found that the HEC ratios of the CD8+ T-cell repertoires from HER2+ breast cancer patients were significantly higher than those of HER2- patients, suggesting that the HER2 protein is released into circulation where it is targeted by CD8+ T cells. Several Vß and CDR3 motifs preferentially used in HER2+ patients were identified. Besides, we found that the circulating CD8+ T-cell repertoires evolved during chemotherapy and correlated with patient clinical responses to chemotherapy. Increased CD8+ T-cell repertoire heterogeneity during chemotherapy was associated with a better clinical response. CONCLUSIONS: Although functional studies of clonally expanded CD8+ T-cell populations are clearly required, our results suggest that the circulating CD8+ T-cell repertoire reflects the characteristics of the tumor-associated biomolecules released into the blood and correlates with the clinical responses of the patients to chemotherapy which might assist in making treatment decisions.