A case study showing highly traceable sources of bacteria on surfaces of university buildings.

University students predominantly spend their time indoors, where prolonged exposure raises the risk of contact with microorganisms of concern. However, our knowledge about the microbial community characteristics on university campus and their underpinnings is limited. To address it, we characterized bacterial communities from the surfaces of various built environments typical of a university campus, including cafeterias, classrooms, dormitories, offices, meeting rooms, and restrooms, in addition to human skin. The classrooms harbored the highest α-diversity, while the cafeterias had the lowest α-diversity. The bacterial community composition varied significantly across different building types. Proteobacteria, Actinobacteria, Firmicutes, Bacteroidetes, and Cyanobacteria were common phyla in university buildings, accounting for more than 90 % of total abundance. Staphylococcus aureus was the most abundant potential pathogen in classrooms, dormitories, offices, restrooms, and on human skin, indicating a potential risk for skin disease infections in these buildings. We further developed a new quantitative pathogenic risk assessment method according to the threat of pathogens to humans and found that classrooms exhibited the highest potential risk. The fast expectation-maximization algorithm identified 59 %-86 % of bacterial sources in buildings, with the human skin as the largest bacterial source for most buildings. As the sources of bacteria were highly traceable, we showed that homogeneous selection, dispersal limitation, and ecological drift were major ecological forces that drove community assembly. Our findings have important implications for predicting the distribution and sources of indoor dust bacterial communities on university campus.

Quorum Sensing Enhances Direct Interspecies Electron Transfer in Anaerobic Methane Production.

Direct interspecies electron transfer (DIET) provides an innovative way to achieve efficient methanogenesis, and this study proposes a new approach to upregulate the DIET pathway by enhancing quorum sensing (QS). Based on long-term reactor performance, QS enhancement achieved more vigorous methanogenesis with 98.7% COD removal efficiency. In the control system, methanogenesis failure occurred at the accumulated acetate of 7420 mg of COD/L and lowered pH of 6.04, and a much lower COD removal of 41.9% was observed. The more significant DIET in QS-enhancing system was supported by higher expression of conductive pili and the c-Cyts cytochrome secretion-related genes, resulting in 12.7- and 10.3-fold improvements. Moreover, QS enhancement also improved the energy production capability, with the increase of F-type and V/A-type ATPase expression by 6.3- and 4.2-fold, and this effect probably provided more energy for nanowires and c-Cyts cytochrome secretion. From the perspective of community structure, QS enhancement increased the abundance of Methanosaeta and Geobacter from 54.3 and 17.6% in the control to 63.0 and 33.8%, respectively. Furthermore, the expression of genes involved in carbon dioxide reduction and alcohol dehydrogenation increased by 0.6- and 7.1-fold, respectively. Taken together, this study indicates the positive effects of QS chemicals to stimulate DIET and advances the understanding of the DIET methanogenesis involved in environments such as anaerobic digesters and sediments.

Research on microbial community structure and treatment of dye wastewater with the enhancement of activated sludge by magnetic field at low temperature.

This study characterized the effect of different magnetic field (MF) intensities (10-40 mT) on the degradation of dye wastewater by activated sludge and the diversity of the microbial community at a low temperature (5 °C). The examined MF range promoted the degradation of dye wastewater by the microorganisms in the activated sludge at a low temperature. It was found that the optimal degradation performance was achieved at 30 mT. Additionally, the maximum degradation efficiency of COD and chromaticity (66.30% and 60.87%, respectively) were also achieved at 30 mT and the peak TTC-dehydrogenase activity (TTC-DHA) was 9.44 mg TF g-1 SS. Furthermore, it was revealed that MF enhancement increased the richness and diversity of activated sludge microorganisms, thus promoting the growth and reproduction of activated sludge microorganisms at low temperatures. Bacterial taxa known to effectively participate in the degradation of pollutants by activated sludge were enriched at 30 mT. The dominant bacteria under 30 mT were Flavobacterium, Hydrogenophaga, Gemmatimonadaceae, Zoogloea, Saprospiraceae, Pseudomonas, and Geothrix.

CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-ß/Smad signaling.

Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prognosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-ß/Smad signaling pathway to promote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.

NOD2 inhibits the proliferation of esophageal adenocarcinoma cells through autophagy.

AIM: To study the regulatory mechanism of NOD2 in the inhibition of esophageal adenocarcinoma cell proliferation. METHODS: Cell experiments: after confirming the decrease in NOD2 expression in esophageal adenocarcinoma, we overexpressed NOD2 in esophageal adenocarcinoma cells via lentivirus, compared and verified the changes in esophageal adenocarcinoma cell proliferation before and after NOD2 overexpression, and compared the overexpression group with the control group by mRNA sequencing to identify pathways that may affect cell proliferation. Then, the autophagy level of multiple groups were assessed, and the results were verified by rescue experiments. In vivo experiments: we administered esophageal adenocarcinoma cells to nude mice to form tumors under their skin and then injected the tumors with NOD2 overexpression lentivirus and negative control lentivirus. After a period of time, the growth curve of the tumor was generated, and the tumor was removed to generate sections. Ki67 was labeled with immunohistochemistry to verify cell proliferation, and the protein was extracted from the tissue to detect the molecular indices of the corresponding pathway. RESULTS: Upregulation of NOD2 expression inhibited the proliferation of esophageal adenocarcinoma cells. Upregulation of NOD2 expression increased the autophagy level of esophageal adenocarcinoma cells via ATG16L1. After ATG16L1 was inhibited, NOD2 had no significant effect on autophagy and proliferation of esophageal adenocarcinoma cells. Enhanced autophagy in esophageal adenocarcinoma cell lines inhibited cell proliferation. In vivo, the upregulation of NOD2 expression improved the autophagy level of tumor tissue and inhibited cells proliferation. CONCLUSION: NOD2 can activate autophagy in esophageal adenocarcinoma cells through the ATG16L1 pathway and inhibit cell proliferation.

Ginsenosides Rg1 and CK Control Temozolomide Resistance in Glioblastoma Cells by Modulating Cholesterol Efflux and Lipid Raft Distribution.

Background: Cholesterol efflux and lipid raft redistribution contribute to attenuating temozolomide resistance of glioblastoma. Ginsenosides are demonstrated to modify cholesterol metabolism and lipid raft distribution, and the brain distribution and central nervous effects of whose isoforms Rb1, Rg1, Rg3, and CK have been identified. This study aimed to reveal the role of Rb1, Rg1, Rg3, and CK in the drug resistance of glioblastoma. Methods: The effects of ginsenosides on cholesterol metabolism in temozolomide-resistant U251 glioblastoma cells were evaluated by cholesterol content and efflux assay, confocal laser, qRT-PCR, and Western blot. The roles of cholesterol and ginsenosides in temozolomide resistance were studied by CCK-8, flow cytometry, and Western blot, and the mechanism of ginsenosides attenuating resistance was confirmed by inhibitors. Results: Cholesterol protected the survival of resistant U251 cells from temozolomide stress and upregulated multidrug resistance protein (MDR)1, which localizes in lipid rafts. Resistant cells tended to store cholesterol intracellularly, with limited cholesterol efflux and LXRα expression to maintain the distribution of lipid rafts. Ginsenosides Rb1, Rg1, Rg3, and CK reduced intracellular cholesterol and promoted cholesterol efflux in resistant cells, causing lipid rafts to accumulate in specific regions of the membrane. Rg1 and CK also upregulated LXRα expression and increased the cytotoxicity of temozolomide in the presence of cholesterol. We further found that cholesterol efflux induction, lipid raft redistribution, and temozolomide sensitization by Rg1 and CK were induced by stimulating LXRα. Conclusions: Ginsenosides Rg1 and CK controlled temozolomide resistance in glioblastoma cells by regulating cholesterol metabolism, which are potential synergists for temozolomide therapy.

Association of long-term visit-to-visit variability of HbA1c and fasting glycemia with hypoglycemia in type 2 diabetes mellitus.

Background: Self-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM. Methods: In this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell's C method. Results: After adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03-1.16; P < 0.01) and HMA events (HR: 1.11; 95% CI: 1.03-1.20; P < 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31-1.49; P < 0.01) and HMA events (HR: 1.46; 95% CI: 1.35-1.57; P < 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P < 0.01). Conclusions: Increased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability. Trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Trifecta achievement in patients undergoing partial nephrectomy: a systematic review and meta-analysis of predictive factors

ABSTRACT Purpose The predictors of trifecta achievement in partial nephrectomy (PN) were poorly inquired and remained a controversial area of discovery. To evaluate predictive factors of trifecta achievement in patients undergoing PN. Materials and Methods A systematic literature search was performed to identify relevant articles. Only studies focusing on postoperative trifecta achievement and exploring its predictor with multivariable analyses were included. The trifecta achievement was defined as negative surgical margins, warm ischemia time <25 minutes, and no complications. Merged odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the predictive effect. Results Thirteen studies with 7066 patients meeting the inclusion criteria were included. The rate of trifecta achievement ranged from 43.3% to 78.6%. Merged results showed that preoperative eGFR (OR: 1.01, 95% CI: 1.00, 1.02, P=0.02), operative time (OR: 0.99, 95% CI: 0.99, 1.00, P=0.02), estimated blood loss (OR: 1.00, 95% CI: 1.00, 1.00, P <0.001), tumor size (OR: 0.70, 95% CI: 0.58, 0.84, P <0.001), medium (OR: 0.39, 95% CI: 0.18, 0.84, P=0.02) and high PADUA score (OR: 0.23, 95% CI: 0.08, 0.64, P=0.005) were independently associated with trifecta achievement. A publication bias was identified for tumor size. Sensitivity analysis confirmed the stability of result for tumor size. Conclusions Larger tumor size, medium and high PADUA score are associated with decreased probability of trifecta achievement. After verifying by further high-quality studies, these variables can be incorporated into tools to predict probability of trifecta achievement during clinical practice.

Tracking virulence genes and their interaction with antibiotic resistome during manure fertilization.

Antibiotic resistance genes, collectively termed as antibiotic resistome, are regarded as emerging contaminants. Antibiotics resistome can be highly variable in different environments, imposing environmental safety concern and public health risk when it is in conjunction with pathogenic bacteria. However, it remains elusive how pathogenic bacteria interact with antibiotic resistome, making it challenging to assess microbial risk. Here, we examined the presence and relative abundance of bacterial virulence genes representing potential pathogens in swine manure, compost, compost-amended soil, and unamended agricultural soil in five suburban areas of Beijing, China. The absolute abundances of virulence genes were marginally significantly (p < 0.100) increased in compost-amended soils than unamended soil, revealing potential health risks in manure fertilization. The composition of potential pathogens differed by sample types and was linked to temperature, antibiotics, and heavy metals. As antibiotics can confer pathogens the resistance to clinic treatment, it was alarming to note that virulence genes tended to co-exist with antibiotic resistance genes, as shown by prevalently positive links among them. Collectively, our results demonstrate that manure fertilization in agriculture might give rise to the development of potentially antibiotic-resistant pathogens, unveiling an environmental health risk that has been frequently overlooked.

Reduction of microbial diversity in grassland soil is driven by long-term climate warming.

Anthropogenic climate change threatens ecosystem functioning. Soil biodiversity is essential for maintaining the health of terrestrial systems, but how climate change affects the richness and abundance of soil microbial communities remains unresolved. We examined the effects of warming, altered precipitation and annual biomass removal on grassland soil bacterial, fungal and protistan communities over 7 years to determine how these representative climate changes impact microbial biodiversity and ecosystem functioning. We show that experimental warming and the concomitant reductions in soil moisture play a predominant role in shaping microbial biodiversity by decreasing the richness of bacteria (9.6%), fungi (14.5%) and protists (7.5%). Our results also show positive associations between microbial biodiversity and ecosystem functional processes, such as gross primary productivity and microbial biomass. We conclude that the detrimental effects of biodiversity loss might be more severe in a warmer world.

Electrospun flexible core-sheath PAN/PU/ß-CD@Ag nanofiber membrane decorated with ZnO: enhance the practical ability of semiconductor photocatalyst.

It is necessary to effectively separate photocatalytic materials from water bodies and reuse catalysts for industrial wastewater treatment. Herein, a novel nanofiber membrane with enhanced light absorption and reusability of photocatalytic materials was prepared. The three-dimensional porous structure of the nanofibers helps the photocatalyst efficiently degrade pollutants. Specifically, a high-efficiency photocatalyst carrier with a nanofiber structure (PAN/PU/ß-CD@Ag nanofiber membrane) was prepared by electrospinning and a simple silver plating process, and then ZnO NPs were synthesized in situ on the nanofiber membrane during the hydrothermal process. Under visible-light irradiation, the ZnO-loaded PAN/PU/ß-CD@Ag nanofiber membranes exhibited excellent photocatalytic performance for the degradation of methylene blue (MB, 71.5%) and tetracycline hydrochloride (TCH, 70.5%). Additionally, a possible pathway of charge migration in this system was proposed. This design may provide a new idea for the preparation of visible-light photocatalytic nanofiber membranes and their treatments of wastewater containing dyes and hormones.

Bacteria are better predictive biomarkers of environmental estrogen transmission than fungi.

The heavy reliance on estrogens in the food industry worldwide greatly contributes to the environmental release of these compounds, begetting serious public concern of their fate. Various microorganisms capable of estrogen degradation, and their catabolic pathways, have been isolated, suggesting that they can eliminate estrogens in both engineered and natural environments. Nonetheless, it remains little understood as to how potential estrogen-degrading microorganisms are distributed within those habitats. An estrogen transmission chain from swine manure to compost, compost-amended soil, and neighboring agricultural soil was investigated in five suburban areas of Beijing, China. The concentrations of major estrogen classes decreased by > 90% from manure to soils, which did not co-vary with environmental antibiotics and heavy metal concentrations. Many bacterial taxa, such as Lactobacillus and Bacteroides, could serve as potential biomarkers of estrogen concentrations, while fungi were only occasionally accurate. To explain this phenomenon, stochasticity was found to be dominant in shaping the fungal communities across all samples, while deterministic selection, arising from biotic interactions, was important for bacterial communities. Metabolic genes involved in oxidizing phenol and catalyzing oxidative ring cleavage of catechol were detected, co-varying with estrogen concentrations. These findings are important as identifying microbial biomarkers of estrogen dynamics, spanning the levels of both taxonomy and functional genes, provides valuable information for assessing estrogen bioavailability and biomarking of estrogen fate in the environment.

Nutrient supply controls the linkage between species abundance and ecological interactions in marine bacterial communities.

Nutrient scarcity is pervasive for natural microbial communities, affecting species reproduction and co-existence. However, it remains unclear whether there are general rules of how microbial species abundances are shaped by biotic and abiotic factors. Here we show that the ribosomal RNA gene operon (rrn) copy number, a genomic trait related to bacterial growth rate and nutrient demand, decreases from the abundant to the rare biosphere in the nutrient-rich coastal sediment but exhibits the opposite pattern in the nutrient-scarce pelagic zone of the global ocean. Both patterns are underlain by positive correlations between community-level rrn copy number and nutrients. Furthermore, inter-species co-exclusion inferred by negative network associations is observed more in coastal sediment than in ocean water samples. Nutrient manipulation experiments yield effects of nutrient availability on rrn copy numbers and network associations that are consistent with our field observations. Based on these results, we propose a "hunger games" hypothesis to define microbial species abundance rules using the rrn copy number, ecological interaction, and nutrient availability.

PTBP3 regulates proliferation of lung squamous cell carcinoma cells via CDC25A-mediated cell cycle progression.

BACKGROUND: The roles of Polypyrimidine tract-binding protein 3 (PTBP3) in regulating lung squamous cell carcinoma (LUSC) cells progression is unclear. The aim of this study was to investigate the role of PTBP3 in LUSC. METHODS: Expression and survival analysis of PTBP3 was firstly investigated using TCGA datasets. Quantitative reverse transcription PCR and Western blot were performed to detect PTBP3 expression in clinical samples. Moreover, cell counting kit 8 (CCK-8) assays, colony formation assays and in vivo tumor formation assays were used to examine the effects of PTBP3 on LUSC cell proliferation. RNA-sequence and analysis explores pathways regulated by PTBP3.Flow cytology was used analyzed cell cycle. Cell cycle-related markers were analyzed by Western blot. RESULTS: PTBP3 was found to be overexpressed in LUSC tissues compared with normal tissues. High PTBP3 expression was significantly correlated with poor prognosis. In vitro and vivo experiments demonstrated that PTBP3 knockdown caused a significant decrease in the proliferation rate of cells. Bioinformatics analysis showed that PTBP3 involved in cell cycle pathway regulation in LUSC. Furthermore, PTBP3 knockdown arrested cell cycle progression at S phase via decreasing CDK2/Cyclin A2 complex. In addition, downregulation of PTBP3 significantly decreased the expression of CDC25A. CONCLUSIONS: Our results suggest that PTBP3 regulated LUSC cell proliferation via cell cycle and might be a potential target for molecular therapy of LUSC.

Trifecta achievement in patients undergoing partial nephrectomy: a systematic review and meta-analysis of predictive factors.

PURPOSE: The predictors of trifecta achievement in partial nephrectomy (PN) were poorly inquired and remained a controversial area of discovery. To evaluate predictive factors of trifecta achievement in patients undergoing PN. MATERIALS AND METHODS: A systematic literature search was performed to identify relevant articles. Only studies focusing on postoperative trifecta achievement and exploring its predictor with multivariable analyses were included. The trifecta achievement was defined as negative surgical margins, warm ischemia time <25 minutes, and no complications. Merged odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the predictive effect. RESULTS: Thirteen studies with 7066 patients meeting the inclusion criteria were included. The rate of trifecta achievement ranged from 43.3% to 78.6%. Merged results showed that preoperative eGFR (OR: 1.01, 95% CI: 1.00, 1.02, P=0.02), operative time (OR: 0.99, 95% CI: 0.99, 1.00, P=0.02), estimated blood loss (OR: 1.00, 95% CI: 1.00, 1.00, P <0.001), tumor size (OR: 0.70, 95% CI: 0.58, 0.84, P <0.001), medium (OR: 0.39, 95% CI: 0.18, 0.84, P=0.02) and high PADUA score (OR: 0.23, 95% CI: 0.08, 0.64, P=0.005) were independently associated with trifecta achievement. A publication bias was identified for tumor size. Sensitivity analysis confirmed the stability of result for tumor size. CONCLUSIONS: Larger tumor size, medium and high PADUA score are associated with decreased probability of trifecta achievement. After verifying by further high-quality studies, these variables can be incorporated into tools to predict probability of trifecta achievement during clinical practice.

Hsa_circ_0005576 promotes osimertinib resistance through the miR-512-5p/IGF1R axis in lung adenocarcinoma cells.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib-resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR-512-5p and subsequently upregulate the miR-512-5p-targeted insulin-like growth factor 1 receptor. Rescue assays indicated that miR-512-5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR-512-5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.

Identifying and Validating Potential Biomarkers of Early Stage Lung Adenocarcinoma Diagnosis and Prognosis.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. At present, most patients with LUAD are diagnosed at an advanced stage, and the prognosis of advanced LUAD is poor. Hence, we aimed to identify novel biomarkers for the diagnosis and treatment of early stage LUAD and to explore their predictive value. METHODS: The microarray datasets GSE63459, GSE27262, and GSE33532 were searched, and the differentially expressed genes (DEGs) were obtained using GEO2R. The DEGs were subjected to gene ontology (GO) and pathway enrichment analyses using METASCAPE. A protein-protein interaction (PPI) network was plotted with STRING and visualized by Cytoscape. Module analysis of the PPI network was performed using MCODE. Overall survival (OS) analysis and analysis of the mRNA expression levels of genes identified by MCODE were performed with UALCAN. Western blot analysis of hub genes in LUAD patients, MTS assays, and clonogenic assays were performed to test the effects of the hub genes on cell proliferation in vitro. RESULTS: A total of 341 DEGs were obtained, which were mainly enriched in terms related to blood vessel development, growth factor binding, and extracellular matrix organization. A PPI network consisting of 300 nodes and 1140 edges was constructed, and a significant module including 15 genes was identified. Elevated expression of ASPM, CCNB2, CDCA5, PRC1, KIAA0101, and UBE2T was associated with poor OS in LUAD patients. In the protein level, the hub gene was overexpressed in LUAD patients. In vitro experiments showed that knockdown of the hub genes in the LUAD cell lines could promote cell proliferation. CONCLUSIONS: DEGs are potential biomarkers for early stage lung adenocarcinoma and could have utility for the diagnosis and predicting treatment efficacy.

Prognostic Significance of Sarcomatoid Differentiation in Patients With Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: To date, the prognostic value of sarcomatoid differentiation in patients having metastatic renal cell carcinoma (mRCC) remains inconclusive. A systematic review and meta-analysis were conducted. MATERIALS AND METHODS: Relevant literatures were obtained from PubMed, Embase, and Cochrane Library published prior to May, 2020. All patients were diagnosed with mRCC and treated with surgery, cytokine therapy, targeted therapy, and immunotherapy. Sarcomatoid differentiation in the pathological specimens was identified. Each endpoint [overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS)] was assessed using a multivariable adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Fifteen observational studies having 5,828 patients with mRCC were included. The merged results showed that patients presenting sarcomatoid differentiation had a significantly inferior OS (HR: 2.26, 95% CI: 1.82-2.81; P < 0.001), PFS (HR: 2.28, 95% CI: 1.63-3.19; P < 0.001), and CSS (HR: 2.27, 95% CI: 1.51-3.40; P < 0.001) compared to those without sarcomatoid differentiation. Subgroup analysis based on publication year, patient population, country, number of cases, and NOS score did not change the direction of results. A significant publication bias was identified for OS, but no publication bias was identified for PFS. Moreover, sensitivity analysis also verified the robustness of the results. CONCLUSION: This study suggested that sarcomatoid differentiation was correlated to unfavorable clinical outcomes in mRCC and may be a poor prognostic factor incorporating to prognostic models for mRCC patients.

Modulation of dynamic modes by interplay between positive and negative feedback loops in gene regulatory networks.

A positive and a negative feedback loop can induce bistability and oscillation, respectively, in biological networks. Nevertheless, they are frequently interlinked to perform more elaborate functions in many gene regulatory networks. Coupled positive and negative feedback loops may exhibit either oscillation or bistability depending on the intensity of the stimulus in some particular networks. It is less understood how the transition between the two dynamic modes is modulated by the positive and negative feedback loops. We developed an abstract model of such systems, largely based on the core p53 pathway, to explore the mechanism for the transformation of dynamic behaviors. Our results show that enhancing the positive feedback may promote or suppress oscillations depending on the strength of both feedback loops. We found that the system oscillates with low amplitudes in response to a moderate stimulus and switches to the on state upon a strong stimulus. When the positive feedback is activated much later than the negative one in response to a strong stimulus, the system exhibits long-term oscillations before switching to the on state. We explain this intriguing phenomenon using quasistatic approximation. Moreover, early switching to the on state may occur when the system starts from a steady state in the absence of stimuli. The interplay between the positive and negative feedback plays a key role in the transitions between oscillation and bistability. Of note, our conclusions should be applicable only to some specific gene regulatory networks, especially the p53 network, in which both oscillation and bistability exist in response to a certain type of stimulus. Our work also underscores the significance of transient dynamics in determining cellular outcome.

Krüppel-like factor 4 promotes c-Met amplification-mediated gefitinib resistance in non-small-cell lung cancer.

Gefitinib has been widely used in the first-line treatment of advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9-14 months of treatment. This study revealed that Krüppel-like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c-Met-overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib-resistant NSCLC cell lines without c-Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib-resistant NSCLC cells with c-Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib-sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells by inhibiting the expression of apoptosis-related proteins under gefitinib treatment and activating the c-Met/Akt signaling pathway by decreasing the inhibition of ß-catenin on phosphorylation of c-Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c-Met overexpression.