Chlorine disinfection to drinking water plays an important role in preventing and controlling waterborne disease outbreaks globally. Nevertheless, little is known about why it enriches the antibiotic ...resistance genes (ARGs) in bacteria after chlorination. Here, ARGs released from killed antibiotic-resistant bacteria (ARB), and culturable chlorine-injured bacteria produced in the chlorination process as the recipient, were investigated to determine their contribution to the horizontal transfer of ARGs during disinfection treatment. We discovered Escherichia coli, Salmonella aberdeen, Pseudomonas aeruginosa and Enterococcus faecalis showed diverse resistance to sodium hypochlorite, and transferable RP4 could be released from killed sensitive donor consistently. Meanwhile, the survival of chlorine-tolerant injured bacteria with enhanced cell membrane permeabilisation and a strong oxidative stress-response demonstrated that a physiologically competent cell could be transferred by RP4 with an improved transformation frequency of up to 550 times compared with the corresponding untreated bacteria. Furthermore, the water quality factors involving chemical oxygen demand (COD
), ammonium nitrogen and metal ions (Ca
and K
) could significantly promote above transformation frequency of released RP4 into injured E. faecalis. Our findings demonstrated that the chlorination process promoted the horizontal transfer of plasmids by natural transformation, which resulted in the exchange of ARGs across bacterial genera and the emergence of new ARB, as well as the transfer of chlorine-injured opportunistic pathogen from non-ARB to ARB. Considering that the transfer elements were quite resistant to degradation through disinfection, this situation poses a potential risk to public health.
The emergence and spread of antibiotic resistance has posed a major threat to both human health and environmental ecosystem. Although the disinfection has been proved to be efficient to control the ...occurrence of pathogens, little effort is dedicated to revealing potential impacts of disinfection on transmission of antibiotic resistance genes (ARGs), particularly for free-living ARGs in final disinfected effluent of urban wastewater treatment plants (UWWTP). Here, we investigated the effects of chlorine disinfection on the occurrence and concentration of both extracellular ARGs (eARGs) and intracellular ARGs (iARGs) in a full-scale UWWTP over a year. We reported that the concentrations of both eARGs and iARGs would be increased by the disinfection with chlorine dioxide (ClO2). Specifically, chlorination preferentially increased the abundances of eARGs against macrolide (ermB), tetracycline (tetA, tetB and tetC), sulfonamide (sul1, sul2 and sul3), β-lactam (ampC), aminoglycosides (aph(2’)-Id), rifampicin (katG) and vancomycin (vanA) up to 3.8 folds. Similarly, the abundances of iARGs were also increased up to 7.8 folds after chlorination. In terms of correlation analyses, the abundance of Escherichia coli before chlorination showed a strong positive correlation with the total eARG concentration, while lower temperature and higher ammonium concentration were assumed to be associated with the concentration of iARGs. This study suggests the chlorine disinfection could increase the abundances of both iARGs and eARGs, thereby posing risk of the dissemination of antibiotic resistance in environments.
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•Impact of chlorination on eARGs pollution in UWWTPs were for the first time reported.•Chlorination disinfection enhanced both eARGs and iARGs pollution.•Extracellular tetM and sul1 were the most dominant eARGs in the final effluent.•E. coli showed a positive correlation with the total eARG concentration after chlorination.
•We observed eARG and iARG pollution in tap water with an evident seasonal pattern.•Extracellular TetC had the highest median level in tap water.•sul1 and sul2 were the most abundant iARGs in tap ...water.•iARG classes were related to the specific physicochemical index of water quality.
Antibiotic resistance genes (ARGs) have gained global attention due to their public health threat. Extracelluar ARGs (eARGs) can result in the dissemination of antibiotic resistance via free-living ARGs in natural environments, where they promote ARB transmission in drinking water distribution systems. However, eARG pollution in tap water has not been well researched. In this study, concentrations of eARGs and intracellular ARGs (iARGs) in tap water, sampled at Tianjin, China, were investigated for one year. Fourteen eARG types were found at the highest concentration of 1.3 × 105 gene copies (GC)/L. TetC was detected in 66.7% of samples, followed by sul1, sul2, and qnrA with the same detection frequency of 41.7%. Fifteen iARGs (including tetA, tetB, tetM, tetQ, tetX, sul1, sul2, sul3, ermB, blaTEM, and qnrA) were continuously detected in all collected tap water samples with sul1 and sul2 the most abundant. Additionally, both eARG and iARG concentrations in tap water presented a seasonal pattern with most abundant prevalence in summer. The concentration of observed intracellular sulfonamide resistance genes showed a significantly positive correlation with total nitrogen concentrations. This study suggested that eARG and iARG pollution of drinking water systems pose a potential risk to human public health.
Adaption to adverse environments plays an important role in bacterial survival and is receiving increasing globe attention now. Here, cultivable chlorine-injured Pseudomonas aeruginosa, produced on ...the chlorination process, was investigated about their resistance to antibiotics. Then, global transcriptional analyses, quantitative PCR (qPCR) validation and antioxidant enzymes measurement were performed to explore the underlying mechanisms. The results showed that chlorine injury enhanced antibiotic resistance in P. aeruginosa and cultivable chlorine-injured P. aeruginosa exposed to 4 mg/L sodium hypochlorite (half of the lethal dose) improved antibiotic resistance against ceftazidime, chloramphenicol and ampicillin by 1.4–5.6 fold. This increase in antibiotic resistance was not hereditable and over expression of the MexEF-OprN efflux pump resulting from oxidative stress contributed to it. These results demonstrate temporal physiological persistence to antibiotics in cultivable chlorine-injured pathogens, suggesting their survival from adverse environments with antibiotic exposure and thereby posing lasting hazards to human health.
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•Chlorine-injury increased antibiotic resistance in P. aeruginosa.•The mechanism of resistance was overexpression of MexEF-OprN.•This process may increase survival of pathogens in the water treatment system.
Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive ...correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho-kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation. We also showed that ANXA1 expression was significantly increased in the NPCs with metastasis relative to NPCs without metastasis and positively correlated with lymphonode and distant metastasis; high ANXA1 expression in the NPC cells promoted in vitro tumor cell migration and invasion and in vivo metastasis. Lastly, we showed that inhibition of autophagy restored the ability of tumor cell migration and invasion, epithelial-mesenchymal transition (EMT)-like alterations and in vivo metastasis in the ANXA1 knockdown NPC cells with autophagy activation; ANXA1-suppresed autophagy induced EMT-like alterations possibly by inhibiting autophagy-mediated degradation of Snail. Our data suggest that ANXA1-suppressed autophagy promotes NPC cell migration, invasion and metastasis by activating PI3K/AKT signaling pathway, highlighting that the activation of autophagy may inhibit metastasis of NPC with high ANXA1 expression.
The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs ...were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse‐transcription polymerase chain reaction (RT‐PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR‐214 was validated to be significantly down‐regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR‐214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR‐214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR‐214. Restoring miR‐214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR‐214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR‐214 on CRC cells. Moreover, miR‐214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down‐regulation of miR‐214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR‐214 may serve as a potential marker to predict survival, and the miR‐214‐FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;60:598–609)
The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S‐1 plus nanoparticle albumin‐bound paclitaxel (Nab‐PTX) as first‐line chemotherapy for advanced ...gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S‐1 in oral doses of 40 mg (BSA <1.25 m2), 50 mg (1.25 ≤ BSA < 1.50 m2) and 60 mg (BSA ≥1.50 m2) b.i.d. on days 1‐14 in combination with Nab‐PTX (120 mg/m2, on days 1 and 8) for each 21‐day cycle. Primary endpoint was progression‐free survival (PFS), and secondary endpoints were overall response rate (ORR), overall survival (OS), disease control rate (DCR), and toxicity. A total of 73 gastric cancer patients with metastatic and measurable lesions were enrolled in the first‐line setting. Median PFS and OS were 9.63 months and 14.60 months, respectively. Four (5.5%) patients had complete responses, 39 (53.4%) had partial responses (PRs), 21 (28.8%) had stable disease, four (5.5%) progressed and five (6.8%) were not evaluable. ORR and DCR were 58.9% and 87.7%, respectively. Most toxicities were mild, and no treatment‐related deaths occurred. Grade 3 to 4 toxicities occurred in 22 patients (30.1%) as follows: leukopenia (13.7%), neutropenia (12.3%), anemia (5.5%), thrombocytopenia (1.4%), diarrhea (6.8%), vomiting (2.7%), stomatitis (1.4%), peripheral neuropathy (1.4%), and hand‐foot syndrome (1.4%). Seven patients achieved good responses and underwent gastrectomy plus metastasectomy. Thirty (41.1%) patients had S‐1 maintenance with a median of four cycles. S‐1 plus Nab‐PTX is an efficient and safe regimen as first‐line treatment for patients with AGC.
As the first phase II study of fluoropyrimidines plus nanoparticle albumin‐bound paclitaxel (Nab‐PTX) in gastric cancer patients, this study found that S‐1 plus Nab‐PTX is an efficient and safe regimen as first‐line treatment for patients with advanced gastric cancer.
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To enhance hexavalent chromium (Cr(VI)) removal performance under acidic conditions, the nanofiltration (NF) membrane with enhanced negative charge was fabricated via introducing 2, ...5-diaminobenzenesulfonic acid (DABSA) into polyamide layer. The control membrane (NF-P) was directly prepared from piperazine and 1, 3, 5-benzenetricarbonyltrichloride. Surface chemical compositions, morphology, surface charge, pore size, permeability and pH-dependent separation performance of the fabricated membranes were characterized. The membranes showed the similar water permeance (∼11.5 L m-2 h−1 bar−1) and Na2SO4 rejections (∼98%) under neutral environments. The DABSA introduced NF membrane (NF-PD) was negatively charged in the pH range of 2.5–11, while the isoelectric point for NF-P was ∼pH 4.0. Cr(VI) removal ability was then evaluated under various concentrations and pH environments. The results indicated that NF-PD showed the better Cr(VI) rejection performance in all tested conditions than NF-P, especially under acidic environments (e.g., pH 4 and pH 5). Moreover, there was a fluctuation of the rejection with the increase of Cr(VI) concentration under acidic environments, which was mainly caused by the formation of Cr2O72− species. The harmful Cr(VI) was efficiently removed by the NF membrane with enhanced negative charge under acidic environments, which indicated the wider application range of the NF membrane.
Extracellular antibiotic resistance genes (eARGs) that help in the transmission and spread of antibiotic-resistant bacteria are emerging environmental contaminants in water, and there is therefore a ...growing need to assess environmental levels and associated risks of eARGs. However, as they are present in low amounts, it is difficult to detect eARGs in water directly with PCR techniques. Here, we prepared a new type of nucleic acid adsorption particle (NAAP) with high capacity and developed an optimal adsorption-elution method to concentrate eARGs from large volumes of water. With this technique, we were able to achieve an eARG recovery rate of above 95% from 10 L of water samples. Moreover, combining this new method with quantitative real-time PCR (qPCR), the sensitivity of the eARG detection was 104 times that of single qPCR, with the detection limit lowered to 100 gene copies (GCs)/L. Our analyses showed that the eARG load, virus load and certain water characteristics such as pH, chemical oxygen demand (CODMn), and turbidity affected the eARGs recovery rate. However, high eARGs recovery rates always remained within the standard limits for natural surface water quality, while eARG levels in water were lower than the detection limits of single qPCR assays. The recovery rates were not affected by water temperature and heterotrophic plate counts (HPC). The eARGs whatever located in the plasmids or the short-length linear DNAs can be recovered from the water. Furthermore, the recovery rate was high even in the presence of high concentrations of plasmids in different natural water (Haihe river, well water, raw water for drinking water, Jinhe river, Tuanbo lake and the Yunqiao reservoir). By this technology, eARGs concentrations were found ranging from (2.70 ± 0.73) × 102 to (4.58 ± 0.47) × 104 GCs/L for the extracellular ampicillin resistance gene and (5.43 ± 0.41) × 102 to (2.14 ± 0.23) × 104 GCs/L for the extracellular gentamicin resistance gene in natural water for the first time, respectively. All these findings suggest that NAAPs have great potential for the monitoring of eARGs pollution in water.
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•We present a technique for eARG recovery with 104 times more sensitive than qPCR.•With our method, eARGs can be concentrated from large volume of water.•We also describe novel nucleic acid adsorption particles with high capacity for eARGs.•We determine eARGs concentration in natural water.
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