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Biofilms are complex multicellular communities formed by bacteria, and their extracellular polymeric substances are observed as surface-attached or non-surface-attached aggregates. Many types of bacterial species found in living hosts or environments can form biofilms. These include pathogenic bacteria such as Pseudomonas, which can act as persistent infectious hosts and are responsible for a wide range of chronic diseases as well as the emergence of antibiotic resistance, thereby making them difficult to eliminate. Pseudomonas aeruginosa has emerged as a model organism for studying biofilm formation. In addition, other Pseudomonas utilize biofilm formation in plant colonization and environmental persistence. Biofilms are effective in aiding bacterial colonization, enhancing bacterial resistance to antimicrobial substances and host immune responses, and facilitating cell‒cell signalling exchanges between community bacteria. The lack of antibiotics targeting biofilms in the drug discovery process indicates the need to design new biofilm inhibitors as antimicrobial drugs using various strategies and targeting different stages of biofilm formation. Growing strategies that have been developed to combat biofilm formation include targeting bacterial enzymes, as well as those involved in the quorum sensing and adhesion pathways. In this review, with Pseudomonas as the primary subject of study, we review and discuss the mechanisms of bacterial biofilm formation and current therapeutic approaches, emphasizing the clinical issues associated with biofilm infections and focusing on current and emerging antibiotic biofilm strategies.

The myocyte enhancer factor 2B (MEF2B) transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its ammino (N)-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of carboxy (C)-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at serine (S)324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. N-terminal mutations in the transcription factor Myocyte Enhancer Factor 2B (MEF2B) are reported to drive lymphomagenesis. Here, the authors show that lymphoma-associated C-terminal mutations in MEF2B impair its phosphorylation, leading to increased stability and transcriptional activity to promote B-cell lymphomagenesis.

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin‐polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin‐15 (IL15) and investigated the effects HPEI–plasmid IL15 (HPEI–pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI–pIL15 complexes on lung metastases of B16‐F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI–pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K–pIL15 and PEI25K–pIL15, and mice treated with HPEI–pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor‐α and interferon‐γ in the serum also increased in the pIL15‐treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI–pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI–pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. (Cancer Sci 2011; 102: 1403–1409)

FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

PurposeThis paper examines the impact and mechanism of China's digital inclusive finance on rural consumption upgrade. First, the impact of the development of digital inclusive finance on the upgrading of rural household consumption structure is to be theoretically analyzed and empirically tested. Secondly, in terms of heterogeneity analysis, it pays attention to the age heterogeneity of users that digital inclusive finance influencing rural residents' developmental consumption upgrade, which is related to the issue of intergenerational “digital gap”. Thirdly, the mechanism of digital inclusive finance in promoting rural consumption upgrade is to be investigated. Finally, how to promote the role of digital inclusive finance in upgrading the structure of rural consumption to a developmental demand level will be showed.Design/methodology/approachFrom the perspective of the micro-household, this study is conducted by using the instrumental variable (IV) method, with 2SLS model and IV-Tobit model, based on the matched city-level data of Digital Inclusive Financial Index (DIFI) with the Chinese Household Financial Survey (CHFS). “The relief degree of land surface” is an ideal instrumental variable of digital inclusive finance, for including regional altitude difference and terrain factors of regional area, has theoretical influence on the development of digital inclusive finance, and is not affected by other economic variables.FindingsThe conclusions show that the digital inclusive finance plays a significant role in promoting the rural households' developmental consumption, but has no significant effect on the rural households' survival-type consumption and hedonistic consumption. Furthermore, this paper examines the impact and mechanism of China's digital inclusive finance on rural consumption upgrade. First, the impact of the development of digital inclusive finance on the upgrading of rural household consumption structure is to be theoretically analyzed and empirically tested. Secondly, it is discovered that digital inclusive finance is age heterogeneous in promoting the upgrade of consumption structure of rural household, and its effect on the elderly is weaker than that on the young for the intergenerational “digital gap”. Thirdly, these conclusions reveal that the digital inclusive finance does affect the consumption of rural residents through three mechanisms: increasing income and wealth, easing liquidity constraints and facilitating payment methods. Finally, how to promote the role of digital inclusive finance in upgrading the structure of rural consumption to a developmental demand level will be showed.Originality/valueThe current research on the relationship between digital inclusive finance and rural consumption only stays at the level of total rural consumption and has not stressed the structural problems of rural consumption. Can digital inclusive finance promote the upgrade of rural consumption structure? To what level can digital inclusive finance promote the upgrading of rural consumption structure? Therefore, it is of great theoretical value to study the upgrading of rural consumption structure from the micro level. Can the current digital inclusive finance benefit the elderly and help break the vulnerability of the elderly to enjoy finance? In this regard, evidence of heterogeneity remains to be provided.

Purpose LKB1 and FUS1 are two kinds of new tumor suppressor genes as well as early-stage genes in lung cancer. Recent studies showed that LKB1 and FUS1 play important roles in lung carcinogenesis process. We hypothesized that combined gene therapy with LKB1 and FUS1 could inhibit lung cancer growth and development synergistically. Methods In this study, two kinds of tumor suppressor genes, LKB1 and FUS1 , were constructed in an eukaryotic coexpression plasmid pVITRO 2 , and then, we evaluated the synergistic effects of the two genes on anticancer activity and explored the relevant molecular mechanisms. Results We defined coexpression of LKB1 and FUS1 could synergistically inhibited lung cancer cells growth, invasion and migration and induced the cell apoptosis and arrested cell cycle in vitro. Intratumoral administration of liposomes: pVITRO 2 – LKB1 – FUS1 complex (LPs–pVITRO 2 – LKB1–FUS1 ) into subcutaneous lung tumor xenograft resulted in more significant inhibition of tumor growth. Furthermore, intravenous injection of LPs–pVITRO 2 – LKB1–FUS1 into mice bearing experimental A549 lung metastasis demonstrated synergistic decrease in the number of metastatic tumor nodules. Finally, combined treatment with LKB1 and FUS1 prolonged overall survival in lung tumor-bearing mice. Further study showed that the synergistic anti-lung cancer effects of coexpression of LKB1 and FUS1 might be related to upregulation of p-p53, p-AMPK and downregulation of p-mTOR, p-FAK, MMPs, NEDD9, VEGF/R and PDGF/R. Conclusions Our results suggest that combined therapy with eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes may be a novel and efficient treatment strategy for human lung cancer.

FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

Cisplatin is one of the most effective antitumor drugs for non-small cell lung carcinoma (NSCLC) patients. However, its efficacy has encountered a plateau due to its side effects and drug resistance. Inducible nitric oxide (NO) synthase (iNOS) gene therapy has been reported to have antitumor effects in several types of cancers and enhances sensitivity to cisplatin, but the effects of iNOS gene therapy alone or its combination with cisplatin in lung cancer remain unclear. In the current study, we evaluated the effects of cationic liposome (LP)-mediated iNOS gene transfection on enhancing low-dose cisplatin-mediated antitumor effects in the A549 human lung adenocarcinoma cell line in vitro. Furthermore, we examined whether iNOS gene therapy enhances the antitumor effects of low-dose cisplatin in two A549 human lung cancer cell xenograft mouse models. The results revealed that iNOS gene therapy may significantly enhance low-dose cisplatin-mediated inhibition of cell proliferation, invasion, migration and promotion of cell apoptosis in A549 cells. Intratumoral administration of the LP-pVAX-iNOS complex significantly enhanced low-dose cisplatin-mediated suppression of subcutaneous tumor growth. Moreover, intravenous injection of the LP-pVAX-iNOS complex greatly enhanced low-dose cisplatin-mediated inhibition of experimental lung metastasis and prolonged the life span of mice without significant organ-related toxicity in a nude mouse model of lung metastasis compared to the cisplatin alone-treated group. Furthermore, iNOS gene-mediated enhancement of cisplatin-mediated antitumor effects in lung cancer may be related to the attenuation of p-mTOR, MMP2 and the activation of p-p53. Thus, the combination treatment with iNOS gene therapy and cisplatin may be a novel and effective therapeutic strategy for lung cancer.

Background and objective Lung cancer is the most dangerous threating tumor to human's health and life. Metastasis is not only the malignant characteristics of lung cancer, but also the chief cause of failure to cure the disease and of high mortality. Ginsenoside Rg3 has been proved to have obvious effect against tumor. The molecular mechanism of Rg3 against lung cancer cell line will be investigated by using two-dimensional gel electrophoresis in this paper. Methods The IC50 of Rg3 against human high-metastatic large cell lung cancer cell line 95D was determined by MTT. Then 95D cells were treated with Rg3 at the concentration of 0.1×IC50 for 72 h. The total proteins of 95D cell line treated with Rg3 and not treated were separated and protein profiles were obtained by using immobilized PH gradient (IPG)-based two-dimensional gel electrophoresis. The differential expression proteins of 95D cell line treated with Rg3 and not treated were analyzed using image analysis software.15 of differentially expressed prot

Lung cancer is the most dangerous threating tumor to human's health and life. Metastasis is not only the malignant characteristics of lung cancer, but also the chief cause of failure to cure the disease and of high mortality. Ginsenoside Rg3 has been proved to have obvious effect against tumor. The molecular mechanism of Rg3 against lung cancer cell line will be investigated by using two-dimensional gel electrophoresis in this paper. The IC50 of Rg3 against human high-metastatic large cell lung cancer cell line 95D was determined by MTT. Then 95D cells were treated with Rg3 at the concentration of 0.1*IC50 for 72 h. The total proteins of 95D cell line treated with Rg3 and not treated were separated and protein profiles were obtained by using immobilized PH gradient (IPG)-based two-dimensional gel electrophoresis. The differential expression proteins of 95D cell line treated with Rg3 and not treated were analyzed using image analysis software.15 of differentially expressed proteins were further identified usin