Antifungal activity of Cinnamaldehyde derivatives against fluconazole-resistant Candida albicans.

BACKGROUND: Candida albicans is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of C. albicans strains worldwide, it is an urgently necessary to explore alternative therapeutic options. OBJECTIVE: This study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against C. albicans through both in vitro experiments and in vivo murine models and to evaluate their potential as new drug candidates for treating C. albicans. METHODS AND RESULTS: The minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against C. albicans were 25 µg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against C. albicans at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against C. albicans biofilm formation, especially at 8 MIC and 16 MIC concentrations. In C. albicans biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing C. albicans cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 µg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular C. albicans infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by C. albicans, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls. CONCLUSION: The 4-Cl CA exhibited inhibitory effects against C. albicans through both in vivo and in vitro models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.

Optimal sequence of LT for symptomatic BM in EGFR-mutant NSCLC: a comparative study of first-line EGFR-TKIs with/without upfront LT.

BACKGROUND: The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can penetrate blood-brain barrier and are effective for brain metastases (BMs). There is no consensus on the optimal sequence of local therapy (LT) and EGFR-TKIs for symptomatic BM patients because patients suffering neurological symptoms were not enrolled in most clinical trials. METHODS: Non-small cell lung cancer (NSCLC) patients with EGFR mutation (EGFRm) and symptomatic BM receiving first-line osimertinib and aumolertinib from two medical centers were collected. All participants were allocated into the third-generation EGFR-TKIs (TKIs) group and the upfront LT (uLT) plus third-generation EGFR-TKIs (TKIs + uLT) group. Demographic data, survival outcomes, treatment failure patterns, and adverse events were evaluated between the two groups. We also conducted subgroup analyses to explore the impact of BM number on survival outcomes. RESULTS: 86 patients were enrolled, 44 in the TKIs group and 42 in the TKIs + uLT group. There were no significant differences in the short-term response between the groups. TKIs + uLT was associated with significantly longer overall survival (OS) (43 vs. 28 months; hazard ratio [HR], 0.36, 95% confidence interval [CI], 0.17-0.77; p = .011). No differences in progression-free survival (PFS), intracranial PFS (iPFS), failure patterns, or safety were observed. In subgroup analyses of oligo-BM patients, TKIs + uLT could prolong OS (43 vs. 31 months; HR 0.22; 95% CI 0.05-0.92; p = .015). CONCLUSIONS: EGFRm NSCLC patients with symptomatic BM might benefit from uLT, particularly oligo-BM patients. However, larger prospective cohort studies should be carried out to confirm the responses of the TKIs + uLT scheme.

Hydrochar drives reduction in bioavailability of heavy metals during composting via promoting humification and microbial community evolution.

This study presented the effects of hydrochar on humification, heavy metals (HMs) bioavailability and bacterial community succession during composting. Results indicated that hydrochar addition led to elevated composting temperature, 7.3% increase in humic acid (HA), and 52.9% increase in ratio of humic acid to fulvic acid. The diethylene triamine pentacetic acid extractable Zn, Cu, Pb, and Ni were reduced by 19.2%, 36.3%, 37.8%, and 27.1%, respectively, in hydrochar-involved composting system. Furthermore, main mechanisms driving the reduced HMs bioavailability by hydrochar addition were revealed. The addition of hydrochar significantly modified the microbial community structure. Correlation analysis and microbial analysis demonstrated that relative abundance of bacterial groups connected with humification and HMs passivation were increased. Consequently, the HA formation was promoted and the HMs bioavailability were reduced through bacterial bioremediation and HA complexation. This study demonstrates the addition of hydrochar as a promising strategy to mitigate the HMs bioavailability during composting.

Reduction of mobile genetic elements determines the removal of antibiotic resistance genes during pig manure composting after thermal pretreatment.

Animal manure is a primary repository of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs). This work explored the efficiency of ARGs and MGEs removal during pig manure composting after thermal pretreatment (TPC) and the underlying mechanisms. TPC resulted in a decrease of 94.7% and 92.3% in the relative abundance of ARGs and MGEs which was 48.9% and 76.6% lower than control, respectively. Network analysis indicated that reductions of ARGs and MGEs in TPC were relevant to decrease in the amount and abundance of bacterial hosts. Furthermore, total ARGs abundance in TPC was correlated with that of intI1 and Tn916/1545 (P < 0.001). Redundancy analysis supported a leading role of MGEs in ARGs dynamics in TPC. Reduction of MGEs rather than bacterial hosts contributed mainly to ARGs removal in TPC, as revealed by structural equation modeling. In conclusion, TPC was an effective method to treat animal manure containing ARGs.

Electrochemical elimination of Microcystis aeruginosa with boron-doped diamond anode in different electrolyte systems: chemical and biological mechanisms.

The chemical and biological mechanisms of electrochemical elimination of Microcystis aeruginosa (M. aeruginosa) using boron-doped diamond (BDD) anode were comparatively explored in three different electrolytes (chloride, sulfate, and phosphate solutions). The most efficient elimination of M. aeruginosa was observed in chloride solution, which was attributed to the greatest total long-lived oxidants from the favorable formation of active chlorine. Moreover, the high permeability of active chlorine resulted in profound intracellular damages to chlorophyll-a, microcystin-LR (MC-LR), superoxide dismutase (SOD) enzyme, and DNA in the chloride system. The change of membrane permeability and degradation of the released MC-LR induced by active chlorine were further confirmed by the increase of extracellular MC-LR in the initial 5 min and a complete decay in the subsequent 15 min, while the change in morphology of algae cells was insignificant from SEM images. In sulfate and phosphate electrolytes, membrane damages were much more pronounced based on lipid peroxidation observation, although changes in cell morphology was found more significant in phosphate system. The higher concentrations of oxidants (·OH, O3, H2O2, S2O82-) generated in sulfate than in phosphate solution explained the greater efficiency of electrochemical elimination of M. aeruginosa in the sulfate electrolyte in terms of changes of cell density, OD680, chlorophyll-a, MC-LR, lipids, SOD enzyme, and DNA.

Interpretation of high perchlorate generated during electrochemical disinfection in presence of chloride at BDD anodes.

Perchlorate is a disinfection by-product (DBP) of serious health concern. Herein, the long sought mechanism of high perchlorate production during electrochemical disinfection at boron-doped diamond (BDD) anode in the presence of chloride was elucidated. The generated perchlorate at BDD during electrochemical disinfection (in 10 mM NaCl) in 60 min reached 0.125 mM, which was 830 times higher than the EPA standard. In contrast, perchlorate at PbO2 and SnO2 anodes was below the detection limit. Further experiments employing NaClO3 revealed that the conversion ratio from ClO3- to ClO4- in 10 h at BDD (98%) was considerably higher than PbO2 (13%) and SnO2 (12%). Such significant difference among anodes was fully interpreted with a two-step mechanism. The first step is essential to produce ·ClO3 by oxidizing ClO3- at electrodes. Otherwise, the conversion to perchlorate would be impossible even with excessive ·OH, which was verified with the photocatalysis process. The second step is the perchlorate generation with radical reaction between ·ClO3 and ·OH, where the primary role of ·OH was substantiated by scavenging test. Interestingly, the capability of perchlorate production was correlated with free ·OH instead of the total amount of ·OH. Despite the similar abilities of electron transfer between anodes and ClO3-, much higher free ·OH exists at BDD anode than at PbO2 and SnO2 anodes through chronoamperometry experiments and work function characterization, which reasonably provides interpretation of high perchlorate production at BDD anode.

Clinical value of a plasma Epstein-Barr virus DNA assay in the diagnosis of recurrent or metastatic nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: To evaluate the diagnostic value of Epstein-Barr virus (EBV) DNA in nasopharyngeal carcinoma (NPC) patients with locoregional or distant recurrence. METHODS: Articles related to the diagnosis of recurrent or metastatic NPC by the detection of EBV DNA in plasma or serum were retrieved from different databases. Sensitivity, specificity, summary receiver operating characteristic (SROC) curves, and likelihood ratios were pooled to assess the diagnostic value of individual diagnostic tests. RESULTS: This meta-analysis pooled 25 eligible studies including 2496 patients with NPC. The sensitivity, specificity, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) of EBV DNA in the diagnosis of NPC were 0.858 (95% confidence interval (CI): 0.801-0.901), 0.890 (95% CI: 0.866-0.909), 7.782 (95% CI: 6.423-9.429) and 0.159 (95% CI: 0.112-0.226), respectively. The diagnostic odds ratio (DOR) was 48.865 (95% CI: 31.903-74.845). The SROC for EBV DNA detection was 0.93 (95% CI: 0.90-0.95). CONCLUSION: The detection of EBV DNA for the diagnosis of recurrent or metastatic NPC has good sensitivity and specificity and might be helpful in monitoring recurrent or metastatic NPC.

Synchronous primary carcinomas of the prostate, thyroid and rectum: case report and review of the literature.

We report a case of rectal cancer with an initial symptom of rectal bleeding. The clinical, morphological, immunohistochemical, and imaging findings supported a diagnosis of synchronous primary carcinoma of the prostate, rectal adenocarcinoma, and papillary thyroid tumor. The patient, whose poor cardiac function contraindicated surgery, underwent long-course chemoradiotherapy and hormonal therapy. The patient is currently asymptomatic, with stable disease and an improved quality of life. To our knowledge, synchronous primary carcinomas of the prostate, thyroid, and rectum are extremely rare in the literature. There are few published reports addressing parallel treatment and outcomes when such a synchronous diagnosis is made; we share here our experience in formulating a treatment plan.

Subcellular mechanism of Escherichia coli inactivation during electrochemical disinfection with boron-doped diamond anode: A comparative study of three electrolytes.

Although the identification of effective oxidant species has been extensively studied, yet the subcellular mechanism of bacterial inactivation has never been clearly elucidated in electrochemical disinfection processes. In this study, subcellular mechanism of Escherichia coli inactivation during electrochemical disinfection was revealed in terms of comprehensive factors such as cell morphology, total organic components, K(+) leakage, membrane permeability, lipid peroxidation, membrane potential, membrane proteins, intracellular enzyme, cellular ATP level and DNA. The electrolysis was conducted with boron-doped diamond anode in three electrolytes including chloride, sulfate and phosphate. Results demonstrated that cell inactivation was mainly attributed to damage to the intracellular enzymatic systems in chloride solution. In sulfate solution, certain essential membrane proteins like the K(+) ion transport systems were eliminated. Thus, the pronounced K(+) leakage from cytosol resulted in gradual collapse of the membrane potential, which would hinder the subcellular localization of cell division-related proteins as well as ATP synthesis and thereby lead to the bacterial inactivation. Remarkable lipid peroxidation was observed, while the intracellular damage was negligible. In phosphate solution, the cells sequentially underwent overall destruction as a whole cell with no captured intermediate state, during which the organic components of the cells were mostly subjected to mineralization. This study provided a thorough insight into the bacterial inactivation mechanism on the subcellular level.

Synergetic antibacterial activity of reduced graphene oxide and boron doped diamond anode in three dimensional electrochemical oxidation system.

A 100% increment of antibacterial ability has been achieved due to significant synergic effects of boron-doped diamond (BDD) anode and reduced graphene oxide (rGO) coupled in a three dimensional electrochemical oxidation system. The rGO, greatly enhanced by BDD driven electric field, demonstrated strong antibacterial ability and even sustained its excellent performance during a reasonable period after complete power cut in the BDD-rGO system. Cell damage experiments and TEM observation confirmed much stronger membrane stress in the BDD-rGO system, due to the faster bacterial migration and charge transfer by the expanded electro field and current-carrying efficiency by quantum tunnel. Reciprocally the hydroxyl-radical production was eminently promoted with expanded area of electrodes and delayed recombination of the electron-hole pairs in presence of the rGO in the system. This implied a huge potential for practical disinfection with integration of the promising rGO and the advanced electrochemical oxidation systems.