关键词： Microbiology   Biotechnology  

摘要： Biofilm plays an important role in the community and hospital-acquired infections. Especially E. coli biofilm that contributes towards the significant part of medical devices associated with microbial infections. OmpR/EnvZ, a two-component system, is one of the regulatory mechanisms involved in transcription regulation in response to environmental osmolarity changes. The main objective of this study was to elucidate the role of the OmpR/EnvZ two-component system in regulating the biofilm through curli and fimbriae (FimH gene), a contrary approach towards biofilm inhibition. In this study, the CRISPRi technique was used to suppress the expression of the OmpR gene. The RT-PCR assay was performed to quantify mRNA gene expression of curli and biofilm producing genes, and the data were further confirmed by different microscopic, spectroscopic and biofilm quantification assay (Crystal Violet). It is the first time we have shown downregulation of the OmpR gene in biofilm causing clinical isolates of E. coli, which further suppressed the FimH gene, leading to biofilm reduction. The crystal violet assay and microscopic studies also confirmed the biofilm reduction. We conclude that the OmpR gene of the OmpR/EnvZ two-component system could be one of the targets for biofilm mediated infection intervention. Our findings open new vistas to explore the pathways and targets to control biofilm mediated infections.

关键词： TEHTM   In silico   T-screen assay   hER and hAR reporter gene assays   Steroidogenesis   Medical devices  

摘要： Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As plasticizers are known to easily migrate when in contact with fatty biological fluids, patient exposure to TEHTM is highly probable. However, there is currently no data on the potential endocrine-disrupting effects of its human metabolites. To evaluate the effects of TEHTM metabolites on endocrine activity, they were first synthesized and their effects on estrogen, androgen and thyroid receptors, as well as steroid synthesis, were investigated by combining in vitro and in silico approaches. Among the primary metabolites, only 4-MEHTM (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, while three diesters were TR antagonists at non-cytotoxic concentrations. These results were completed by docking experiments which specified the ER and TR isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol level and reduced the testosterone level in H295R cell culture supernatants. The oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or on steroid hormone synthesis. Among the fourteen metabolites, these data showed that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in vitro. However, by comparing the concentrations of the primary metabolites found in human urine with the active concentrations determined in bioassays, it can be suggested that the metabolites will not be active with regard to estrogen, androgen, thyroid receptors and steroidogenesis-mediated effects.

关键词： angiogenesis   gastric adenocarcinoma   ramucirumab   vascular endothelial growth factor receptor  

摘要： Simple Summary Ramucirumab is indicated at a dosage of 8 mg/kg every 2 weeks as monotherapy or in combination with paclitaxel for second-line advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. A post hoc analysis of the phase III trials REGARD and RAINBOW suggested a positive correlation between ramucirumab exposure and efficacy. Studies JVDB and JVCZ explored different ramucirumab dosing regimens as monotherapy and in combination with paclitaxel, respectively. Here we report results from these studies, in which JVDB evaluated the pharmacokinetics and safety of the currently registered dosing regimen for ramucirumab monotherapy and three exploratory dosing regimens, and JVCZ evaluated the efficacy and safety of a higher dosing regimen of ramucirumab in combination with paclitaxel in second-line gastric/GEJ adenocarcinoma. Overall, the safety profiles were similar between the registered dose and the exploratory dosing regimens. However, a lack of a dose/exposure-response relationship supports the standard dose of ramucirumab as second-line treatment for patients with advanced/metastatic gastric/GEJ adenocarcinoma. Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m(2)-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regi

关键词： Gene-expression score   personalized medicine   shock  

摘要： Purpose: Among patients with vasodilatory shock, gene expression scores may identify different immune states. We aimed to test whether such scores are robust in identifying patients' immune state and predicting response to hydrocortisone treatment in vasodilatory shock. Materials and Methods: We selected genes to generate continuous scores to define previously established subclasses of sepsis. We used these scores to identify a patient's immune state. We evaluated the potential for these states to assess the differential effect of hydrocortisone in two randomized clinical trials of hydrocortisone versus placebo in vasodilatory shock. Results: We initially identified genes associated with immune-adaptive, immune-innate, immune-coagulant functions. From these genes, 15 were most relevant to generate expression scores related to each of the functions. These scores were used to identify patients as immune-adaptive prevalent (IA-P) and immune-innate prevalent (IN-P). In IA-P patients, hydrocortisone therapy increased 28-day mortality in both trials (43.3% vs 14.7%, P = 0.028) and (57.1% vs 0.0%, P = 0.99). In IN-P patients, this effect was numerically reversed. Conclusions: Gene expression scores identified the immune state of vasodilatory shock patients, one of which (IA-P) identified those who may be harmed by hydrocortisone. Gene expression scores may help advance the field of personalized medicine.

关键词： Photosafety   Fragrance   Photoirritation   Dermal toxicity   Safety   Risk assessment  

摘要： The safety assessment of fragrance materials for photoirritation utilized by The Research Institute for Fragrance Materials has recently been modified and is described in detail. Materials demonstrating significant absorbance in the ultraviolet and visible light (UV/VIS) range (290-700 nm) may present a concern for photoirritation and require further investigation. If there are no photoirritation data or data are insufficient, then data on read-across materials are considered before a tiered approach for testing begins. The hazard-based 3T3-Neutral Red Uptake (NRU) Phototoxicity Test (OECD TG 432) is used as a first-tier assay;if it predicts photoirritation, it is followed by the reconstructed human epidermis (RhE) phototoxicity assay (OECD TG 498). The RhE phototoxicity assay is used to determine a No Observed Effect Level (NOEL) for photoirritation that is used in a confirmatory human photoirritation test. Data are presented on 108 fragrance materials exhibiting significant UV/VIS absorbance and evaluated in the 3T3-NRU Phototoxicity Assay. Twenty-one materials were predicted to be phototoxic;twenty were evaluated in the RhE Phototoxicity Assay to establish a NOEL. Fourteen materials were then evaluated in a confirmatory human phototoxicity test. The tiered testing approach presented represents a scientifically pragmatic method to minimize the likelihood of photoirritation from fragrance materials.

关键词： Deferoxamine   ferroptosis   myocardial dysfunction   post-resuscitation   treatment   UAMC-3203  

摘要： Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 +/- 0.060 vs. 0.021 +/- 0.016, 1 +/- 0.145 vs. 3.338 +/- 0.221, 52.010 +/- 3.587 ug/g vs. 70.500 +/- 3.158 ug/g, all P < 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 +/- 0.043, 2.848 +/- 0.169, all P < 0.05), (72.43 +/- 4.920 ug/g, P > 0.05)], or Deferoxamine (0.203 +/- 0.025, 2.683 +/- 0.273, 55.95 +/- 2.497 ug/g, all P < 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.

关键词： Acute coronary syndrome   cardiogenic shock   elderly   tertiary care  

摘要： Introduction: Despite advances in treatment of patients with cardiogenic shock following acute myocardial infarction (AMICS) in-hospital mortality remains around 50%. Outcome varies among patient subsets and the elderly often have a poor a priori prognosis. We sought to investigate outcome among elderly AMICS patients referred to evaluation and treatment at a tertiary university hospital. Methods: Current analysis was based on the RETROSHOCK registry comprising consecutive AMICS patients admitted to tertiary care. Patients in the registry were individually identified and validated. Results: Of 1,716 admitted patients, 496 (28.9%) patients were >= 75 years old. Older patients were less likely to be admitted directly to a tertiary centre (59.4% vs. 69.9%, P = 0.003), receive mechanical support devices (i.e., Impella (R) (8.9% vs. 15.0%, P = 0.003), and undergo revascularization attempt (76.8% vs. 90.2%, P < 0.001). Thirty-day survivors >= 75 years were characterized by having higher left ventricular ejection fraction (30.2% +/- 12.5% vs. 26.5% +/- 11.8%, P = 0.004) and lower arterial lactate (3.2[2.2-5.2] mmol/L vs. 5.5[3.3-8.2] mmol/L, P < 0.001) at admission. In a multivariable analysis of patients >= 75 years, higher age (HR 1.09, 95% CI 1.05-1.14, P < 0.001), higher heart rate (HR 1.01, 95% CI 1.001-1.014, P = 0.03), and higher lactate (HR 1.11, 95% CI 1.07-1.16, P < 0.001) at admission were associated with an increased risk of 30-day mortality. Conclusion: Among patients >= 75 years with AMICS referred for tertiary specialized treatment, 30-day mortality was 73.4%. Survivors were characterized by lower arterial lactate and heart rate at admission.

关键词： Bacillus   Bacteriocin   Food bio-preservative   Protective culture   Production  

摘要： Live microorganisms with generally recognized as safe (GRAS) status and antagonistic effect against undesired microbes have been extensively applied in different types of food as protective culture. Bacillus could be a promising bio-preservative, due to its ability to efficiently grow in low cost, large-scale fermentation, and to produce pH tolerant bacteriocins which exert broader antimicrobial spectra than those of lactic acid bacteria (LAB). Many research groups have therefore conducted a systematic investigation in all aspects of Bacillus including bacteriocin properties and production. This review presents intensive information of bio-preservative and available commercial bio-protective culture of the Bacillus in comparison with LAB, including (i) bacteriocin classification and properties, (ii) the use of Bacillus as an alternative bio-preservative, (iii) approaches in production of bio-protective culture from Bacillus, and (iv) safety evaluation for a novel bio-protective culture. The results from those studies helped exploring a potential of Bacillus in production and utilization as protective culture.

关键词： Antioxidant   Antitumor agent   Resveratrol   Quercetin  

摘要： Herein we present the synthesis, structure and NMR and mass spectroscopic analyses of the antioxidant 2-(3,5-dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (1), a member of the 2-aryl-2,3-dihydroquinolin-4(1H)-one family of molecules that have been shown to display a range of potent biological properties. The title molecule, prepared by an alternative methodology to that recently reported, crystallizes in the centrosymmetric space group P2(1)/c with unit cell dimensions a = 11.775(17) angstrom, b = 5.3592(8) angstrom, c = 22.462(3) angstrom and beta = 96.576(11)degrees. Close analysis of the solid state structure reveals an array of weak N-H center dot center dot center dot O hydrogen bonding as well as C-H center dot center dot center dot O, and C-H center dot center dot center dot pi interactions between the neighboring molecules. The presence of 1 was also confirmed via NMR and mass spectroscopic analyses. Herein we present the solid state structure and results of mass spectroscopic and nuclear magnetic resonance analyses of the powerful antitumor compound 2-(3,5-dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one prepared by an alternative synthetic avenue. [GRAPHICS]