bluuebunny/crossref_metadata_2025_split huggingface dataset:
LIGHTWEIGHT GEOPOLYMER WOOD COMPOSITE SYNTHESIZED FROM ALKALI-ACTIVATED FLY ASH AND METAKAOLIN
Authors: Sarmin Siti Noorbaini , Welling Johannes 
Published: November 2016

This research paper presents the report on the use of wood particle as reinforcement to produce lightweight geopolymer wood composite. In this study, Class F fly ash and metakaolin used as alumino-silicate source were activated by alkaline activator and samples were cured at two different temperatures, 80°C and 20°C. Wood particle, 3 to 5 mm in size was added to fly ash/metakaolin based geopolymers for 10 – 60% solid content, and its influence on the compressive strength has been investigated. The microstructure investigation using field emission scanning electron microscopy (FESEM) illustrated fly ash; metakaolin and wood particle were embedded in a dense alumino-silicate matrix, though there was some unreacted phase occurred. The compressive strength of lightweight geopolymer matrix without wood particle added samples cured at 80°C temperature was 5.4 MPa which significantly increased 45% when the 10% wood particle were added. However, the addition of wood particle from 20 to 60% has not shown a major improvement in compressive strength. It was found that the density of the lightweight geopolymer composite was decrease relevant to the amount of wood particles addition. It is suggested that wood particle are one of the potential candidates as reinforcement for lightweight geopolymer composite development.
Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole
Authors: Reis de Sá L. F. , Toledo F. T. , Gonçalves A. C. , Sousa B. A. , dos Santos A. A. , Brasil P. F. , Duarte da Silva V. A. , Tessis A. C. , Ramos J. A. , Carvalho M. A. , Lamping E. , Ferreira-Pereira A. 
Published: November 2016

ABSTRACT

Invasive
Candida albicans
infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse the fluconazole resistance of
C. albicans
clinical isolates. Compounds 1 to 4, at <10 μg/ml, ameliorated the fluconazole resistance of
Saccharomyces cerevisiae
strains overexpressing the major
C. albicans
multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p-overexpressing strains to fluconazole. Compounds 1 to 4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five of compounds 1 to 5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump-overexpressing fluconazole-resistant
C. albicans
clinical isolates, isolate 95-142 overexpressing
CDR1
and
CDR2
, isolate 96-25 overexpressing
MDR1
and
ERG11
, and isolate 12-99 overexpressing
CDR1
,
CDR2
,
MDR1
, and
ERG11
. Overall, organotellurium compounds 1 and 2 were the most promising fluconazole chemosensitizers of fluconazole-resistant
C. albicans
isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps: the ATP-binding cassette transporter Cdr1p and the major facilitator superfamily transporter Mdr1p.
Pharmacodynamics of Voriconazole against Wild-Type and Azole-Resistant Aspergillus flavus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis
Authors: Rudramurthy Shivaprakash M. , Seyedmousavi Seyedmojtaba , Dhaliwal Manpreet , Chakrabarti Arunaloke , Meis Jacques F. , Mouton Johan W. 
Published: November 2016

ABSTRACT

Invasive aspergillosis (IA) due to
Aspergillus flavus
is associated with high mortality. Although voriconazole (VRC) is widely recommended as the first-line treatment for IA, emergence of azole resistance in
Aspergillus
spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a nonneutropenic murine model of disseminated
A. flavus
infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the
cyp51C
gene) and two wild-type isolates without mutations. All isolates exhibited a dose-response relationship, and voriconazole treatment improved mouse survival in a dose-dependent manner. At 40 mg/kg of body weight, 100% efficacy was observed for 1 susceptible isolate and 1 resistant isolate (with mutation), whereas for another susceptible isolate and resistant isolate (without mutation), survival rates were 81% and 72%, respectively. The Hill equation with a variable slope fitted the relationship between the area under the concentration-time curve (AUC)/MIC ratio and 14-day survival well for each strain. An
F
test showed the 50% effective doses to be significantly different from each other (
P
= 0.0023). However, contrary to expectation, there was a significant difference in exposure-response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective pharmacokinetic/pharmacodynamic (PK/PD) index (EI
50
) required being negatively and log-linearly related to the MIC (
P
= 0.04). We conclude that the efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates, but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.
β-Lactamase Inhibitors Enhance the Synergy between β-Lactam Antibiotics and Daptomycin against Methicillin-Resistant Staphylococcus aureus
Authors: Henson Karl Evans R. , Yim Juwon , Smith Jordan R. , Sakoulas George , Rybak Michael J. 
Published: November 2016

ABSTRACT

The evidence for using combination therapy for the treatment of serious methicillin-resistant
Staphylococcus aureus
(MRSA) infections is growing. In this study, we investigated the synergistic effect of daptomycin (DAP) combined with piperacillin-tazobactam and ampicillin-sulbactam against MRSA in time-kill experiments. Six of eight strains demonstrated synergy between DAP and the β-lactam–β-lactamase inhibitor (BLI) combination. In 5/8 strains, the synergy occurred only in the presence of the BLI, highlighting a role for BLIs in peptide–β-lactam synergy.
Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model
Authors: Landersdorfer Cornelia B. , Nguyen Tri-Hung , Lieu Linh Thuy , Nguyen Gary , Bischof Robert J. , Meeusen Els N. , Li Jian , Nation Roger L. , McIntosh Michelle P. 
Published: November 2016

ABSTRACT
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.
Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent
Authors: Capparelli Edmund V. , Bricker-Ford Robin , Rogers M. John , McKerrow James H. , Reed Sharon L. 
Published: November 2016

ABSTRACT

Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against
Entamoeba histolytica
and
Giardia intestinalis
, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective
in vitro
and
in vivo
against
E. histolytica
and both metronidazole-sensitive and -resistant strains of
Giardia
. We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (
C
max
) at day 7 was 0.312 μg/ml and the half-life (
t
1/2
) 35 days, so steady-state blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 μM (auranofin equivalent), or more than 25× the 50% inhibitory concentration (IC
50
) for
E. histolytica
and 4× that for
Giardia
, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 μg/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broad-spectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.)
Sustained Nitric Oxide-Releasing Nanoparticles Interfere with Methicillin-Resistant Staphylococcus aureus Adhesion and Biofilm Formation in a Rat Central Venous Catheter Model
Authors: Mihu Mircea Radu , Cabral Vitor , Pattabhi Rodney , Tar Moses T. , Davies Kelvin P. , Friedman Adam J. , Martinez Luis R. , Nosanchuk Joshua D. 
Published: November 2016

ABSTRACT

Staphylococcus aureus
is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with
S. aureus
adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial numbers compared to those of control biofilms
in vitro
and
in vivo
, respectively. Although both phenotypes, planktonic and biofilm-associated staphylococci, of multiple clinical strains were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated into the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices.
Model of Host-Pathogen Interaction Dynamics Links
In Vivo
Optical Imaging and Immune Responses
Authors: Ale Angelique , Crepin Valerie F. , Collins James W. , Constantinou Nicholas , Habibzay Maryam , Babtie Ann C. , Frankel Gad , Stumpf Michael P. H. 
Published: November 2016

ABSTRACT

Tracking disease progression
in vivo
is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for
in vivo
tracking of bacterial population development and therapeutic response. For a precise understanding of
in vivo
imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of
Citrobacter rodentium
infection, a mouse model for enteropathogenic
Escherichia coli
(EPEC). We connect
in vivo
disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions.
Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection
Authors: Rajamanickam Anuradha , Munisankar Saravanan , Bhootra Yukthi , Dolla Chandrakumar , Nutman Thomas B. , Babu Subash 
Published: November 2016

ABSTRACT

Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic
Strongyloides stercoralis
infection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN])
S. stercoralis
infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of
S. stercoralis
infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1β) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of
S. stercoralis
infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that
S. stercoralis
infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic
S. stercoralis
infection and is associated with an inflammatory response.
Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study
Authors: Chandrasekaran Saravanan , Patil Sooraj , Suthar Renu , Attri Savita Verma , Sahu Jitendra Kumar , Sankhyan Naveen , Tageja Mini , Singhi Pratibha 
Published: November 2016

ObjectiveLong-term therapy with phenytoin and carbamazepine is known to cause hyperhomocysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration and the effect of folic acid supplementation on plasma homocysteine.MethodsIn this cross-sectional observational study we enrolled consecutive children aged 2–12 years with epilepsy who had received phenytoin or carbamazepine monotherapy for >6 months. Plasma total homocysteine, folic acid, vitamin B12 and antiepileptic drug concentrations were measured. Healthy age- and sex-matched controls were recruited. Children with homocysteine >10.4 µmol/L received folic acid supplementation for 1 month and homocysteine and folic acid concentrations were measured after 1 month follow-up.ResultsA total of 112 children receiving antiepileptic monotherapy for >6 months were enrolled. Hyperhomocysteinaemia was present in 54 children (90%) receiving phenytoin, 45 children (90%) receiving carbamazepine therapy and 17 (34%) controls (p<0.05). Mean plasma homocysteine concentrations were significantly higher (18.9±10.2 vs 9.1±3 µmol/L) and serum folic acid concentrations (10.04±8.5 ng/ml vs 12.6±4.8 p<0.001) and vitamin B12 concentrations (365±155 pg/mL vs 474±332 pg/mL, p=0.02) were significantly lower in the study group compared with the control group. Duration of antiepileptic drug therapy correlated significantly with elevated homocysteine and reduced folic acid concentrations (p<0.05). Supplementation with folic acid for 1 month led to a reduction in plasma homocysteine concentrations in the study group (from 20.9±10.3 µmol/L to 14.2±8.2 µmol/L, p<0.05).ConclusionsPhenytoin or carbamazepine monotherapy for >6 months duration is associated with hyperhomocysteinaemia in 90% of North Indian children. Elevated homocysteine concentrations were normalised in these children with folic acid supplementation.
Protein and glycomic plasma markers for early detection of adenoma and colon cancer
Authors: Rho Jung-hyun , Ladd Jon J , Li Christopher I , Potter John D , Zhang Yuzheng , Shelley David , Shibata David , Coppola Domenico , Yamada Hiroyuki , Toyoda Hidenori , Tada Toshifumi , Kumada Takashi , Brenner Dean E , Hanash Samir M , Lampe Paul D 
Published: November 2016

ObjectiveTo discover and confirm blood-based colon cancer early-detection markers.DesignWe created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.ResultsIn the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.ConclusionsA panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.
Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer
Authors: Audet-Walsh Étienne , Yee Tracey , McGuirk Shawn , Vernier Mathieu , Ouellet Carlo , St-Pierre Julie , Giguère Vincent 
Published: November 2016

Abstract
How androgen signaling contributes to the oncometabolic state of prostate cancer remains unclear. Here, we show how the estrogen-related receptor γ (ERRγ) negatively controls mitochondrial respiration in prostate cancer cells. Sustained treatment of prostate cancer cells with androgens increased the activity of several metabolic pathways, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis. An analysis of the intersection of gene expression, binding events, and motif analyses after androgen exposure identified a metabolic gene expression signature associated with the action of ERRγ. This metabolic state paralleled the loss of ERRγ expression. It occurred in both androgen-dependent and castration-resistant prostate cancer and was associated with cell proliferation. Clinically, we observed an inverse relationship between ERRγ expression and disease severity. These results illuminate a mechanism in which androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERRγ signaling as a generalized therapeutic approach to manage prostate cancer. Cancer Res; 77(2); 378–89. ©2016 AACR.