bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo
Authors: Dhar Shanta , Kolishetti Nagesh , Lippard Stephen J. , Farokhzad Omid C. 
Published: January 2011

Targeted delivery and controlled release of inactive platinum (Pt) prodrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)-targeted poly(D,L-lactic-
co
-glycolic acid)-
b
-poly(ethylene glycol) (PLGA-
b
-PEG) nanoparticles (NPs) encapsulating a Pt(IV) prodrug
c
,
t
,
c
[Pt(NH
3
)
2
-(O
2
CCH
2
CH
2
CH
2
CH
2
CH
3
)
2
Cl
2
] (
1
) (Pt-PLGA-
b
-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-
b
-PEG-Apt-NP (150±15 nm encapsulating ∼5% wt/wt Pt(IV) prodrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-
b
-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-
b
-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-
b
-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-
b
-PEG-Apt NP provides a remarkable improvement in the drug therapeutic index.
Production of Complex Multiantennary N-Glycans in Nicotiana benthamiana Plants
Authors: Nagels Bieke , Van Damme Els J.M. , Pabst Martin , Callewaert Nico , Weterings Koen 
Published: January 2011

Abstract
In recent years, plants have been developed as an alternative expression system to mammalian hosts for the production of therapeutic proteins. Many modifications to the plant glycosylation machinery have been made to render it more human because of the importance of glycosylation for functionality, serum half-life, and the safety profile of the expressed proteins. These modifications include removal of plant-specific β1,2-xylose and core α1,3-fucose, and addition of bisecting N-acetylglucosamine, β1,4-galactoses, and sialic acid residues. Another glycosylation step that is essential for the production of complex human-type glycans is the synthesis of multiantennary structures, which are frequently found on human N-glycans but are not generated by wild-type plants. Here, we report both the magnICON-based transient as well as stable introduction of the α1,3-mannosyl-β1,4-N-acetylglucosaminyltransferase (GnT-IV isozymes a and b) and α1,6-mannosyl-β1,6-N-acetylglucosaminyltransferase (GnT-V) in Nicotiana benthamiana plants. The enzymes were targeted to the Golgi apparatus by fusing their catalytic domains to the plant-specific localization signals of xylosyltransferase and fucosyltransferase. The GnT-IV and -V modifications were tested in the wild-type background, but were also combined with the RNA interference-mediated knockdown of β1,2-xylosyltransferase and α1,3-fucosyltransferase. Results showed that triantennary Gn[GnGn] and [GnGn]Gn N-glycans could be produced according to the expected activities of the respective enzymes. Combination of the two enzymes by crossing stably transformed GnT-IV and GnT-V plants showed that up to 10% tetraantennary [GnGn][GnGn], 25% triantennary, and 35% biantennary N-glycans were synthesized. All transgenic plants were viable and showed no aberrant phenotype under standard growth conditions.
Anti-thymoglobulin (ATG) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) model
Authors: Bresson D , von Herrath M G 
Published: January 2011

Summary
Immune modulators such as anti-thymoglobulin (ATG) are under clinical evaluation for the treatment of type 1 diabetes (T1D). Although such agents have cured T1D in the non-obese diabetic (NOD) model, their clinical efficacy has been much lower. In order to improve the odds of successful translation from bench to bedside, we propose to evaluate this agent under more stringent conditions. Here, we evaluated the capacity of ATG to reverse T1D in the acute rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) model. RIP-LCMV-glycoprotein (GP) mice were treated after new-onset T1D with murine ATG antibodies. Although ATG treatment did not impair viral clearance it failed to reverse new-onset T1D in this model. The CD4 : CD8 ratio was reduced drastically upon LCMV infection due to an expansion of CD8 effectors but ameliorated in ATG-treated mice. Although the percentage of CD4+CD25+ regulatory T cells (Tregs) within the CD4+ population was increased significantly after ATG therapy, their frequency in the periphery was reduced dramatically and never returned to normal baseline. The inability of ATG treatment to cure T1D in a stringent viral model (RIP-LCMV mice) is due at least partially to the inability to maintain or increase a sufficient CD4+CD25+ Tregs frequency, in striking contrast with what was reported in the NOD model. Our data would argue for the use of multiple animal models to assess efficacy of promising immune-based interventions and select the most potent therapies for future clinical trials.
Alleviating psychological distress of suicide survivors: evaluation of a volunteer care programme
Authors: LU Y‐J. , CHANG H‐J. , TUNG Y‐Y. , HSU M‐C. , LIN M‐F. 
Published: January 2011

Accessible summary

A supervised volunteer programme can provide safe care for suicide survivors.
Compared with newly trained volunteers, volunteers with at least 1 year of experience are more effective with suicide survivors with greater psychological distress.
Changes in psychological distress of suicide survivors occur after 2 months.

AbstractThe crisis level in the worldwide suicide rate has revealed a severe suicide problem in Taiwan that is now well above the world average of 16 per 100 000 individuals. Many countries have relied on suicide care volunteers training programmes to conduct suicide prevention programmes. However, there is a dearth of research evaluating the effect of volunteers on psychological distress and the impact of volunteer experience level. An evaluation of the impact of experienced and novice volunteers in alleviating psychological distress of suicide survivors was conducted. A supervised programme trained 15 volunteers at Years 1 and 2. Year 1 volunteers completed 400 h of service with continuing education. Programme evaluation occurred after Year 2 volunteers had completed training. Eighty‐two suicide survivors were recruited. With 60 suicide survivors completing 3 month of volunteer care, a significant group difference with time interaction in suicide survivors who exhibited moderate to severe distress between the veteran care and novice care groups was found. Compared with novice volunteers, veteran volunteers with at least 1 year of experience are more effective with suicide survivors reporting higher psychological distress.
Chlorinated phenols control the expression of the multidrug resistance efflux pump MexAB–OprM in Pseudomonas aeruginosa by interacting with NalC
Authors: Ghosh Sudeshna , Cremers Claudia M. , Jakob Ursula , Love Nancy G. 
Published: January 2011

SummaryNalC is a TetR type regulator that represses the multidrug efflux pump MexAB–OprM in Pseudomonas aeruginosa. Here we explain the mechanism of NalC‐mediated regulation of MexAB–OprM. We show that NalC non‐covalently binds chlorinated phenols and chemicals containing chlorophenol side‐chains such as triclosan. NalC‐chlorinated phenol binding results in its dissociation from promoter DNA and upregulation of NalC's downstream targets, including the MexR antirepressor ArmR. ArmR upregulation and MexR–ArmR complex formation have previously been shown to upregulate MexAB–OprM. In vivo mexB and armR expression analyses were used to corroborate in vitro NalC‐chlorinated phenol binding. We also show that the interaction between chlorinated phenols and NalC is reversible, such that removal of these chemicals restored NalC promoter DNA binding. Thus, the NalC‐chlorinated phenol interaction is likely a pertinent physiological mechanism that P. aeruginosa uses to control expression of the MexAB–OprM efflux pump.
Structural determinants for membrane insertion, pore formation and translocation ofClostridium difficiletoxin B
Authors: Genisyuerek Selda , Papatheodorou Panagiotis , Guttenberg Gregor , Schubert Rolf , Benz Roland , Aktories Klaus 
Published: January 2011

SummaryClostridium difficiletoxins A and B bind to eukaryotic target cells, are endocytosed and then deliver their N‐terminal glucosyltransferase domain after processing into the cytosol. Whereas glucosyltransferase, autoprocessing and cell‐binding domains are well defined, structural features involved in toxin delivery are unknown. Here, we studied structural determinants that define membrane insertion, pore formation and translocation of toxin B. Deletion analyses revealed that a large region, covering amino acids 1501–1753 of toxin B, is dispensable for cytotoxicity in Vero cells. Accordingly, a chimeric toxin, consisting of amino acids 1–1550 and the receptor‐binding domain of diphtheria toxin, caused cytotoxic effects. A large N‐terminal part of toxin B (amino acids 1–829) was not essential for pore formation (measured by86Rb+release in mammalian cells). Studies using C‐terminal truncation fragments of toxin B showed that amino acid residues 1–990 were still capable of inducing fluorescence dye release from large lipid vesicles and led to increased electrical conductance in black lipid membranes. Thereby, we define the minimal pore‐forming region of toxin B within amino acid residues 830 and 990. Moreover, we identify within this region a crucial role of the amino acid pair glutamate‐970 and glutamate‐976 in pore formation of toxin B.
Time demands of caring for children with cerebral palsy: what are the implications for maternal mental health?
Authors: SAWYER MICHAEL G , BITTMAN MICHAEL , LA GRECA ANNETTE M , CRETTENDEN ANGELA D , BOROJEVIC NINA , RAGHAVENDRA PARIMALA , RUSSO RAY 
Published: January 2011

Aim  To examine the relationship between maternal mental health problems and the time required by mothers to care for children with cerebral palsy (CP).Method  Cross‐sectional study of 158 mothers of children with cerebral palsy (98 males, 60 females; mean age 11y 3mo, range 6–17y). Gross Motor Function Classification System levels of the children were 37% level I, 20% level II, 9% level III, 12% level IV, and 22% level V. Manual Ability Classification System levels were 19% level I, 27% level II, 22% level III, 13% level IV, and 19% level V. Maternal mental health problems were assessed using the General Health Questionnaire. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression Scale. A time‐diary was used to measure caregiving time. Experience of time pressure was assessed using the Time Crunch Scale.Results  On average, mothers spent 6.0 hours per 24 hours on weekdays and 8.3 hours per 24 hours on weekends caring for children with CP. There was a significant positive relationship between maternal psychological problems and both caregiving time required per 24 hours (p=0.03) and mothers’ experience of time pressure (p<0.001). There was also a significant positive association between maternal depressive symptoms and experience of time pressure (p=0.003).Interpretation  It is important to support mothers to find ways of reducing the real and perceived impact of caregiving. This might include identifying sources of ‘respite’ support for caregivers, training in stress and time management, and appropriate treatment of mental health problems.
Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple sclerosis
Authors: Zheng Jianzheng , Bizzozero Oscar A. 
Published: January 2011

J. Neurochem. (2011) 117, 143–153.AbstractCarbonylated (oxidized) proteins are known to accumulate in the cerebral white matter (WM) and gray matter (GM) of patients with multiple sclerosis (MS). Although oxidative stress is necessary for carbonyl generation, it is the failure of the degradation systems that ultimately leads to the build‐up of carbonylated proteins within tissues. In this study, we measured the activity of the 20S proteasome and other proteolytic systems in the cerebral WM and GM of 13 MS patients and 13 controls. We report that the activities of the three peptidases of the 20S proteasome (i.e. chymotrypsin‐like, caspase‐like and trypsin‐like) in both MS–WM and MS–GM are greatly reduced. Interestingly, neither the amount of proteasome nor the levels of the catalytic subunits (β1, β2, and β5) are diminished in this disease. Proteins containing Lys‐48 poly‐ubiquitin also accumulate in MS tissues, indicating failure of the 26S proteasome as well. Levels of the regulatory caps 11S α and 19S are also lower in MS than in controls, suggesting that the activity of the more complex proteasomes may be reduced further. Finally, the activities of other proteases that might also remove oxidized proteins (calpain, cathepsin B, mitochondrial LonP) are not lessened in MS. Together, these studies suggest that direct inactivation of proteolytic centers in the 20S particle and/or the presence of specific inhibitors is the underlying cause of proteasomal dysfunction in MS.
Modern carbonate microbialites from an asbestos open pit pond, Yukon, Canada
Authors: POWER I. M. , WILSON S. , DIPPLE G. M. , SOUTHAM G. 
Published: January 2011

AbstractMicrobialites were discovered in an open pit pond at an abandoned asbestos mine near Clinton Creek, Yukon, Canada. These microbialites are extremely young and presumably began forming soon after the mine closed in 1978. Detailed characterization of the periphyton and microbialites using light and scanning electron microscopy was coupled with mineralogical and isotopic analyses to investigate the mechanisms by which these microbialites formed. The microbialites are columnar in form (cm scale), have an internal spherulitic fabric (mm scale), and are mostly made of aragonite, which is supersaturated in the subsaline pond water. Initial precipitation is seen as acicular aragonite crystals nucleating onto microbial biomass and detrital particles. Continued precipitation entombs benthic diatoms (e.g. Brachysira vitrea), filamentous algae (e.g. Oedogonium sp.), dinoflagellates, and cyanobacteria. The presence of phototrophs at spherulite centers strongly suggests that these microbes play an important initial role in aragonite precipitation. Substantial growth of individual spherulites occurs abiotically through periodic precipitation of aragonite that forms concentric laminations around spherulite centers while pauses in spherulite growth allow for colonization by microbes. Aragonite associated with biomass (δ13C = −4.6‰ VPDB) showed a 13C‐enrichment of 0.8‰ relative to aragonite exhibiting no biomass (δ13C = −5.4‰ VPDB), which suggests a modest removal of isotopically light dissolved inorganic carbon by phototrophs. The combination of a low sedimentation rate, high calcification rate, and low microbial growth rate appears to result in the formation of these microbialites. The formation of microbialites at an historic mine site demonstrates that an anthropogenically constructed environment can foster microbial carbonate formation.
Do Control Effectiveness Disclosures Require SOX 404(b) Internal Control Audits? A Natural Experiment with Small U.S. Public Companies
Authors: KINNEY, JR. WILLIAM R. , SHEPARDSON MARCY L. 
Published: January 2011

ABSTRACTWe use incremental and joint implementation of multiple SOX‐based control effectiveness disclosure and audit mandates to assess relative performance of alternatives for small U.S. public companies. Using data from several low‐ and high‐effort management disclosure and audit regimes implemented from 2003 to 2008, we find substantial and statistically significant increases in material weakness disclosure rates for small firms undergoing initial SOX 404(b) internal control audits, but find quantitatively and statistically similar increases for initial management reports of small firms exempt from such audits. As to audit cost, fees more than double for initial 404(b) audits in 2004 and remain high, while 404(b)‐exempt firms’ fees grow about 10% annually. Our results support the view that, for small firms, management internal control reports and traditional financial audits may be a cost effective disclosure alternative to full application of SOX 404(b). Also, our results suggest that, even without management reports on internal control, analysis of the cause of known accounting mistakes may yield substantial material weakness disclosures.
Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is dependent on reactive oxygen species
Authors: Furieri Lorena B , Galán María , Avendaño María S , García‐Redondo Ana B , Aguado Andrea , Martínez Sonia , Cachofeiro Victoria , Bartolomé M Visitación , Alonso María J , Vassallo Dalton V , Salaices Mercedes 
Published: January 2011

BACKGROUND AND PURPOSE Exposure to mercury is known to increase cardiovascular risk but the underlying mechanisms are not well explored. We analysed whether chronic exposure to low mercury doses affects endothelial modulation of the coronary circulation.EXPERIMENTAL APPROACH Left coronary arteries and hearts from Wistar rats treated with either HgCl2 (first dose 4.6 µg·kg−1, subsequent doses 0.07 µg·kg−1 day−1, 30 days) or vehicle were used. Endothelial cells from pig coronary arteries incubated with HgCl2 were also used.KEY RESULTS Mercury treatment increased 5‐HT‐induced vasoconstriction but reduced acetylcholine‐induced vasodilatation. It also reduced nitric oxide (NO) production and the effects of NO synthase inhibition with L‐NAME (100 µmol·L−1) on 5‐HT and acetylcholine responses. Superoxide anion production and mRNA levels of NOX‐1 and NOX‐4 were all increased. The superoxide anion scavenger tiron (1 mmol·L−1) reduced 5‐HT responses and increased acetylcholine responses only in vessels from mercury‐treated rats. In isolated hearts from mercury‐treated rats, coronary perfusion and diastolic pressure were unchanged, but developed isovolumetric systolic pressure was reduced. In these hearts, L‐NAME increased coronary perfusion pressure and diastolic pressure while it further reduced developed systolic pressure.CONCLUSIONS AND IMPLICATIONS Chronic exposure to low doses of mercury promotes endothelial dysfunction of coronary arteries, as shown by decreased NO bioavailability induced by increased oxidative stress. These effects on coronary function increase resistance to flow, which under overload conditions might cause ventricular contraction and relaxation impairment. These findings provide further evidence that mercury, even at low doses, could be an environmental risk factor for cardiovascular disease.
A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes
Authors: Stefanich EG , Danilenko DM , Wang H , O'Byrne S , Erickson R , Gelzleichter T , Hiraragi H , Chiu H , Ivelja S , Jeet S , Gadkari S , Hwang O , Fuh F , Looney C , Howell K , Albert V , Balazs M , Refino C , Fong S , Iyer S , Williams M 
Published: January 2011

BACKGROUND AND PURPOSE rhuMAb Beta7 is a humanized anti‐human β7 monoclonal antibody currently in phase I in inflammatory bowel disease. rhuMAb Beta7 binds the β7 subunit of the integrins α4β7 and αEβ7, blocking interaction with their ligands. These integrins play key roles in immune cell homing to and retention in mucosal sites, and are associated with chronic inflammatory diseases of the gastrointestinal tract. The goal of this study was to evaluate the mucosal specificity of rhuMAb Beta7.EXPERIMENTAL APPROACH We assessed the effect of murine anti‐Beta7 on lymphocyte homing in mouse models of autoimmune disease. We also compared the effect of rhuMAb Beta7 on circulating mucosal‐homing versus peripheral‐homing T cells in naïve non‐human primates.KEY RESULTS In cynomolgus monkeys, occupancy of β7 integrin receptors by rhuMAb Beta7 correlated with an increase in circulating β7+ mucosal‐homing lymphocytes, with no apparent effect on levels of circulating β7‐ peripheral‐homing lymphocytes. rhuMAb Beta7 also inhibited lymphocyte homing to the inflamed colons of severe combined immunodeficient mice in CD45RBhigh CD4+ T‐cell transfer models. Consistent with a lack of effect on peripheral homing, in a mouse model of experimental autoimmune encephalomyelitis, anti‐β7 treatment resulted in no amelioration of CNS inflammation.CONCLUSIONS AND IMPLICATIONS The results presented here suggest that rhuMAb Beta7 selectively blocks lymphocyte homing to the gastrointestinal tract without affecting lymphocyte trafficking to non‐mucosal tissues. rhuMAb Beta7 provides a targeted therapeutic approach with the potential for a more attractive benefit : risk ratio than currently available inflammatory bowel disease therapies.
Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells
Authors: Szentandrássy N , Harmati G , Bárándi L , Simkó J , Horváth B , Magyar J , Bányász T , Lőrincz I , Szebeni A , Kecskeméti V , Nánási PP 
Published: January 2011

BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration‐dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts.EXPERIMENTAL APPROACH Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts.KEY RESULTS At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase‐1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration‐dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC50 value for this inhibition was 25.2 ± 2.7 µM for the transient outward K+ current (Ito), 72.3 ± 9.3 µM for the rapid delayed rectifier K+ current (IKr) and 82.5 ± 9.4 µM for the L‐type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of Ito, IKr, and ICa was confirmed also under action potential voltage clamp conditions.CONCLUSIONS AND IMPLICATIONS Alterations in the densities and kinetic properties of ion currents may carry serious pro‐arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients.LINKED ARTICLE This article is commented on by Hancox, pp. 496–498 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01281.x