bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishing In Vitro-In Vivo Correlations for
Aspergillus fumigatus
: the Challenge of Azoles versus Echinocandins
Authors: Arendrup Maiken Cavling , Perkhofer Susanne , Howard Susan J. , Garcia-Effron Guillermo , Vishukumar Aimanianda , Perlin David , Lass-Flörl Cornelia 
Published: July 2008

ABSTRACT

Two clinical isolates of
Aspergillus fumigatus
, designated AT and DK, were recently obtained from patients failing caspofungin and itraconazole therapy, respectively. The isolates were tested by microdilution for susceptibility to itraconazole, voriconazole, posaconazole, ravuconazole, and caspofungin and by Etest for susceptibility to amphotericin B and caspofungin. Susceptibility testing documented that the DK isolate was azole resistant (itraconazole and posaconazole MICs, >4 μg/ml; voriconazole MIC, 2 μg/ml; ravuconazole MIC, 4 μg/ml), and the resistance was confirmed in a hematogenous mouse model, with mortality and the galactomannan index as the primary and secondary end points. Sequencing of the
cyp51A
gene revealed the M220K mutation, conferring multiazole resistance. The Etest, but not microdilution, suggested that the AT isolate was resistant to caspofungin (MIC, >32 μg/ml). In the animal model, this isolate showed reduced susceptibility to caspofungin. Sequencing of the
FKS1
gene revealed no mutations; the enzyme retained full sensitivity in vitro; and investigation of the polysaccharide composition showed that the β-(1,3)-glucan proportion was unchanged. However, gene expression profiling by Northern blotting and real-time PCR demonstrated that the
FKS
gene was expressed at a higher level in the AT isolate than in the susceptible control isolate. To our knowledge, this is the first report to document the presence of multiazole-resistant clinical isolates in Denmark and to demonstrate reduced susceptibility to caspofungin in a clinical
A. fumigatus
isolate with increased expression of the
FKS
gene. Further research to determine the prevalence of resistance in
A. fumigatus
worldwide, and to develop easier and reliable tools for the identification of such isolates in routine laboratories, is warranted.
Disposition, Metabolism, and Excretion of [
14
C]Doripenem after a Single 500-Milligram Intravenous Infusion in Healthy Men
Authors: Cirillo Iolanda , Mannens Geert , Janssen Cor , Vermeir Marc , Cuyckens Filip , Desai-Krieger Daksha , Vaccaro Nicole , Kao L. Mark , Devineni Damayanthi , Redman Rebecca , Turner Kenneth 
Published: July 2008

ABSTRACT

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [
14
C]doripenem, containing 50 μCi of [
14
C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from β-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting. Further metabolite profiling was conducted on urine samples using liquid chromatography coupled to radiochemical detection and high-resolution mass spectrometry. Unchanged doripenem and doripenem-M-1 accounted for means of 80.7% and 12.7% of the area under the plasma total-radioactivity-versus-time curve (area under the concentration-time curve extrapolated to infinity) and exhibited elimination half-lives of 1.1 and 2.5 h, respectively. Total clearance of doripenem was 16 liters/h, and renal clearance was 12.5 liters/h. At 7 days after the single dose, 95.3% of total doripenem-related radioactivity was recovered in urine and 0.72% in feces. A total mean of 97.2% of the administered dose was excreted in the urine as unchanged doripenem (78.7% ± 5.7%) and doripenem-M-1 (18.5% ± 2.6%). Most of the urinary recovery occurred within 4 h of dosing. Three additional minor metabolites were identified in urine: the glycine and taurine conjugates of doripenem-M-1 and oxidized doripenem-M-1. These results show that doripenem is predominantly eliminated in urine as unchanged drug, with only a fraction metabolized to doripenem-M-1 and other minor metabolites.
Bilateral facial nerve palsy associated with HIV seroconversion illness
Authors: Yeo J C L , Trotter M I , Wilson F 
Published: July 2008

Abstract
Bilateral facial nerve palsy is a rare but recognised manifestation of HIV seroconversion illness. The pathophysiology of this clinical presentation is thought to be associated with the immune response of the dissemination of virus throughout the body. We describe a case of bilateral facial nerve palsy, subsequently diagnosed with HIV. Related medical literature is also reviewed. The case highlights the vigilance required in unusual, atypical signs and symptoms if a diagnosis of HIV infection is not to be missed. Clinicians should be aware of the potential presentation of HIV seroconversion illness to provide opportunity for early diagnosis and intervention.
Multi-system complications of hypothermia: a case of recurrent episodic hypothermia with a review of the pathophysiology of hypothermia
Authors: Alty J E , Ford H L 
Published: July 2008

Abstract
A 61-year-old woman with secondary progressive multiple sclerosis presented on six occasions over a 2-year period with severe hypothermia (31–33.5°C). This resulted in numerous multi-system complications comprising acute pancreatitis, hepatitis, gastrointestinal haemorrhage, psychiatric disturbance, bradycardia, paradoxical sweating, thrombocytopenia, anaemia and raised inflammatory markers. Septic screens were consistently normal. On each occasion she was successfully treated with passive external rewarming and made a complete recovery. This is the first reported case of such extensive sequelae in a single patient with recurrent hypothermic episodes. This unusual patient provides an invaluable insight into the natural history and pathophysiology of hypothermia. The case report is followed by a review of dysfunctional thermoregulation and pathophysiology of hypothermia-induced multi-system complications. A key learning point is to recognise that the clinical manifestations of hypothermia may be widespread and serious but are nonetheless reversible. In addition, one should consider the differential diagnosis of covert hypothermia in those patients with episodic confusion, as hypothermia is under-recognised, particularly in older people, who are prone to accidental hypothermia, and in those with common neurological conditions, such as stroke, head injury and multiple sclerosis, that may have suboptimal thermoregulation.
Electromagnetic mapping of saline contamination at an active brine pit
Authors: Ferguson I J , Taylor W J , Schmigel K 
Published: July 2008

Frequency-domain and time-domain electromagnetic methods were used to investigate groundwater contamination at an active brine pit in southwestern Manitoba, Canada. The objectives of the survey were to delineate contamination suspected to be occuring at the site and to compare frequency-domain electromagnetic (FDEM) and time-domain electromagnetic (TDEM) measurements in a survey area containing pipelines, fences, and power lines. The survey successfully delineated a region of high conductivity around brine pit, confirming that leakage is occurring from the pit. Modelling of the FDEM results suggests the contamination is spreading within a series of shallow sand units. Comparison of FDEM and TDEM survey results indicate that small-separation FDEM systems are much more useful for mapping in a developed area containing sources of cultural noise. The FDEM systems permit rapid mapping of spatial variations in conductivity, are affected to only a limited degree by cultural features, and provide some resolution of the depth variation of conductivity at shallow depth. It was not possible to obtain useful TDEM measurements anywhere near the active brine pit because of the signal distortion in the late-time response. Key words: geophysics, electromagnetic, brine pit, saline contamination.
Field estimation of waterice phase composition of permafrost samples using a calorimetric method
Authors: Fortier Richard , Allard Michel , Sheriff Fernando 
Published: July 2008

Waterice phase composition of undisturbed frozen ground samples obtained with a U.S. Army Cold Regions Research and Engineering Laboratory (CRREL) core barrel at different depths in permafrost mounds at Kangiqsualujjuaq and Umiujaq in northern Quebec was measured in the field using an adiabatic calorimetric method. Although the theoretical basis of adiabatic calorimetry is not fully established and the required correction factors are not available, the phase composition curves of the Kangiqsualujjuaq silty clay and Umiujaq fine sand are close to the ones determined by nuclear magnetic resonance and isothermal calorimetry for two soils with similar grain size distributions (Suffield silty clay and Manchester fine sand). A better understanding of thermal and physicomechanical aspects of frozen ground could be gained from the stratigraphic profile of waterice phase composition in permafrost mounds measured with the adiabatic calorimetric method. Key words: adiabatic calorimetry, unfrozen water content, permafrost, field tests.
Emplacement of the Etive Dyke Swarm, Scotland: implications of dyke morphology and AMS data
Authors: Morris George A. , Kamada Masumi , Martinez Victor 
Published: July 2008

Abstract
The Etive Dyke Swarm is the largest Caledonian dyke swarm in Britain and Ireland. Field and petrophysical (AMS–anisotropy of magnetic susceptibility) data are presented that indicate the dykes resulted from passive upwelling of magmas into fractures created by regional tectonic stresses. During the period of dyke intrusion (around 415 Ma) periodic episodes of sinistral transpression affected the region and were probably associated with sinistral movement on the Great Glen and other regional faults that lie subparallel (approximately 5° clockwise) from the long axis of the swarm. AMS data show that magma upwelled subvertically across the swarm and suggests that the dykes fed a volcanic field much larger than the now preserved Glencoe Volcano complex.
On the long-distance transport of Ferrar magmas
Authors: Leat Philip T. 
Published: July 2008

Abstract
The distribution and geochemical relationships of the Early Jurassic Ferrar large igneous province (LIP) are examined and it is concluded that they support the lateral flow model for the emplacement of the province, with a source along the strongly magmatic Early Jurassic Antarctica–Africa rifted margin. Published data and new analyses from the Pensacola Range are used to show that the dominant magma type in the Ferrar, the Mount Fazio chemical type (MFCT), occurs in the Theron Mountains, Shackleton Range, Whichaway Nunataks, Pensacola Mountains (all Antarctica) and South Africa, as well as well-known outcrops in Victoria Land, Antarctica, SE Australia and New Zealand. Chemical compositions are shown to be somewhat varied, but similar enough for them to be considered as representing closely related magmas. Examination of geochemical trends with distance from the interpreted magma source indicates that Mg# and MgO abundances decline with distance travelled, and it is argued that this is consistent with the lateral flow model. The Scarab Peak chemical type (SPCT), which occurs as sills in the Theron Mountains and Whichaway Nunataks, and as lavas in Victoria Land, is geochemically very homogeneous. Despite this, Mg#, MgO, Ti/Y and Ti/Zr all fall with distance from the interpreted source, consistent with fractional crystallization occurring during the lateral flow of the magmas. Flow took place in dykes or (more likely) sills. No feeder dyke swarm has been identified. The distances flowed, at least 4100 km for MFCT and 3700 km for SPCT, are the longest interpreted lateral magma flows on Earth.
Hyaloclastites, peperites and soft-sediment deformation textures of a shallow subaqueous Miocene rhyolitic dome-cryptodome complex, Pálháza, Hungary
Authors: Németh Károly , Pécskay Zoltán , Martin Ulrike , Gméling Katalin , Molnár Ferenc , Cronin Shane J. 
Published: July 2008

Abstract

The NE Tokaj Mountains at Pálháza in NE Hungary are made up of a complex association of Miocene rhyolitic shallow intrusions, cryptodomes and endogenous lava domes emplaced into and onto soft, wet pelitic sediment in a shallow submarine environment. The intrusive–extrusive complex shows a range of interaction textures with the host muddy sediment, ranging from blocky peperites, formed on a 0.1 m-scale, through to irregular contacts closely resembling globular mega-peperites, on a >10 m-scale. The over 200 m-thick igneous succession is interpreted to result from the pulsatory growth of shallow cryptodomes through muddy saturated host sediment. The intrusions eventually breached the sedimentary cover to build up thick
in situ
hyaloclastite piles in the shallow subaqueous environment. The coherent rhyolitic cryptodome facies is surrounded by intrusive hyaloclastite in the contact zone to the pelitic host sediment. In the upper level of the complex, rhyolitic dome rock is capped and surrounded by hyaloclastite formed due to quench fragmentation upon contact of the lava surface with sea water.
Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-κB and activator protein-1 related mechanisms
Authors: Chen Zhong , Ricker Justin L. , Malhotra Pramit S. , Nottingham Liesl , Bagain Lorena , Lee Tin Lap , Yeh Ning T. , Van Waes Carter 
Published: July 2008

AbstractHead and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), which are modulated by the proteasome and promote resistance to cell death. HNSCC show variable sensitivity to the proteasome inhibitor bortezomib in vitro as well as in murine xenografts and patient tumors in vivo, and the mechanisms are not well understood. To address this question, the sensitivities of nine HNSCC cell lines to bortezomib were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and the potential relationship between the sensitivity and bortezomib effects on biological processes was examined in HNSCC lines of differential bortezomib sensitivity. The most sensitive cell line (UM-SCC-11B) underwent cell death at 10−9 mol/L in vitro and tumor regression at a maximally tolerated dose of bortezomib in a murine xenograft model. The differential sensitivity between UM-SCC-11A and UM-SCC-11B cells corresponded to differences in the extent of suppression of proteasome activity, ubiquitinated protein degradation, and NF-κB and AP-1 activation. Lower concentrations of bortezomib transiently increased NF-κB and sustained AP-1 activation in UM-SCC-11A cells. AP-1 reporter activity and cell density of UM-SCC-11A were suppressed when bortezomib was combined with c-Jun NH2-terminal kinase and p38 kinase pathways inhibitors. Thus, the differential sensitivities to bortezomib corresponded to dissimilar effects on the proteasome, NF-κB and AP-1 activities. Inhibition of c-Jun NH2-terminal kinase and p38 pathways blocked AP-1 activity and enhanced the antitumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance, which are under development as biomarkers for clinical trials in patients with HNSCC. [Mol Cancer Ther 2008;7(7):1949–60]
Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models
Authors: Pchejetski Dimitri , Doumerc Nicolas , Golzio Muriel , Naymark Maria , Teissié Justin , Kohama Takafumi , Waxman Jonathan , Malavaud Bernard , Cuvillier Olivier 
Published: July 2008

AbstractWe have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the up-regulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B-5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway. [Mol Cancer Ther 2008;7(7):1836–45]
eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling
Authors: Soni Alpana , Akcakanat Argun , Singh Gopal , Luyimbazi David , Zheng Yuhuan , Kim Doyil , Gonzalez-Angulo Ana , Meric-Bernstam Funda 
Published: July 2008

Abstract
Activation of translation initiation is essential for the malignant phenotype and is emerging as a potential therapeutic target. Translation is regulated by the expression of translation initiation factor 4E (eIF4E) as well as the interaction of eIF4E with eIF4E-binding proteins (e.g., 4E-BP1). Rapamycin inhibits translation initiation by decreasing the phosphorylation of 4E-BP1, increasing eIF4E/4E-BP1 interaction. However, rapamycin also inhibits S6K phosphorylation, leading to feedback loop activation of Akt. We hypothesized that targeting eIF4E directly would inhibit breast cancer cell growth without activating Akt. We showed that eIF4E is ubiquitously expressed in breast cancer cell lines. eIF4E knockdown by small interfering RNA inhibited growth in different breast cancer cell subtypes including triple-negative (estrogen receptor/progesterone receptor/HER-2–negative) cancer cells. eIF4E knockdown inhibited the growth of cells with varying total and phosphorylated 4E-BP1 levels and inhibited rapamycin-insensitive as well as rapamycin-sensitive cell lines. eIF4E knockdown led to a decrease in expression of cyclin D1, Bcl-2, and Bcl-xL. eIF4E knockdown did not lead to Akt phosphorylation but did decrease 4E-BP1 expression. We conclude that eIF4E is a promising target for breast cancer therapy. eIF4E-targeted therapy may be efficacious in a variety of breast cancer subtypes including triple-negative tumors for which currently there are no targeted therapies. Unlike rapamycin and its analogues, eIF4E knockdown is not associated with Akt activation. [Mol Cancer Ther 2008;7(7):1782–8]
Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids
Authors: Ackerman Margaret E. , Pawlowski David , Wittrup K. Dane 
Published: July 2008

AbstractPoor tissue penetration is a significant obstacle to the development of successful antibody drugs for immunotherapy of solid tumors, and diverse alterations to the properties of antibody drugs have been made to improve penetration and homogeneity of exposure. However, in addition to properties of the antibody drug, mathematical models of antibody transport predict that the antigen expression level and turnover rate significantly influence penetration. As intrinsic antigen properties are likely to be difficult to modify, they may set inherent limits to penetration. Accordingly, in this study, we assess their contribution by evaluating the distance to which antibodies penetrate spheroids when these antigen properties are systematically varied. Additionally, the penetration profiles of antibodies against carcinoembryonic antigen and A33, two targets of clinical interest, are compared. The results agree well with the quantitative predictions of the model and show that localizing antibody to distal regions of tumors is best achieved by selecting slowly internalized targets that are not expressed above the level necessary for recruiting a toxic dose of therapeutic. Each antibody-bound antigen molecule that is turned over or present in excess incurs a real cost in terms of penetration depth—a limiting factor in the development of effective therapies for treating solid tumors. [Mol Cancer Ther 2008;7(7):2233–40]
Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation
Authors: Zhou Jing , Lu Guo-Dong , Ong Chye-Sun , Ong Choon-Nam , Shen Han-Ming 
Published: July 2008

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy. Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer activities. Here, we showed that pretreatment with Andro significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells. Such sensitization is achieved through transcriptional up-regulation of death receptor 4 (DR4), a death receptor of TRAIL. In search of the molecular mechanisms responsible for DR4 up-regulation, we found that the tumor suppressor p53 plays an essential role in DR4 transcriptional activation. Andro is capable of activating p53 via increased p53 phosphorylation and protein stabilization, a process mediated by enhanced reactive oxygen species production and subsequent c-Jun NH2-terminal kinase activation. Pretreatment with an antioxidant (N-acetylcysteine) or a c-Jun NH2-terminal kinase inhibitor (SP600125) effectively prevented Andro-induced p53 activation and DR4 up-regulation and eventually blocked the Andro-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of Andro and support its potential application in cancer therapy to overcome TRAIL resistance. [Mol Cancer Ther 2008;7(7):2170–80]
c-Jun knockdown sensitizes osteosarcoma to doxorubicin
Authors: Dass Crispin R. , Khachigian Levon M. , Choong Peter F.M. 
Published: July 2008

Abstract
The oncogene c-Jun has been found to be up-regulated in a variety of cancers, including osteosarcoma. Doxorubicin is a frontline chemotherapeutic against osteosarcoma, but is limited by toxicity. DNAzymes are oligonucleotides capable of specific catalysis of target mRNA. A biocompatible c-Jun DNAzyme nanoparticle formulated from chitosan regressed the growth and metastasis of pre-established tumors, especially in combination with doxorubicin. In vitro data confirmed that c-Jun knockdown chemosensitized these cells to doxorubicin treatment. c-Jun down-regulation–mediated tumor inhibition also led to concomitant decreased osteolysis. Clinically, knockdown of c-Jun with chitosan nanobiotechnology may proffer an improved treatment outcome for osteosarcoma. [Mol Cancer Ther 2008;7(7):1909–12]