bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, efficacy and safety profiles of preserved and preservative‐free tafluprost in healthy volunteers
Authors: Uusitalo Hannu , Kaarniranta Kai , Ropo Auli 
Published: August 2008

Abstract.Purpose:  Prostanoid F2α (PF2α) analogues are commonly used as first‐line treatment of glaucoma. Tafluprost is a newly synthesized PF2α derivative and represents the first PF2α analogue with a fully preservative‐free formulation.Methods:  A randomized, investigator‐masked, single‐centre, crossover phase I study evaluated the pharmacokinetics, efficacy and safety profiles of preserved and preservative‐free tafluprost 0.0015% eyedrops in healthy volunteers. Both formulations were administered once/day for 8 days each. Plasma concentrations and, consequently, area under the curve (AUC0–last), maximum concentration (Cmax) and time to maximum concentration (tmax) were determined for tafluprost acid, the biologically active metabolite. Intraocular pressure, adverse events, and ocular and systemic safety parameters were analysed.Results:  There were no statistically significant differences in pharmacokinetic parameters between preserved and preservative‐free formulations after either single (day 1) or repeated (day 8) dosing. The mean (± standard deviation) results for preserved and preservative‐free formulations on day 8 were, respectively: AUC0–last 581.1 ± 529.9 pg/min/ml versus 431.9 ± 457.8 pg/min/ml (p = 0.462); Cmax 31.4 ± 19.5 pg/ml versus 26.6 ± 18.0 pg/ml (p = 0.294), and median (range) tmax 10 (5–15) for both. Generally, plasma concentrations of tafluprost acid were low at all time‐points and were cleared rapidly from the circulatory system. There were no unexpected safety findings. The incidence of ocular hyperaemia was similar in both formulations and was of predominantly moderate severity with preserved tafluprost and mild severity with preservative‐free tafluprost.Conclusions:  Preservative‐free tafluprost appeared to have similar pharmacokinetic properties to the preserved formulation and was generally well tolerated.
Experimental muscle pain during a forward lunge — the effects on knee joint dynamics and electromyographic activity
Authors: Henriksen M , Alkjær T , Simonsen E B , Bliddal H 
Published: August 2008

Objective:The purpose of this study was to investigate whether the knee joint dynamics during a forward lunge could be modulated by experimentally induced vastus medialis pain in healthy subjects.Design:Randomised cross-over study.Setting:Biomechanical movement laboratory.Participants:20 healthy subjects were included. One subject was excluded during data collection.Intervention:The subjects performed forward lunges before, during and 20 minutes after induction of experimental quadriceps muscle pain. Muscle pain was induced using hypertonic saline (5.8%) injected intramuscularly. Isotonic saline (0.9%) was used as control.Main outcome measurements:Three-dimensional movement analyses were performed and inverse dynamics were used to calculate joint kinematics and kinetics for ankle, knee and hip joints. Electromyographic (EMG) signals of the hamstrings and quadriceps muscles were recorded.Results:During and after pain, significant decreases in knee joint dynamics and EMG recordings were observed.Conclusion:The study shows that local pain in the quadriceps is capable of modulating movements with high knee joint dynamics. The results may have implications in the management of muscle pain and prevention of injuries during activities involving the knee joint.
Cost-effectiveness of the Australian National Tobacco Campaign
Authors: Hurley S F , Matthews J P 
Published: August 2008

Background:The Australian National Tobacco Campaign (NTC) was an intensive mass media anti-smoking campaign, the first phase of which commenced in 1997, cost around $A9 million, and reduced smoking prevalence by 1.4%.Objective:To assess the cost-effectiveness of phase one of the NTC, which ran from June to November 1997.Design and study population:The quit benefits model (QBM), a Markov-cycle simulation model was used to predict the benefits of smoking cessation for the estimated 190 000 quitters from the time of quitting until death, censored at age 85 years. Measures of effectiveness were cases of lung cancer, acute myocardial infarction (AMI), stroke and chronic obstructive pulmonary disease (COPD) avoided; deaths prevented, and life-years and quality-adjusted life-years (QALYs) gained. The savings in healthcare costs through prevention of the four specified smoking-associated diseases were estimated. Future costs, life-years and QALYS were discounted at 3% per year.Results:The QBM predicted that the NTC avoided over 32 000 cases of COPD, 11 000 cases of AMI, 10 000 cases of lung cancer, and 2500 cases of stroke. Prevention of around 55 000 deaths, gains of 323 000 life-years and 407 000 QALYs, and healthcare cost savings of $A740.6 million were predicted. The NTC was therefore both cost saving and effective.Conclusions:As well as reducing smoking prevalence, the NTC was unequivocally cost-effective.
The White River Ash: largest Holocene Plinian tephra
Authors: Lerbekmo J. F. 
Published: August 2008

The White River Ash is a bi-lobate tephra in eastern Alaska, Yukon Territory, and western Northwest Territories. Plinian-type eruptions produced the north lobe ∼1900 years BP and the larger east lobe ∼1250 years BP (14C years). Present evidence favors the vent for the east lobe to be beneath the Klutlan Glacier. East lobe pumice is not present atop Mt. Churchill, so the pumice there must belong to the north lobe and is also likely to have come from a vent beneath the Klutlan Glacier. Isopachs of the east lobe, now known to stretch as far east as Great Bear Lake, indicate an east lobe volume of ∼47 km3. Thickness and grain size of the east lobe decay in exponential fashion, producing straight line plots when the thickness half-distance and clast half-distance are plotted against the square root of the isopach area, the proximal slope being steeper than the distal. The east lobe eruption is indicated to have been into a wind of about 10 m/s and to have produced an eruptive cloud height of ∼45 km. The eruption rate was at least 2.8 × 108 kg/s.
Improved Density Of States and Effective Charge Density in Si/Pecvd Sioxny Interface
Authors: Albertin Katia F. , Pereyra Inés 
Published: August 2008

SiOxNy films deposited by the PECVD (Plasma Enhanced Chemical Vapor Deposition) technique at low temperatures from silane (SiH4) nitrous oxide (N2O) and helium (He) as precursor gases at different RF power and R = N2O/SiH4, in order to produce films with good SiOxNy/Si interface quality and low effective charge density were deposited and characterized. In order to compare the film structural properties with the interface (SiOxNy/Si) quality and interface charge density MOS capacitors were fabricated using these films as dielectric layer.	The structure of the films was investigated by Fourier Transform Infrared Spectroscopy (FTIR).	The MOS capacitors were characterized by low and high frequency capacitance (C-V) measurements, from where the interface state density, the effective charge density and the electrical breakdown were extracted. The better interface properties and a relatively low effective charge density were obtained for a film deposited with R=10 and RF power of 125 mW/cm2.
Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice
Authors: Marchetti Serena , de Vries Nienke A. , Buckle Tessa , Bolijn Maria J. , van Eijndhoven Maria A.J. , Beijnen Jos H. , Mazzanti Roberto , van Tellingen Olaf , Schellens Jan H.M. 
Published: August 2008

AbstractWe tested whether erlotinib hydrochloride (Tarceva, OSI-774), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, is a substrate for the ATP-binding cassette drug transporters P-glycoprotein (P-gp; MDR1, ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance protein 2 (MRP2; ABCC2) in vitro and whether P-gp and BCRP affect the oral pharmacokinetics of erlotinib hydrochloride in vivo. In vitro cell survival, drug transport, accumulation, and efflux of erlotinib were done using Madin-Darby canine kidney II [MDCKII; wild-type (WT), MDR1, Bcrp1, and MRP2] and LLCPK (WT and MDR1) cells and monolayers as well as the IGROV1 and the derived human BCRP-overexpressing T8 cell lines. In vivo, the pharmacokinetics of erlotinib after p.o. and i.p. administration was studied in Bcrp1/Mdr1a/1b−/− (triple-knockout) and WT mice. In vitro, erlotinib was actively transported by P-gp and BCRP/Bcrp1. No active transport of erlotinib by MRP2 was observed. In vivo, systemic exposure (P = 0.01) as well as bioavailability of erlotinib after oral administration (5 mg/kg) were statistically significantly increased in Bcrp1/Mdr1a/1b−/− knockout mice (60.4%) compared with WT mice (40.0%; P = 0.02). Conclusion: Erlotinib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, absence of P-gp and Bcrp1 significantly affected the oral bioavailability of erlotinib. Possible clinical consequences for drug-drug and drug-herb interactions in patients in the gut between P-gp/BCRP-inhibiting substrates and oral erlotinib need to be addressed. [Mol Cancer Ther 2008;7(8):2280–7]
Tumor necrosis factor-α–induced accentuation in cryoinjury: mechanisms in vitro and in vivo
Authors: Jiang Jing , Goel Raghav , Iftekhar M. Arif , Visaria Rachana , Belcher John D. , Vercellotti Gregory M. , Bischof John C. 
Published: August 2008

Abstract
Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-α (TNF-α) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5°C) over the current clinical recommendation of reaching temperatures lower than -40°C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-α-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-α. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-α doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-κB–mediated inflammatory or caspase-mediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-α both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-α. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-α doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-κB–mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelial-mediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-α to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball. [Mol Cancer Ther 2008;7(7):2547–55]
Fatty acid synthase inhibition results in a magnetic resonance–detectable drop in phosphocholine
Authors: Ross James , Najjar Amer M. , Sankaranarayanapillai Madhuri , Tong William P. , Kaluarachchi Kumaralal , Ronen Sabrina M. 
Published: August 2008

Abstract
Expression of fatty acid synthase (FASN), the key enzyme in de novo synthesis of long-chain fatty acids, is normally low but increases in cancer. Consequently, FASN is a novel target for cancer therapy. However, because FASN inhibitors can lead to tumor stasis rather than shrinkage, noninvasive methods for assessing FASN inhibition are needed. To this end, we combined 1H, 31P, and 13C magnetic resonance spectroscopy (MRS) (a) to monitor the metabolic consequences of FASN inhibition and (b) to identify MRS-detectable metabolic biomarkers of response. Treatment of PC-3 cells with the FASN inhibitor Orlistat for up to 48 h resulted in inhibition of FASN activity by 70%, correlating with 74% inhibition of fatty acid synthesis. Furthermore, we have determined that FASN inhibition results not only in lower phosphatidylcholine levels but also in a 59% drop in the phospholipid precursor phosphocholine (PCho). This drop resulted from inhibition in PCho synthesis as a result of a reduction in the cellular activity of its synthetic enzyme choline kinase. The drop in PCho levels following FASN inhibition was confirmed in SKOV-3 ovarian cancer cells treated with Orlistat and in MCF-7 breast cancer cells treated with Orlistat as well as cerulenin. Combining data from all treated cells, the drop in PCho significantly correlated with the drop in de novo synthesized fatty acid levels, identifying PCho as a potential noninvasive MRS-detectable biomarker of FASN inhibition in vivo. [Mol Cancer Ther 2008;7(8):2556–65]
Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2
Authors: Kitagaki Jirouta , Agama Keli K. , Pommier Yves , Yang Yili , Weissman Allan M. 
Published: August 2008

Abstract
The tumor suppressor protein p53 is a potent inducer of apoptosis in transformed cells. Hdm2 is an ubiquitin ligase (E3) that acts as a major regulator of p53 by promoting its ubiquitylation and proteasomal degradation. For this reason, inhibiting the E3 activity of Hdm2 has been proposed as a therapeutic approach for cancers expressing wild-type p53. We previously identified a family of small molecules (HLI98s, 7-nitro-10-aryl-5-deazaflavins) that inhibit the E3 activity of Hdm2, increase cellular p53, and selectively kill transformed cells expressing wild-type p53. However, issues of both potency and solubility in aqueous solution limit the utility of the HLI98s. Here, we report that a highly soluble derivative of the HLI98s, which has a 5-dimethylaminopropylamino side chain but lacks the 10-aryl group (HLI373), has greater potency than the HLI98s in stabilizing Hdm2 and p53, activating p53-dependent transcription, and inducing cell death. Furthermore, we show that HLI373 is effective in inducing apoptosis of several tumor cells lines that are sensitive to DNA-damaging agents. These results suggest that HLI373 could serve as a potential lead for developing cancer therapeutics based on inhibition of the ubiquitin ligase activity of Hdm2. [Mol Cancer Ther 2008;7(8):2445–54]
Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells
Authors: Gu Hongtao , Chen Xiequn , Gao Guangxun , Dong Hongjuan 
Published: August 2008

Abstract
Multiple myeloma is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in multiple myeloma cells; however, the mechanism by which this compound acts remains unknown. Here, we, using immunoblotting analysis, observed that the expression of BiP, CHOP, and XBP-1 is up-regulated in bortezomib-induced apoptosis in human multiple myeloma cell lines NCI-H929 and RPMI-8226/S, strongly suggesting that endoplasmic reticulum (ER) stress response or the unfolded protein response (UPR), a signaling pathway activated by the accumulation of unfolded proteins within ER, is initiated. In the meantime, we also showed that bortezomib inhibited classic ER stressor brefeldin A–induced up-regulation of prosurvival UPR components BiP and XBP-1, resulting in increased induction of apoptosis in multiple myeloma cell lines, raising the possibility that bortezomib induces apoptosis of multiple myeloma cells by means of evoking the severe ER stress but disrupting the prosurvival UPR required. Using caspase inhibitors and a RNA interference approach, we finally confirmed that bortezomib-triggered apoptosis in multiple myeloma cells is dependent on caspase-2 activation, which is associated with ER stress and required for release of cytochrome c, breakdown of mitochondrial transmembrane potential, and its downstream caspase-9 activation. Taken together, these data strongly suggest that caspase-2 can serve as a proximal caspase that functions upstream of mitochondrial signaling during ER stress-induced apoptosis by bortezomib in multiple myeloma cells. [Mol Cancer Ther 2008;7(8):2298–307]
Cellular commitment to reentry into the cell cycle after stalled DNA is determined by site-specific phosphorylation of Chk1 and PTEN
Authors: Martin Sarah A. , Ouchi Toru 
Published: August 2008

Abstract
In this study, we show that depletion of Chk1 by small interfering RNA (siRNA) results in failure of reentry to the cell cycle after DNA replication has been stalled by exposure to hydroxyurea (HU). Casein kinase II (CKII) is degraded in these cells in a proteasome-dependent manner, resulting in decreased phosphorylation and PTEN levels. We show that phosphorylation of Chk1 at Ser317 but not at Ser345 is required for phosphorylation of PTEN at Thr383 by CKII, making cell cycle reentry after HU treatment possible. Like Chk1 depletion, loss of PTEN due to siRNA is followed by inability to return to the cell cycle following HU. In Chk1-siRNA cells, reintroduction of wild-type PTEN but not PTEN T383A restores the ability of the cell to reenter the G2-M phase of the cell cycle after stalled DNA replication. We conclude that, in response to stalled DNA replication, Chk1 is phosphorylated at Ser317 by ATR resulting in stabilization of CKII, which in turn leads to phosphorylation of PTEN at Thr383. [Mol Cancer Ther 2008;7(8):2509–16]
Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms
Authors: Shankar Sharmila , Chen Qinghe , Ganapathy Suthakar , Singh Karan P. , Srivastava Rakesh K. 
Published: August 2008

AbstractRecent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-XL, survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII–positive blood vessels and hypoxia-inducible factor-1α, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-κB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2328–38]
SN52, a novel nuclear factor-κB inhibitor, blocks nuclear import of RelB:p52 dimer and sensitizes prostate cancer cells to ionizing radiation
Authors: Xu Yong , Fang Fang , St. Clair Daret K. , Sompol Pradoldej , Josson Sajni , St. Clair William H. 
Published: August 2008

AbstractThe activation of nuclear factor-κB (NF-κB) is thought to protect cancer cells against therapy-induced cytotoxicity. RelB, a member of the NF-κB family in the alternative pathway, is uniquely expressed at a high level in prostate cancer with high Gleason scores. Here, we show that ionizing radiation (IR) enhances nuclear import of RelB, leading to up-regulation of its target gene, manganese superoxide dismutase (MnSOD), and renders prostate cancer cells resistant to IR. To selectively block RelB nuclear import, we designed a cell-permeable SN52 peptide, a variant of the SN50 peptide that has been shown to block nuclear import of NF-κB family members in the classic pathway. Inhibition of IR-induced NF-κB activation by SN50 and SN52 was achieved by selectively interrupting the association of p50 and p52 with nuclear import factors importin-α1 and importin-β1. Importantly, SN52 seems to be more efficient for radiosensitization of prostate cancer cells at clinically relevant radiation doses and has less cytotoxicity to normal prostate epithelial cells compared with the toxicity observed with SN50. These results suggest that targeting the alternative pathway is a promising approach to selectively radiosensitize prostate cancers and that SN52 may serve as a prototype biological agent for sensitizing prostate cancers to clinically relevant doses of IR. [Mol Cancer Ther 2008;7(8):2367–76]
Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma
Authors: Longo Luigia , Platini Francesca , Scardino Anna , Alabiso Oscar , Vasapollo Giuseppe , Tessitore Luciana 
Published: August 2008

Abstract
Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H2O2 and 1,1-diphenyl-2-picryl-hydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2α, an autophagy inducer, and down-regulation of mTOR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase–mediated dUTP nick-end labeling–positive fragmented nuclei, and cells with sub-G1 DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanin-triggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents. [Mol Cancer Ther 2008;7(8):2476–85]