bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Amprenavir Pharmacokinetics and Tolerability following Administration of 1,400 Milligrams of Fosamprenavir Once Daily in Combination with either 100 or 200 Milligrams of Ritonavir in Healthy Volunteers
Authors: Ruane Peter J. , Luber Andrew D. , Wire Mary Beth , Lou Yu , Shelton Mark J. , Lancaster C. Tracey , Pappa Keith A. 
Published: January 2007

ABSTRACT

Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (
C
max
), the area under the plasma concentration-time curve over the dosing period (AUC
0-τ
), and trough concentrations (
C
τ
) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC
0-τ
(GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and
C
max
(0.97 [90% CI, 0.91 to 1.04]). The APV
C
τ
was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV
C
τ
observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV
C
τ
was 2.5 times higher than the historical
C
τ
for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.
Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against
Plasmodium falciparum
In Vitro
Authors: Skinner-Adams T. S. , Andrews K. T. , Melville L. , McCarthy J. , Gardiner D. L. 
Published: January 2007

ABSTRACT
The antimalarial activity of several antiretroviral protease inhibitor combinations was investigated. Data demonstrate that ritonavir and saquinavir behave synergistically with chloroquine and mefloquine. These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins.
Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks’ gestation: a randomised controlled trial
Authors: Hosono S , Mugishima H , Fujita H , Hosono A , Minato M , Okada T , Takahashi S , Harada K 
Published: January 2007

Objective:To investigate the effects of umbilical cord milking on the need for red blood cell (RBC) transfusion and morbidity in very preterm infants.Patients and Methods:40 singleton infants born between 24 and 28 weeks’ gestation were randomly assigned to receive umbilical cord clamped either immediately (control group, n = 20) or after umbilical cord milking (milked group, n = 20). Primary outcome measures were the probability of not needing transfusion, determined by Kaplan–Meier analysis, and the total number of RBC transfusions. Secondary outcome variables were haemoglobin value and blood pressure at admission.Results:There were no significant differences in gestational age and birth weight between the two groups. The milked group was more likely not to have needed red cell transfusion (p = 0.02) and had a decreased number (mean (SD)) of RBC transfusions (milked group 1.7 (3.0) vs controls 4.0 (4.2); p = 0.02). The initial mean (SD) haemoglobin value was higher in the milked group (165 (14) g/l) than in the controls (141 (16) g/l); p<0.01). Mean (SD) blood pressure at admission was significantly higher in the milked group (34 (9) mm Hg) than in the controls 28 (8) mm Hg; p = 0.03). There was no significant difference in mortality between the groups. The milked group had a shorter duration of ventilation or supplemental oxygen than the control group.Conclusion:Milking the umbilical cord is a safe procedure, reducing the need for RBC transfusions, and the need for circulatory and respiratory support in very preterm infants.
A SIC PAIR GENERATOR FOR A BILBO ENVIRONMENT
Authors: VOYIATZIS I. , KEHAGIAS D. 
Published: January 2007

Built-In Self Test (BIST) techniques are commonly used as an efficient alternative to external testing in today's high-complexity VLSI chips since they provide on-chip test pattern generation and response verification. Among the BIST techniques, Built-In Logic Block Observation (BILBO) has been widely used in practice. Test patterns generated by BILBO structures target the detection of stuck-at faults. It has been shown that most common failure mechanisms that appear into current CMOS VLSI circuits cannot be modeled as stuck-at faults. These mechanisms, modeled by sequential (i.e., stuck-open and delay) faults models, require the application of two-pattern tests (vector pairs) in the circuit-under-test inputs. Single Input Change (SIC) pairs are pairs of patterns where the second pattern differs from the first in only one bit and have been successfully used for two-pattern testing. In this paper we present the BILBO-oriented SIC pair Generator technique that extends BILBO in order to generate SIC pairs; in this way, sequential faults are also detected.
HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor
Authors: Kogan Natalya M. , Schlesinger Michael , Priel Esther , Rabinowitz Ruth , Berenshtein Eduard , Chevion Mordechai , Mechoulam Raphael 
Published: January 2007

Abstract
Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer. Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms. A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice. In this study, we investigated its mode of action and present evidence on its unique mechanism. HU-331 does not cause cancer cell cycle arrest, cell apoptosis, or caspase activation. HU-331–caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations but has only a slight nonsignificant effect on DNA topoisomerase I action. The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones. It might represent a new potent anticancer drug. [Mol Cancer Ther 2007;6(1):173–83]
Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma
Authors: Kato Yukihiko , Salumbides Brenda C. , Wang Xiao-Fei , Qian David Z. , Williams Simon , Wei Yongfeng , Sanni Tolib B. , Atadja Peter , Pili Roberto 
Published: January 2007

AbstractResistance to chemotherapy is a major hurdle in the treatment of malignant melanoma. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor β (RARβ). In this study, we tested the antitumor effect of the HDAC inhibitor LAQ824 in combination with 13-cis-retinoic acid (CRA) on two human melanoma cell lines both in vitro and in vivo. Treatment of LAQ824 showed a dose-dependent inhibitory effect on A2058 and HMV-I cell lines in a clonogenic assay. These cell lines were relatively resistance to CRA. On treatment with combination of LAQ824 and CRA, a greater inhibitory effect (up to 98%) was achieved compared with single agents. Lack of RARβ2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARβ2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G2 cell cycle arrest in A2058 and apoptosis in HMV-I cell line. The induction of apoptosis by LAQ824 was associated with increased reactive oxygen species and induction of SM22 gene expression in HMV-I but not in A2058 cell line. Administration of the free radical scavenger l-N-acetylcysteine blocked LAQ824 + CRA–mediated apoptosis in HMV-I cells, suggesting a primary role for reactive oxygen species generation in LAQ824 + CRA–associated lethality. Combination treatment showed 61% and 82% growth inhibition in A2058 and HMV-I tumors, respectively. Greater induction of in vivo apoptosis was observed in the HMV-I but not in the A2058 tumors treated with combination therapy compared with single agents. These results suggest that the HDAC inhibitor LAQ824 has a greater antitumor activity in combination with CRA in melanoma tumors but the degree of induced apoptosis may vary. Combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for malignant melanoma that warrants clinical testing. [Mol Cancer Ther 2007;6(1):70–81]
Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib
Authors: An Jiabin , Rettig Matthew B. 
Published: January 2007

AbstractIn renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor κB (NF-κB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-κB activation. Thus, we sought to investigate whether inhibition of the EGFR sensitizes RCC cells to the cytotoxic effects of bortezomib. We first established that constitutive NF-κB activity is dependent on signaling through the EGFR in RCC cells. Indeed, blockade of EGFR signaling with an EGFR tyrosine kinase inhibitor (TKI) resulted in inhibition of NF-κB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-κB activation occurs through the phosphotidylinositol-3-OH kinase/AKT pathway. Combinations of the EGFR-TKI and bortezomib resulted in synergistic cytotoxic effects when RCC cells were pretreated with the EGFR-TKI, but an antagonistic interaction was observed with bortezomib pretreatment. Evaluation of the effects of drug sequencing on inhibition of NF-κB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-κB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-κB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-κB activity observed in RCC cells is mediated, at least in part, through an EGFR/phosphotidylinositol-3-OH kinase/AKT signaling cascade. Pretreatment with an EGFR-TKI sensitizes to bortezomib-mediated cytotoxicity by inhibiting constitutive NF-κB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation. [Mol Cancer Ther 2007;6(1):61–9]
Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly
Authors: Cazales Martine , Boutros Rose , Brezak Marie-Christine , Chaumeron Sophie , Prevost Grégoire , Ducommun Bernard 
Published: January 2007

Abstract
The CDC25 cell cycle regulators are promising targets for new pharmacologic approaches in cancer therapy. Inhibitory compounds such as BN82685 have proven to be effective in specifically targeting CDC25 in cultured cells and in inhibiting tumor cell growth. Here, we report that BN82685 impairs microtubule dynamic instability and alters microtubule organization and assembly at the centrosome in interphase cells. Treatment of mitotic cells with BN82685 delays mitotic spindle assembly, chromosome capture, and metaphase plate formation. Furthermore, we show that combining low concentrations of both BN82685 and paclitaxel inhibits the proliferation of HT29 human colon cancer cells. Our results show a role for CDC25 phosphatases in regulating microtubule dynamics throughout the cell cycle and suggest that combinations of CDC25 inhibitors with microtubule-targeting agents may be of therapeutic value. [Mol Cancer Ther 2007;6(1):318–25]
Novel cell death pathways induced by N-(4-hydroxyphenyl)retinamide: therapeutic implications
Authors: Venè Roberta , Arena Giuseppe , Poggi Alessandro , D'Arrigo Cristina , Mormino Michele , Noonan Douglas M. , Albini Adriana , Tosetti Francesca 
Published: January 2007

Abstract
We previously reported that N-(4-hydroxyphenyl)retinamide (4HPR) inhibits retinoblastoma tumor growth in a murine model in vivo and kills Y79 retinoblastoma cells in vitro. In this work, we assayed different cell death–related parameters, including mitochondrial damage and caspase activation, in Y79 cells exposed to 4HPR. 4HPR induced cytochrome c release from mitochondria, caspase-3 activation, and oligonucleosomal DNA fragmentation. However, pharmacologic inactivation of caspases by the pan-caspase inhibitor BOC-D-fmk, or specific caspase-3 inhibition by Z-DEVD-fmk, was not sufficient to prevent cell death, as assessed by loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, disruption of mitochondrial transmembrane potential (Δψm), and ATP depletion. We found that 4HPR causes lysosomal membrane permeabilization and cytosolic relocation of cathepsin D. Pepstatin A partially rescued cell viability and reduced DNA fragmentation and cytosolic cytochrome c. The antioxidant N-acetylcysteine attenuated cathepsin D relocation into the cytosol, suggesting that lysosomal destabilization is dependent on elevation of reactive oxygen species and precedes mitochondrial dysfunction. Activation of AKT, which regulates energy level in the cell, by the retinal survival facto]r insulin-like growth factor I was impaired and insulin-like growth factor I was ineffective against ATP and Δψm loss in the presence of 4HPR. Lysosomal destabilization, associated with mitochondrial dysfunction, was induced by 4HPR also in other cancer cell lines, including PC3 prostate adenocarcinoma and the vascular tumor Kaposi sarcoma KS-Imm cells. The novel finding of a lysosome-mediated cell death pathway activated by 4HPR could have implications at clinical level for the development of combination chemoprevention and therapy of cancer. [Mol Cancer Ther 2007;6(1):286–98]
Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells
Authors: Chaudhuri Devyani , Orsulic Sandra , Ashok Badithe T. 
Published: January 2007

Abstract
Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC50 40 μmol/L) and mouse ovarian cancer cell lines C3 and T3 (IC50 25 μmol/L each) by cell viability assays. The loss of viability is reflected by a down-regulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser473) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention. [Mol Cancer Ther 2007;6(1):334–45]
Pulmonary adenocarcinoma–targeted gene therapy by a cancer- and tissue-specific promoter system
Authors: Fukazawa Takuya , Maeda Yutaka , Durbin Mary L. , Nakai Toru , Matsuoka Junji , Tanaka Hirotoshi , Naomoto Yoshio , Tanaka Noriaki 
Published: January 2007

Abstract
Gene therapy is one of the approaches used to treat lung cancer. The benefit of cancer gene therapy is that different types of tumors can be selectively targeted by tumor-specific expression of therapeutic genes that include an apoptosis gene to destroy the tumor. Previously, we described a promoter (TTS promoter) that we designed that is specifically targeted to lung cancer cells but not to other types of cancer or normal cells including stem cells. In this pursuit, we further characterize the specificity of the TTS promoter in four types of lung cancer cells (squamous cell lung carcinoma, pulmonary adenocarcinoma, small-cell lung carcinoma, large-cell lung carcinoma). The TTS promoter is highly active only in pulmonary adenocarcinoma cells but not in the other three types of lung cancer cells. The specificity seems to be derived from transcription factor thyroid transcription factor 1–associating cofactors that affect human surfactant protein A1 promoter activity in pulmonary adenocarcinoma. We inserted the proapoptotic gene Bcl-2–associated X protein (Bax) into the TTS promoter (TTS/Bax). The TTS/Bax selectively causes BAX expression and cell death in pulmonary adenocarcinoma but not in other cells. Cell death caused by the BAX expression was also observed in pulmonary adenocarcinoma that is resistant to the anticancer drug gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor). BAX expression and cell death can be suppressed by dexamethasone (a glucocorticoid) treatment through negative glucocorticoid elements in the TTS promoter. Here we report a drug-controllable TTS/Bax system targeting pulmonary adenocarcinoma. [Mol Cancer Ther 2007;6(1):244–52]
Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma
Authors: Huynh Hung , Soo Khee Chee , Chow Pierce K.H. , Tran Evelyn 
Published: January 2007

Abstract
Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs. Targeted inhibition of the MEK-ERK pathway with AZD6244 may represent an alternative approach for the treatment of this disease. [Mol Cancer Ther 2007;6(1):138–45]
Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy
Authors: Chang Hong , Schimmer Aaron D. 
Published: January 2007

AbstractLivin, also called melanoma inhibitor of apoptosis protein (IAP) or kidney IAP, is a member of the IAP family of caspase inhibitors that selectively binds the endogenous IAP antagonist SMAC and caspase-3, caspase-7, and caspase-9. As such, Livin inhibits apoptosis, and its overexpression renders malignant cells resistant to chemotherapy. Therefore, inhibitors of Livin could be useful adjuncts to chemotherapy in the treatment of malignancies. This review will discuss Livin as a potential therapeutic target and strategies for its inhibition, including antisense oligonucleotides, small-molecule inhibitors, and immune-mediated approaches. [Mol Cancer Ther 2007;6(1):24–30]
Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair
Authors: Fischer Joshua L. , Mihelc Elaine M. , Pollok Karen E. , Smith Martin L. 
Published: January 2007

Abstract
Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-l-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-l-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells. [Mol Cancer Ther 2007;6(1):355–61]