bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up
Authors: Adjei George O , Kurtzhals Jorgen AL , Rodrigues Onike P , Alifrangis Michael , Hoegberg Lotte CG , Kitcher Emmanuel D , Badoe Ebenezer V , Lamptey Roberta , Goka Bamenla Q 
Published: July 2008

Abstract

Background
Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments.

Methods
Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted.

Results
Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up.

Conclusion
AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation.

Trial registration
NCT 00406146 http://www.clinicaltrials.gov
Dominant negative mutant Cyclin T1 proteins inhibit HIV transcription by specifically degrading Tat
Authors: Jadlowsky Julie K , Nojima Masanori , Schulte Antje , Geyer Matthias , Okamoto Takashi , Fujinaga Koh 
Published: July 2008

Abstract

Background
The positive transcription elongation factor b (P-TEFb) is an essential cellular co-factor for the transcription of the human immunodeficiency virus type 1 (HIV-1). The cyclin T1 (CycT1) subunit of P-TEFb associates with a viral protein, Tat, at the transactivation response element (TAR). This represents a critical and necessary step for the stimulation of transcriptional elongation. Therefore, CycT1 may serve as a potential target for the development of anti-HIV therapies.

Results
To create effective inhibitors of HIV transcription, mutant CycT1 proteins were constructed based upon sequence similarities between CycT1 and other cyclin molecules, as well as the defined crystal structure of CycT1. One of these mutants, termed CycT1-U7, showed a potent dominant negative effect on Tat-dependent HIV transcription despite a remarkably low steady-state expression level. Surprisingly, the expression levels of Tat proteins co-expressed with CycT1-U7 were significantly lower than Tat co-expressed with wild type CycT1. However, the expression levels of CycT1-U7 and Tat were restored by treatment with proteasome inhibitors. Concomitantly, the dominant negative effect of CycT1-U7 was abolished by these inhibitors.

Conclusion
These results suggest that CycT1-U7 inhibits HIV transcription by promoting a rapid degradation of Tat. These mutant CycT1 proteins represent a novel class of specific inhibitors for HIV transcription that could potentially be used in the design of anti-viral therapy.
Epitope characterization of the protective monoclonal antibody VN04-2 shows broadly neutralizing activity against highly pathogenic H5N1
Authors: Lim Angeline PC , Wong Steven KK , Chan Annie HY , Chan Conrad EZ , Ooi Eng Eong , Hanson Brendon J 
Published: July 2008

Abstract
The monoclonal antibody VN04-2 was previously shown to protect mice against lethal A/Vietnam/1203/04 H5N1 virus challenge when administered pre- and post-infection. In this study, we characterized the binding requirements of this antibody using direct binding to hemagglutinin and neutralization assays with H5N1 virus-like particles (H5N1-VLP) of eight recent H5N1 strains representing the major mutations within the 140s antigenic loop. Binding was clade independent and 3 mutations within this antigenic region are required before escape is possible, suggesting that apart from the H5N1 viruses circulating in Indonesia, VN04-2 may provide protection against H5N1 viruses from all other regions.
Nuclear and Extranuclear Pathway Inputs in the Regulation of Global Gene Expression by Estrogen Receptors
Authors: Madak-Erdogan Zeynep , Kieser Karen J. , Kim Sung Hoon , Komm Barry , Katzenellenbogen John A. , Katzenellenbogen Benita S. 
Published: July 2008

Abstract
Whereas estrogens exert their effects by binding to nuclear estrogen receptors (ERs) and directly altering target gene transcription, they can also initiate extranuclear signaling through activation of kinase cascades. We have investigated the impact of estrogen-mediated extranuclear-initiated pathways on global gene expression by using estrogen-dendrimer conjugates (EDCs), which because of their charge and size remain outside the nucleus and can only initiate extranuclear signaling. Genome-wide cDNA microarray analysis of MCF-7 breast cancer cells identified a subset of 17β-estradiol (E2)-regulated genes (∼25%) as EDC responsive. The EDC and E2-elicited increases in gene expression were due to increases in gene transcription, as observed in nuclear run-on assays and RNA polymerase II recruitment and phosphorylation. Treatment with antiestrogen or ERα knockdown using small interfering RNA abolished EDC-mediated gene stimulation, whereas GPR30 knockdown or treatment with a GPR30-selective ligand was without effect, indicating ER as the mediator of these gene regulations. Inhibitors of MAPK kinase and c-Src suppressed both E2 and EDC stimulated gene expression. Of note, in chromatin immunoprecipitation assays, EDC was unable to recruit ERα to estrogen-responsive regions of regulated genes, whereas ERα recruitment by E2 was very effective. These findings suggest that other transcription factors or kinases that are downstream effectors of EDC-initiated extranuclear signaling cascades are recruited to regulatory regions of EDC-responsive genes in order to elicit gene stimulation. This study thus highlights the importance of inputs from both nuclear and extranuclear ER signaling pathways in regulating patterns of gene expression in breast cancer cells.
Mechanism of radiation-induced bystander effects: a unifying model
Authors: Hei Tom K , Zhou Hongning , Ivanov Vladimir N , Hong Mei , Lieberman Howard B , Brenner David J , Amundson Sally A , Geard Charles R 
Published: July 2008

Abstract
The radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation, in that extranuclear and extracellular events may also contribute to the final biological consequences of exposure to low doses of radiation. Although radiation-induced bystander effects have been well documented in a variety of biological systems, the mechanism is not known. It is likely that multiple pathways are involved in the bystander phenomenon, and different cell types respond differently to bystander signalling. Using cDNA microarrays, a number of cellular signalling genes, including cyclooxygenase-2 (COX-2), have been shown to be causally linked to the bystander phenomenon. The observation that inhibition of the phosphorylation of extracellular signal-related kinase (ERK) suppressed the bystander response further confirmed the important role of the mitogen-activated protein kinase (MAPK) signalling cascade in the bystander process. Furthermore, cells deficient in mitochondrial DNA showed a significantly reduced response to bystander signalling, suggesting a functional role of mitochondria in the signalling process. Inhibitors of nitric oxide (NO) synthase (NOS) and mitochondrial calcium uptake provided evidence that NO and calcium signalling are part of the signalling cascade. The bystander observations imply that the relevant target for various radiobiological endpoints is larger than an individual cell. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon, together with evidence of their occurrence in-vivo, will allow us to formulate a more accurate model for assessing the health effects of low doses of ionizing radiation.
Radiation quality-dependent bystander effects elicited by targeted radionuclides
Authors: Boyd Marie , Sorensen Annette , McCluskey Anthony G , Mairs Robert J 
Published: July 2008

AbstractThe efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzyl-guanidine ([*I]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBqmL−1 of the α-emitter meta-[211At]astatobenzylguanidine ([211At]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [131I]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [131I]MIBG and [131I]IUdR (low linear energy transfer (LET) β-emitters) as well as [123I]MIBG and [123I]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [131I]MIBG- or [131I]IUdR-treated cells demonstrated a dose-response relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [123I]MIBG or [123I]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.
Cellular effects of long wavelength UV light (UVA) in mammalian cells
Authors: McMillan T J , Leatherman E , Ridley A , Shorrocks J , Tobi S E , Whiteside J R 
Published: July 2008

Abstract
UVA should receive significant consideration as a human health risk as it is a large proportion of the solar spectrum that reaches the earth's surface and because of its ability to penetrate human skin. It is only relatively recently that this has been recognized and this previously under-researched part of the UV spectrum is becoming increasingly well characterized at doses that are quite low in relation to those experienced by humans. Absorption of UVA in a cell leads to the production of reactive oxygen and nitrogen species that can damage major biomolecules including DNA and membrane lipids. Various types of damage induced in these molecules lead to significant biological effects including cytotoxicity, mutations and alterations in cell signalling pathways. Longer-term effects such as persistent genomic instability and bystander effects have also been observed following UVA treatment of mammalian cells and, as with ionizing radiation, this changes some of the fundamental thinking around tissue effects of irradiation. Antioxidants have been assessed extensively for their ability to protect against the biological effects of UVA and a number have been shown to be successful at least in-vitro, for example vitamin E and epigallocatechin-3-gallate. Other potential targets for protection are suggested through the increased understanding of some of the signalling mechanisms activated following treatment, for example the inhibition of NADPH oxidase is seen to reduce a bystander effect. The search for appropriate and successful photoprotective agents remains an important area of research.
Radiotherapy enhancement with gold nanoparticles
Authors: Hainfeld James F , Dilmanian F Avraham , Slatkin Daniel N , Smilowitz Henry M 
Published: July 2008

Abstract
Gold is an excellent absorber of X-rays. If tumours could be loaded with gold, this would lead to a higher dose to the cancerous tissue compared with the dose received by normal tissue during a radiotherapy treatment. Calculations indicate that this dose enhancement can be significant, even 200% or greater. In this paper, the physical and biological parameters affecting this enhancement are discussed. Gold nanoparticles have shown therapeutic efficacy in animal trials and these results are reviewed. Some 86% long-term (&gt;1 year) cures of EMT-6 mouse mammary subcutaneous tumours was achieved with an intravenous injection of gold nanoparticles before irradiation with 250-kVp photons, whereas only 20% were cured with radiation alone. The clinical potential of this approach is also discussed.
New insights into the mechanisms of action of radioimmunotherapy in lymphoma
Authors: Ivanov Andrei , Swann Ruth , Illidge Tim 
Published: July 2008

Abstract
The exquisite sensitivity of haematological malignancies to targeted radiation alongside the impressive results achieved by the pioneers in this field suggests that radioimmunotherapy is likely to be a productive area for future clinical research. Recent experimental work has demonstrated that the combination of targeted radiation and antibody effector mechanisms are critical to long-term clearance of tumour. This review provides the background of clinical and biological insights into the mechanisms of action of radioimmunotherapy.
Gene therapy via inducible nitric oxide synthase: a tool for the treatment of a diverse range of pathological conditions
Authors: McCarthy Helen O , Coulter Jonathan A , Robson Tracy , Hirst David G 
Published: July 2008

AbstractNitric oxide (NO·) is a reactive nitrogen radical produced by the NO synthase (NOS) enzymes; it affects a plethora of downstream physiological and pathological processes. The past two decades have seen an explosion in the understanding of the role of NO· biology, highlighting various protective and damaging modes of action. Much of the controversy surrounding the role of NO· relates to the differing concentrations generated by the three isoforms of NOS. Both calcium-dependent isoforms of the enzyme (endothelial and neuronal NOS) generate low-nanomolar/picomolar concentrations of NO·. By contrast, the calcium-independent isoform (inducible NOS (iNOS)) generates high concentrations of NO·, 2–3 orders of magnitude greater. This review summarizes the current literature in relation to iNOS gene therapy for the therapeutic benefit of various pathological conditions, including various states of vascular disease, wound healing, erectile dysfunction, renal dysfunction and oncology. The available data provide convincing evidence that manipulation of endogenous NO· using iNOS gene therapy can provide the basis for future clinical trials.
Antiangiogenics and radiotherapy
Authors: Shannon Aoife M , Williams Kaye J 
Published: July 2008

Abstract
Antiangiogenic therapies are one of the fore-runners of the new generation of anticancer drugs aimed at tumour-specific molecular targets. Up until the beginning of this century, the general opinion was that targeted agents should show antitumour activity when used as single agents. However, it has now become clear that much greater improvements in therapeutic activity may be achieved by combining the novel agents with conventional cytotoxic therapies already in use in the clinic. Radiotherapy is currently used to treat half of all cancer patients at some stage in their therapy, although the development of radioresistance is an ongoing problem. It is therefore reasonable to expect that any novel molecularly-targeted agent which reaches the clinic will be used in combination with radiotherapy. The rationale for combining antiangiogenics in particular with radiotherapy exists, as radiotherapy has been shown to kill proliferating endothelial cells, suggesting that inhibiting angiogenesis may sensitise endothelial cells to the effects of radiation. Furthermore, targeting the vasculature may paradoxically increase oxygenation within tumours, thereby enhancing radiotherapy efficacy. In this review we present an update on the use of antiangiogenic methods in combination with radiotherapy.
Assessment of tissue redox status using metabolic responsive contrast agents and magnetic resonance imaging
Authors: Hyodo Fuminori , Soule Benjamin P , Matsumoto Ken-ichiro , Matusmoto Shingo , Cook John A , Hyodo Emi , Sowers Anastasia L , Krishna Murali C , Mitchell James B 
Published: July 2008

Abstract
Regulation of tissue redox status is important to maintain normal physiological conditions in the living body. Disruption of redox homoeostasis may lead to oxidative stress and can induce many pathological conditions such as cancer, neurological disorders and ageing. Therefore, imaging of tissue redox status could have clinical applications. Redox imaging employing magnetic resonance imaging (MRI) with nitroxides as cell-permeable redox-sensitive contrast agents has been used for non-invasive monitoring of tissue redox status in animal models. The redox imaging applications of nitroxide electron paramagnetic resonance imaging (EPRI) and MRI are reviewed here, with a focus on application of tumour redox status monitoring. While particular emphasis has been placed on differences in the redox status in tumours compared to selected normal tissues, the technique possesses the potential to have broad applications to the study of other disease states, inflammatory processes and other circumstances where oxidative stress is implicated.
High-throughput screening technologies for drug glucuronidation profiling
Authors: Trubetskoy Olga , Finel Moshe , Trubetskoy Vladimir 
Published: July 2008

AbstractA significant number of endogenous and exogenous compounds, including many therapeutic agents, are metabolized in humans via glucuronidation, catalysed by uridine diphosphoglucurono-syltransferases (UGTs). The study of the UGTs is a growing field of research, with constantly accumulated and updated information regarding UGT structure, purification, substrate specificity and inhibition, including clinically relevant drug interactions. Development of reliable UGT assays for the assessment of individual isoform substrate specificity and for the discovery of novel isoform-specific substrates and inhibitors is crucial for understanding the function and regulation of the UGT enzyme family and its clinical and pharmacological relevance. High-throughput screening (HTS) is a powerful technology used to search for novel substrates and inhibitors for a wide variety of targets. However, application of HTS in the context of UGTs is complicated because of the poor stability, low levels of expression, low affinity and broad substrate specificity of the enzymes, combined with difficulties in obtaining individual UGT isoforms in purified format, and insufficient information regarding isoform-specific substrates and inhibitors. This review examines the current status of HTS assays used in the search for novel UGT substrates and inhibitors, emphasizing advancements and challenges in HTS technologies for drug glucuronidation profiling, and discusses possible avenues for future advancement of the field.
Effect of oil-in-water lipid emulsions prepared with fish oil or soybean oil on the growth of MCF-7 cells and HepG2 cells
Authors: Ueda Kumiko , Asai Yukiko , Yoshimura Yoshimizu , Iwakawa Seigo 
Published: July 2008

Abstract
The growth of human breast cancer-derived MCF-7 cells was affected by oil-in-water lipid emulsions prepared with fish oil (FO) rich in n-3 fatty acids (FAs) and egg-yolk phosphatides (EYP) (FO-emulsions), but not by lipid emulsions prepared with soybean oil (SO) and EYP (SO-emulsions). On the other hand, the growth of human hepatocarcinoma HepG2 cells was affected by neither SO-emulsions nor FO-emulsions. The growth inhibition of MCF-7 cells in the presence of FO-emulsions was not affected by trolox, but was inhibited by α-lipoic acid, and was even potentiated by ebselen, which works as an antioxidant as well as a lipoxygenase inhibitor. Since prostaglandin E3, generated from n-3 FAs by cyclooxygenases, has a suppressive effect on tumour cell growth, and increases when lipoxygenases are inhibited, these findings suggest that lipid emulsions incorporating triglycerides of n-3 FAs might be effective in suppressing the growth of MCF-7 cells, possibly via oxidative stress and through eicosanoid production with anti-proliferating activity against cancer cells.
Inflammatory factors that contribute to upregulation of ERG and cardiac arrhythmias are suppressed by CPU86017, a class III antiarrhythmic agent
Authors: Du Rong-Hui , Yi Hong-Wei , Dai De-Zai , Tang Wei-Hua , Dai Yin 
Published: July 2008

Abstract
The aim of this study was to verify whether exaggerated arrhythmogenesis is attributed to inflammatory factors actively involving an excess of reactive oxygen species (ROS), transforming growth factor (TGF)-β and endothelin (ET). We hypothesized that CPU86017, derived from berberine, which possesses multi-channel blocking activity, could suppress inflammatory factors, resulting in inhibition of over-expression of ether-a-go-go (ERG) and an augmented incidence of ventricular fibrillation (VF) in ischaemia/reperfusion (I/R). Rats with cardiomyopathy (CMP) induced by thyroxine (0.2 mg−1kg−1 s.c. daily for 10 days) were treated with propranolol (10 mg kg−1 p.o.) or CPU86017 (80 mg kg−1 p.o.) on days 6–10. On the 11th day, arrhythmogenesis of the CMP was evaluated by I/R. In the CMP control group, an increase in VF incidence was found with the I/R episode, accompanied by increased ROS, which manifested as an increased level of malondialdehyde and decreased activities of SOD, glutathione peroxidase and catalase in the myocardium. Levels of inducible nitric oxide synthase and TGF-β mRNA were increased in association with upregulation of preproET-1 and ET- converting enzyme. We found increased levels of ERG, which correlated well with arrhythmogenesis. Treatment with CPU86017 or propranolol reversed these changes. These experiments verified our hypothesis that the inflammatory factors ROS, iNOS, TGF-β and ET-1 are actively involved in upregulation of ERG and arrhythmogenesis. CPU86017 and propranolol reduced VF by suppressing these inflammatory factors in the myocardium.