bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma
Authors: Kim Won , Yoon Jung-Hwan , Jeong Jae-Min , Cheon Gi-Jeong , Lee Tae-Sup , Yang Jong-In , Park Su-Cheol , Lee Hyo-Suk 
Published: September 2007

AbstractHypoxia stimulates hepatocellular carcinoma (HCC) cell growth via hexokinase (HK) II induction, and alternatively, HK II inhibition induces apoptosis by activating mitochondrial signaling. This study was to investigate whether the induction of HK II by hypoxia is associated with enhanced mitochondrial stability and to confirm the apoptosis-inducing efficacy of HK II inhibitor in an in vivo model of HCC. Mitochondrial stability was examined by treating isolated mitochondria with deoxycholate, a permeability-enhancing agent. Alteration of permeability transition pore complex composition was analyzed by immunoprecipitation and immunoblotting. An in vivo model of HCC was established in C3H mice i.d. implanted with MH134 cells. The antitumor efficacy of i.p. given 3-bromopyruvate (3-BrPA), a HK II inhibitor, was evaluated by measuring tumor volumes and quantifying apoptosis using terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining and 99mTc-hydrazinonicotinamide-Annexin V scans. Hypoxia enhanced mitochondrial stability, and this was inhibited by 3-BrPA treatment. In particular, HK II levels in permeability transition pore complex immunoprecipitates were reduced after 3-BrPA treatment. In mice treated with 3-BrPA, mean tumor volumes and tumor volume growth were found to be significantly reduced. Moreover, percentages of terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive cells were significantly increased in 3-BrPA–treated mice, and this apoptosis-inducing efficacy was reflected in vivo by 99mTc-hydrazinonicotinamide-Annexin V imaging. Our results show that hypoxia enhances mitochondrial stability via HK II induction and that HK II inhibitor treatment exhibits an in vivo antitumor effect by inducing apoptosis. Therefore, HK II inhibitors may be therapeutically useful for the treatment of advanced infiltrative hypovascular HCCs, which are growing in a hypoxic environment. [Mol Cancer Ther 2007;6(9):2554–62]
Gambogic acid inhibits the catalytic activity of human topoisomerase IIα by binding to its ATPase domain
Authors: Qin Yuxin , Meng Linghua , Hu Chaoxin , Duan Wenhu , Zuo Zhili , Lin Liping , Zhang Xiongwen , Ding Jian 
Published: September 2007

Abstract
This study is intended to characterize the cellular target of gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hurburyi tree, which possesses potent in vitro and in vivo antitumor activities. The antiproliferative activity of GA was further confirmed here in a panel of human tumor cells and multidrug-resistant cells. We found that GA significantly inhibited the catalytic activity of topoisomerase (Topo) II and, to a comparatively less extent, of Topo I, without trapping and stabilizing covalent topoisomerase-DNA cleavage complexes. Down-regulation of Topo IIα but not Topo I and Topo IIβ, reduced GA-induced apoptosis and the phosphorylation of c-Jun, and restored cell proliferation upon GA treatment. Moreover, GA antagonized etoposide-induced DNA damage and abrogated the antiproliferative activity of etoposide, whereas it did not affect camptothecin-induced DNA damage. By dissecting the actions of GA on the individual steps of Topo IIα catalytic cycle, we found that GA inhibited DNA cleavage and ATP hydrolysis. Moreover, GA directly bound to the ATPase domain of Topo IIα, and may share common binding sites with ATP. The results reported here show that GA exerts its antiproliferative effect by inhibiting the catalytic activity Topo IIα. They also indicate that GA inhibits Topo IIα-mediated DNA cleavage and modulate the activity of Topo II poisons, which provide rationale for further clinical evaluation of GA. [Mol Cancer Ther 2007;6(9):2429–40]
The novel melphalan prodrug J1 inhibits neuroblastoma growthin vitroandin vivo
Authors: Wickström Malin , Johnsen John Inge , Ponthan Frida , Segerström Lova , Sveinbjörnsson Baldur , Lindskog Magnus , Lövborg Henrik , Viktorsson Kristina , Lewensohn Rolf , Kogner Per , Larsson Rolf , Gullbo Joachim 
Published: September 2007

AbstractNeuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group. [Mol Cancer Ther 2007;6(9):2409–17]
Characterization of novel inhibitors of histone acetyltransferases
Authors: Eliseeva Elena D. , Valkov Vassil , Jung Manfred , Jung Mira O. 
Published: September 2007

Abstract
Modification of proteins by histone acetyltransferases (HAT) or histone deacetylases plays an important role in the control of gene expression, and its dysregulation has been linked to malignant transformation and other diseases. Although histone deacetylase inhibitors have been extensively studied and several are currently in clinical trials, there is little information available on inhibitors of HATs (HATi). Starting from the natural product lead HATi anacardic acid, a series of 28 analogues was synthesized and investigated for HAT-inhibitory properties and effects on cancer cell growth. The compounds inhibited up to 95% HAT activity in vitro, and there was a clear correlation between their inhibitory potency and cytotoxicity toward a broad panel of cancer cells. Interestingly, all tested compounds were relatively nontoxic to nonmalignant human cell lines. Western blot analysis of MCF7 breast carcinoma cells treated with HATi showed significant reduction in acetylation levels of histone H4. To directly show effect of the new compounds on HAT activity in vivo, MCF7 cells were cotransfected with the p21 promoter fused to firefly luciferase and a full-length p300 acetyltransferase, and luciferase activity was determined following treatment with HATi. Significant inhibition of p300 activity was detected after treatment with all tested compounds except one. Effects of the new HATi on protein acetylation and HAT activity in vivo make them a suitable tool for discovery of molecular targets of HATs and, potentially, for development of new anticancer therapeutics. [Mol Cancer Ther 2007;6(9):2391–8]
Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway
Authors: Chen Li-Hua , Fang Jing , Li Huaixing , Demark-Wahnefried Wendy , Lin Xu 
Published: September 2007

Abstract
The mammalian lignan enterolactone is a major metabolite of plant-based lignans that has been shown to inhibit the growth and development of prostate cancer. However, little is known about the mechanistic basis for its anticancer activity. In this study, we report that enterolactone selectively suppresses the growth of LNCaP prostate cancer cells by triggering apoptosis. Mechanistic studies showed that enterolactone-induced apoptosis was characterized by a dose-dependent loss of mitochondrial membrane potential, release of cytochrome c and cleavage of procaspase-3 and poly(ADP-ribose)-polymerase (PARP). Caspase dependence was indicated by the ability of the pan-caspase inhibitor z-VAD-fmk to attenuate enterolactone-mediated apoptosis. Mechanistic studies suggested roles for Akt, GSK-3β, MDM2, and p53 in enterolactone-dependent apoptosis. Our findings encourage further studies of enterolactone as a promising chemopreventive agent against prostate cancer. [Mol Cancer Ther 2007;6(9):2581–90]
Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms
Authors: Yu Bolan , Dietz Birgit M. , Dunlap Tareisha , Kastrati Irida , Lantvit Daniel D. , Overk Cassia R. , Yao Ping , Qin Zhihui , Bolton Judy L. , Thatcher Gregory R.J. 
Published: September 2007

Abstract
The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are “oxidatively labile” and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)H-dependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity. [Mol Cancer Ther 2007;6(9):2418–28]
Calculation of the“Net Additions to Stock” Indicator for the Czech Republic Using a Direct Method
Authors: Kovanda Jan , Havranek Miroslav , Hak Tomas 
Published: September 2007

Abstract: Net additions to stock (NAS) are an indicator based on economy‐wide material flow accounting and analysis. NAS, a measure of the physical growth rate of an economy, can be used for estimates of future waste flows. It is calculated using two methods: The indirect method of calculation is a simple difference between all input and output flows, whereas the direct method involves measuring the amounts of materials added to particular categories of physical stock and the amounts of waste flows from these stocks.The study described in this article had one leading objective: to make available direct NAS data for the Czech Republic, which could later be used for predicting future waste flows. Two additional objectives emerged from the first: (1) to develop a method for direct NAS calculation from data availability in the Czech Republic; (2) to calculate NAS directly, compare the results with those achieved in indirect NAS calculation, and discuss the identified differences.The NAS for the Czech Republic calculated by the direct method is equal to approximately 65 million tonnes on average in 2000–2002 and is approximately 27% lower than the NAS acquired by the indirect method of calculation. The actual values of directly calculated NAS and its uncertainties suggest that the indirect NAS is more likely to be an overestimation than an underestimation. Durables account for about 2% of the total direct NAS, whereas the rest is attributed to infrastructure and buildings. The direct NAS is dominated by nonmetal construction commodities such as building stone and bricks, which equal approximately 89% of the total direct NAS.Calculation of NAS by the direct method has been proved to be feasible in the Czech Republic. Moreover, uncertainties related to direct NAS are lower than those related to indirectly acquired NAS.
A Dynamic Model for Determining the Temporal Distribution of Environmental Burden
Authors: Levine Stephen H. , Gloria Thomas P. , Romanoff Eliahu 
Published: September 2007

Abstract: In an article on the role of temporal information in life‐cycle assessment in this journal, Field and colleagues argued that frequently it is not the single product but the “fleet” (or cohort) of products that “is the appropriate unit of analysis,” and that in focusing on the fleet one “explicitly introduces the notion of time as a critical element of comparative life‐cycle assessments. …” Major transitions, such as replacement of one fleet of products by an alternative fleet, correspond to a system in a transient rather than steady state, and explicit consideration of time is central to transient analysis.One tool increasingly used as part of life‐cycle assessment, economic input‐output (EIO) analysis, at best deals with time in an implicit fashion. This article illustrates how the sequential interindustry model (SIM), a formulation of the EIOmodel that explicitly represents time, might be utilized in life‐cycle assessment. SIM introduces this temporal component by explicitly accounting for the time required by production activities and the resulting sequencing of the inputs. This can be thought of as engineering rather than accounting information. The data demands of such a model are not likely to be met at present or at any time in the near future. Even so, simulation methods and the use of so‐called synthetic data have a history of productive use in a number of fields, including the social sciences.SIM also utilizes the contribution of Joshi on the application of the EIO model to environmental impact and the inclusion of the use as well as the production phases of a product in EIO analysis. The possibility of accounting for discounting of future events, with its impact on decision making, is also briefly discussed.
Factors Associated with Changing Patient Needs in an Assertive Outreach Team
Authors: MacPherson Rob , Gregory Nathan , Slade Mike , Foy Chris 
Published: September 2007

Background, aims: Although clinical use of needs assessment tools is widespread, there is little evidence about their value in longitudinal use. This study aimed to identify the factors associated with changing needs in an assertive outreach (AO) team's caseload, over a 6-month rating period. Methods: The Camberwell Assessment of Needs Short Appraisal Schedule (CANSAS) and the Engagement Measure (EM) were used to assess need and engagement with services respectively, in an AO team caseload. Care planning was based partly on awareness of current unmet needs. The patients were then reassessed at a 6-month follow-up, to determine to what extent identified unmet need had been successfully addressed, and whether levels of engagement had altered. Results: Data were obtained for 79 of 82 patients on the AO team caseload. At 6-month follow-up patient-rated unmet need, but not staff-rated unmet need, was significantly reduced. Patient-, but not staff-rated met need was significantly increased. Measures of engagement were unchanged. Patients' needs changed across a variety of physical, social and psychological domains, rather than in one specific area. In regression analyses, only accommodation type was independently associated with patient-rated changing met need; only diagnosis was significantly related to changing patient-related unmet need. Conclusion: In this study, the CANSAS was used routinely in a standard AO team, and the finding that over a 6-month period patient-rated unmet need reduced significantly suggests that formal rating of needs assessment may have helped to target care planning effectively.The results suggest that accommodation type and diagnosis may play an important role in the ability of services to effectively meet patient needs, but further work in larger samples is needed to address these questions.
Civil Conflict in Northern Ireland and the Prevalence of Psychiatric Disturbance Across the United Kingdom: a Population Study Using the British Household Panel Survey and the Northern Ireland Household Panel Survey
Authors: Murphy Helen , Lloyd Katrina 
Published: September 2007

Background: To date, no large-scale cross-comparative study of psychiatric morbidity in the United Kingdom has been carried out until recently when the Northern Ireland Household Panel Survey (NIHPS) included the General Health Questionnaire (GHQ-12) in 2001. The GHQ-12 has been included in the British Household Panel Survey (BHPS) since 1991 for England and since 1999 for both Scotland and Wales. The purpose of this article is to compare rates of psychiatric morbidity across the United Kingdom, given that one region in particular, Northern Ireland, has experienced political conflict and civil strife for more than 35 years. Aims: To assess the impact of low-intensity warfare on rates of psychiatric morbidity in Northern Ireland and to compare these with psychiatric morbidity rates across England, Scotland and Wales. Method: The sample consisted of 17,343 respondents completing the GHQ-12 across the United Kingdom. In England, 8286 respondents completed the GHQ-12 while 2729, 3165 and 3163 respondents from Wales, Scotland and Northern Ireland completed the GHQ-12 respectively. Results were then weighted according to population size. Results: Rates of psychiatric morbidity varied across each UK region. Wales had the highest mean GHQ-12 score (11.54), followed by Northern Ireland (11.41). English respondents had the lowest mean score (11.02). The difference in mean scores across the four regions in the UK was statistically significant ( F = 5.04, df = 3, p < 0.001). Post-hoc analyses indicated that the mean scores for England differed significantly from those for Wales and Northern Ireland but not for Scotland. Region accounted for less than 1% of the variation in GHQ-12 scores. Conclusions: Psychiatric morbidity rates for adults in Northern Ireland are comparable to other parts of the United Kingdom and we propose that individuals in Northern Ireland use a range of coping strategies to moderate the impact of the conflict in everyday life. These include habituation to the violence, denial and social cohesion, evidenced in the tightly knit Unionist and Nationalist communities. Particular concern was noted over GHQ-12 scores for Wales and while social and economic factors are acknowledged in our commentary, we conclude that further research appears to be crucial in understanding and preventing poorer rates of mental health in this region.
Young People's Recognition and Understanding of Schizophrenia: a Cross-Cultural Study of Young People From Britain and Nigeria
Authors: Furnham Adrian , Igboaka Anuli 
Published: September 2007

Aim: This cross-cultural study set out to compare the beliefs about the manifestations, causes and treatment of schizophrenia in a similar sample of 95 Nigerian and 76 British (western control) young people in their respective countries. Method: Participants completed a three-part questionnaire that was based on Furnham & Chan (2004) with additional questions. Results: Results revealed differences between the two groups regarding the `normality' of behaviours associated with schizophrenia. Other than hallucinations, all the behaviours described were considered to be manifestations of schizophrenia more so by the Nigerians than the British. The Nigerians were found not only to agree with supernatural explanations for causes of schizophrenia, as was predicted, but also favoured biological (genetics, neurochemical changes, and brain damage) and sociological explanations more so than the British. Both cultural groups favoured orthodox psychiatric practices and supportive environments as treatments for schizophrenia. However, unlike the British, the Nigerians also recognized religious and traditional practices as possible treatment options for schizophrenia. Conclusions: As predicted, young Nigerians, compared with young British participants, tended to believe more in supernatural and sociological causes of schizophrenia.
Volunteer Stroke Service (VSS) groups for patients with communication difficulties after stroke: a qualitative analysis of the value of groups to their users
Authors: Legg Lynn , Stott David , Ellis Graham , Sellars Cameron 
Published: September 2007

Objectives: To identify the functions that Volunteer Stroke Service (VSS) groups fulfil for their members. Design: Qualitative focus group study. Setting: Mixed urban and rural community settings in Scotland. Participants: Seven focus groups comprising a total of 24 men and 14 women, with dysarthria or aphasia following stroke, who were members of VSS groups funded by Chest Heart and Stroke Scotland. Results: We identified eight main themes. VSS groups (1) include members in an interpersonal network, (2) provide members with the opportunity to develop interpersonal relations, (3) provide members with support, (4) provide opportunities for personal growth and development, (5) supply members with a purpose, structure and routine, (6) help members establish and confirm their identify, beliefs and values, (7) help members accomplish individual and shared goals, and (8) provide members with the opportunity to influence others and be influenced. Conclusion: VSS groups appear to provide a range of functions that meet members' personal, interpersonal and psychological needs.