bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANALYZING INFANT CRIES USING A COMMITTEE OF NEURAL NETWORKS IN ORDER TO DETECT HYPOXIA RELATED DISORDER
Authors: POEL MANNES , EKKEL TACO 
Published: May 2006

Based on the hypothesis that the sound of the infant cry contains information on the infant's health status, research has been done on how to improve classification of neonate crying sounds into categories called 'normal' and 'abnormal' - the latter referring to some hypoxia-related disorder. Research in this field is hindered by lack of test cases and limited understanding of feature relevance. The research described here combines various ways of dealing with the small data set problem. First, feature pre-selection is done using sequential backwards elimination of possible combinations where the performance of the set of features is tested by a Probabilistic Neural Network which has the advantage of fast learning. Using these features a neural network committee, consisting of Radial Basis Function Neural Networks, was trained on the data, using bootstrapping. This construction yields a multi-classifier system with an overall classification performance of 85% on the so-called "All Cry Units" (ACU) data set, an increase of 34% with respect to the a priori probability of 51%.Several leave-1-out experiments for Linear Discriminant Analysis (LDA), Support Vector Machines (SVM) and Neural Networks (NN) have been conducted in order to compare the performance of the multi-classifier system.
AN EASY AND FAST ALGORITHM FOR OBTAINING MINIMAL DISCRETE KNOTS
Authors: BRIBIESCA ERNESTO 
Published: May 2006

An easy and fast algorithm for obtaining minimal discrete knots is presented. A minimal discrete knot is the digitalized representation of a knot, which is composed of the minimum number of constant orthogonal straight-line segments and is represented by the knot-number notation. The proposed algorithm for obtaining minimal discrete knots tries to reduce the number of straight-line segments of a given discrete knot preserving its shape. This algorithm is based on two fundamental transformations: U and L. In order to prove the efficiency and rapidity of the algorithm, a great variety of examples of discrete knots are presented: complete families of discrete knots at different orders; random discrete knots; examples of non-trivial and unsolved discrete knots.
Point-Counterpoint: Active venoconstriction is/is not important in maintaining or raising end-diastolic volume and stroke volume during exercise and orthostasis
Authors: Rothe Carl F. 
Published: May 2006

PURPOSE AND SCOPE OF THE POINT:COUNTERPOINT DEBATESThis series of debates was initiated for the Journal of Applied Physiology because we believe an important means of searching for truth is through debate where contradictory viewpoints are put forward. This dialectic process whereby a thesis is advanced, then opposed by an antithesis, with a synthesis subsequently arrived at, is a powerful and often entertaining method for gaining knowledge and for understanding the source of a controversy. Before reading these Point:Counterpoint manuscripts or preparing a brief commentary on the content, the reader should understand that authors on each side of the debate are expected to advance a polarized viewpoint and to select the most convincing data to support their position. This approach differs markedly from the review article where the reader expects the author to present balanced coverage of the topic. Each of the authors has been strictly limited in the lengths of both the manuscript (1,200 words) and the rebuttal (400). The number of references to publications is also limited to 30, and citation of unpublished findings is prohibited.
Novel triiodophenol derivatives induce caspase-independent mitochondrial cell death in leukemia cells inhibited by Myc
Authors: Parreño Matilde , Vaqué Jose P. , Casanova Isolda , Frade Pilar , Céspedes M. Virtudes , Pavón Miguel Angel , Molins Antoni , Camacho Mercedes , Vila Luis , Nomdedeu Josep F. , Mangues Ramon , León Javier 
Published: May 2006

Abstract2,4,6-Triiodophenol (Bobel-24, AM-24) was originally described as a nonsteroid antiinflammatory molecule. We have synthesized three derivatives of Bobel-24 (Bobel-4, Bobel-16, and Bobel-30) and tested their activities as putative antileukemic agents. We have found that Bobel-24 and Bobel-16 were dual inhibitors of cyclooxygenase and 5-lipoxygenase, whereas Bobel-4 and Bobel-30 were selective against 5-lipoxygenase. We have tested the antiproliferative activity of these compounds on a panel of cell lines derived from myeloid and lymphoid leukemias (K562, Raji, HL-60, and Molt4). The cytotoxic IC50 in these cell lines ranged between 14 and 50 μmol/L, but it was higher for nontransformed cells such as 32D, NIH3T3, or human leukocytes. All compounds showed cytotoxic activity on all tested cell lines, accompanied by DNA synthesis inhibition and arrest in the G0/G1 phase. Bobel-16, Bobel-4, and Bobel-24 induced a caspase-independent cell death in K562 and Raji cells, accompanied by chromatin condensation, cytochrome c release, and dissipation of mitochondrial membrane potential in a concentration-dependent manner and production of reactive oxygen species. As the proto-oncogene MYC is involved in mitochondrial biogenesis and survival of leukemia cells, we tested its effect on bobel activity. Bobel-24 induced down-regulation of MYC in K562 and, consistently, ectopic expression of MYC results in partial protection towards the cytotoxic effect of Bobel-24. In conclusion, Bobel derivatives induce a caspase- and Bcl-2-independent cell death in which mitochondrial permeabilization and MYC down-regulation are involved. Bobels may serve as prototypes for the development of new agents for the therapy of leukemia. [Mol Cancer Ther 2006;5(5):1166–75]
Motexafin gadolinium modulates levels of phosphorylated Akt and synergizes with inhibitors of Akt phosphorylation
Authors: Ramos Jason , Sirisawad Mint , Miller Richard , Naumovski Louie 
Published: May 2006

Abstract
Motexafin gadolinium (MGd, Xcytrin) is a tumor-selective expanded porphyrin that targets oxidative stress–related proteins. MGd treatment of the follicular lymphoma–derived cell line HF-1 resulted in growth suppression and apoptosis whereas MGd treatment of the Burkitt's lymphoma–derived cell line Ramos resulted in growth suppression but not apoptosis. Because phosphorylation status of Akt/protein kinase B is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd-treated HF-1 and Ramos cells. Levels of pAkt increased within 30 minutes after MGd treatment of HF-1 but after 4 hours began to show a progressive decline to below baseline levels before cells underwent apoptosis. In MGd-treated Ramos cells, pAkt increased ∼2-fold within 4 hours and remained persistently elevated. Because pAkt activates survival pathways, we determined if MGd-induced cell death could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (Akt inhibitor 1 or SH-5) reduced pAkt levels in MGd-treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with celecoxib, an inhibitor of Akt phosphorylation, or docetaxel, a microtubule inhibitor that can decrease Akt phosphorylation. The combination of MGd/celecoxib or MGd/docetaxel resulted in decreased Akt phosphorylation and in synergistic cytotoxicity compared with either agent alone. These data point to a potential protective role for pAkt in MGd-induced apoptosis and suggest that MGd activity may be enhanced by combining it with agents that inhibit Akt phosphorylation. [Mol Cancer Ther 2006;5(5);1176–82]
Inhibition of human nasopharyngeal carcinoma growth and metastasis in mice by adenovirus-associated virus–mediated expression of human endostatin
Authors: Li Xiang-Ping , Li Christine Y.S. , Li Xiaohua , Ding Yanqing , Chan Lally L.Y. , Yang Pai-Hao , Li Gang , Liu Xiong , Lin Jennifer S. , Wang Jide , He Mingliang , Kung Hsiang-fu , Lin Marie C. , Peng Ying 
Published: May 2006

Abstract
Nasopharyngeal carcinoma (NPC) is a highly malignant and frequently metastasized tumor. Endostatin has been shown to inhibit NPC growth, but its efficacy against NPC metastasis has not been shown in vivo. Here, we established a NPC metastasis model in mice by transplanting EBV-positive NPC cells, C666-1, in the livers of nude mice and observed lung metastasis. Furthermore, we showed that tail vein injection of recombinant adeno-associated virus encoding human endostatin (rAAV-hEndo) significantly prolonged the median survival rate of NPC metastasis–bearing mice (from 22 to 37 days, P &lt; 0.01). The rAAV-hEndo treatment resulted in a statistically significant reduction in tumor growth and microvessel formation. It also increased the apoptotic index in the primary liver tumor but not in the normal liver tissue. Importantly, no formation of liver or lung metastasis was detected. The potent inhibition of NPC metastasis suggests the feasibility of combining rAAV-hEndo gene therapy with other therapies for the prevention and treatment of NPC metastasis. [Mol Cancer Ther 2006;5(5):1290–8]
Survivin, a cancer target with an emerging role in normal adult tissues
Authors: Fukuda Seiji , Pelus Louis M. 
Published: May 2006

AbstractSurvivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in normal adult cells, particularly primitive hematopoietic cells, T lymphocytes, polymorphonuclear neutrophils, and vascular endothelial cells, and may regulate their proliferation or survival. In preclinical animal models, targeted antisurvivin therapies show efficacy without overt toxicity. However, consequences of prolonged survivin disruption in normal cells, particularly those associated with continuous renewal, have not been clearly determined. Understanding the role of survivin in normal versus malignant cells will be important in identifying strategies that maximally disrupt survivin in cancer cells with minimal effect on normal tissues. In this review, we summarize the prognostic relevance of survivin in cancer that justifies the pursuit of antisurvivin therapies and discuss differences in survivin expression between normal and cancer cells. We subsequently review expression of survivin in normal adult tissues and evaluate preclinical antisurvivin therapies reported to date in light of emerging roles for survivin in normal physiology, particularly hematopoiesis, angiogenesis, and immune function. [Mol Cancer Ther 2006;5(5):1087–98]
Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer
Authors: Albert Jeffrey M. , Kim Kwang Woon , Cao Carolyn , Lu Bo 
Published: May 2006

Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be activated by radiation. The mammalian target of rapamycin (mTOR) is downstream of Akt, and we investigated the effects of radiation on Akt/mTOR signaling in breast cancer cell models. RAD001 (everolimus), a potent derivative of the mTOR inhibitor rapamycin, was used to study the effects of mTOR inhibition, as the role of mTOR inhibition in enhancing radiation remains unexplored. RAD001 decreased clonogenic cell survival in both breast cancer cell lines MDA-MB-231 and MCF-7, although the effect is greater in MDA-MB-231 cells. Irradiation induced Akt and mTOR signaling, and this signaling is attenuated by RAD001. The radiation-induced signaling activation is mediated by PI3K because inhibition of PI3K with LY294002 inhibited the increase in downstream mTOR signaling. Additionally, caspase-dependent apoptosis is an important mechanism of cell death when RAD001 is combined with 3 Gy radiation, as shown by induction of caspase-3 cleavage. An increase in G2-M cell cycle arrest was seen in the combination treatment group when compared with controls, suggesting that cell cycle arrest may have been a contributing factor in the increased radiosensitization seen in this study. We conclude that RAD001 attenuates radiation-induced prosurvival Akt/mTOR signaling and enhances the cytotoxic effects of radiation in breast cancer cell models, showing promise as a method of radiosensitization of breast cancer. [Mol Cancer Ther 2006;5(5):1183–9]
CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo
Authors: Buggy Joseph J. , Cao Z. Alexander , Bass Kathryn E. , Verner Erik , Balasubramanian Sriram , Liu Liang , Schultz Brian E. , Young Peter R. , Dalrymple Stacie A. 
Published: May 2006

Abstract
CRA-024781 is a novel, broad spectrum hydroxamic acid–based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a Ki of 0.007 μmol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of α-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity. [Mol Cancer Ther 2006;5(5):1309–17]
Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT
Authors: Sain Nivedita , Krishnan Bhavani , Ormerod Michael G. , De Rienzo Assunta , Liu Wai M. , Kaye Stanley B. , Workman Paul , Jackman Ann L. 
Published: May 2006

Abstract
Activation of the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway is a mechanism of cytotoxic drug resistance in ovarian cancer, and inhibitors of this pathway can sensitize to cytotoxic drugs. The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) depletes some proteins involved in PI3K/AKT signaling, e.g., ERBB2, epidermal growth factor receptor (EGFR), and phosphorylated AKT (p-AKT). 17-AAG and paclitaxel were combined (at a fixed 1:1 ratio of their IC50) in four ovarian cancer cell lines that differ in expression of p-AKT, EGFR, and ERBB2. The EGFR-overexpressing A431 and KB epidermoid cell lines were also included. Combination indices (CI) were calculated using the median-effect equation and interpreted in the context of 17-AAG-mediated inhibition of PI3K signaling. Synergy was observed in IGROV-1- and ERBB2-overexpressing SKOV-3 ovarian cancer cells that express a high level of constitutively activated p-AKT [CI at fraction unaffected (fu)0.5 = 0.50 and 0.53, respectively]. Slight synergy was observed in A431 cells (moderate p-AKT/overexpressed EGFR; CI at fu0.5 = 0.76) and antagonism in CH1 (moderate p-AKT), HX62 cells (low p-AKT), and KB cells (low p-AKT/overexpressed EGFR; CI at fu50 = 3.0, 3.5, and 2.0, respectively). The observed effects correlated with changes in the rate of apoptosis induction. 17-AAG induced a decrease in HSP90 client proteins (e.g., C-RAF, ERBB2, and p-AKT) or in downstream markers of their activity (e.g., phosphorylated extracellular signal-regulated kinase or p-AKT) in SKOV-3, IGROV-1, and CH1 cells at IC50 concentrations. A non–growth-inhibitory concentration (6 nmol/L) reduced the phosphorylation of AKT (but not extracellular signal-regulated kinase) and sensitized SKOV-3 cells to paclitaxel. In conclusion, 17-AAG may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by ERBB2 and/or p-AKT. [Mol Cancer Ther 2006;5(5):1197–208]
Sequential combination of flavopiridol and docetaxel reduces the levels of X-linked inhibitor of apoptosis and AKT proteins and stimulates apoptosis in human LNCaP prostate cancer cells
Authors: Gomez Lourdes A. , de las Pozas Alicia , Perez-Stable Carlos 
Published: May 2006

Abstract
Clinical trials have shown that chemotherapy with docetaxel combined with prednisone can improve survival of patients with androgen-independent prostate cancer. It is likely that the combination of docetaxel with other novel chemotherapeutic agents would also improve the survival of androgen-independent prostate cancer patients. We investigated whether the combination of docetaxel and flavopiridol, a broad cyclin-dependent kinase inhibitor, can increase apoptotic cell death in prostate cancer cells. Treatment of DU 145 prostate cancer cells with 500 nmol/L flavopiridol and 10 nmol/L docetaxel inhibited apoptosis probably because of their opposing effects on cyclin B1–dependent kinase activity. In contrast, when LNCaP prostate cancer cells were treated with flavopiridol for 24 hours followed by docetaxel for another 24 hours (FD), there was a maximal induction of apoptosis. However, there was greater induction of apoptosis in DU 145 cells when docetaxel was followed by flavopiridol or docetaxel. These findings indicate a heterogeneous response depending on the type of prostate cancer cell. Substantial decreases in X-linked inhibitor of apoptosis (XIAP) protein but not survivin, both being members of the IAP family, were required for FD enhanced apoptosis in LNCaP cells. Androgen ablation in androgen-independent LNCaP cells increased activated AKT and chemoresistance to apoptosis after treatment with FD. The proteasome inhibitor MG-132 blocked FD-mediated reduction of XIAP and AKT and antagonized apoptosis, suggesting that the activation of the proteasome pathway is one of the mechanisms involved. Overall, our data suggest that the docetaxel and flavopiridol combination requires a maximal effect on cyclin B1–dependent kinase activity and a reduction of XIAP and AKT prosurvival proteins for augmentation of apoptosis in LNCaP cells. [Mol Cancer Ther 2006;5(5):1216–26]
Silibinin inhibits UVB- and epidermal growth factor–induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-κB in mouse epidermal JB6 cells
Authors: Singh Rana P. , Dhanalakshmi Sivanandhan , Mohan Sarumathi , Agarwal Chapla , Agarwal Rajesh 
Published: May 2006

Abstract
UVB radiation is the major etiologic factor in the development of nonmelanoma skin cancer. In addition to tumor-initiating effect, UVB also causes tumor promotion via mitogenic and survival signaling. Studies have shown strong preventive effects of silibinin against both UVB-induced and chemically induced tumor promotion in mouse skin models; however, mechanisms are not understood completely. Here, we used tumor promoter–sensitive JB6 mouse epithelial cell model and studied the effect of silibinin on two different mitogens [UVB and epidermal growth factor (EGF)] that induce mitogenic and cell survival signaling pathways. UVB (50–800 mJ/cm2) dose-dependently induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-NH2-kinase 1/2 (JNK1/2), and p38 kinase (p38K) as well as Akt, with an optimum response at 400 mJ/cm2 UVB dose. UVB caused a biphasic phosphorylation of ERK1/2 in a time kinetics study. Silibinin treatment before or immediately after UVB exposure, or both, resulted in a strong decrease in UVB-caused phosphorylation of ERK1/2 and Akt in both dose- and time-dependent manner, without any substantial response on JNK1/2 and p38K. Silibinin also suppressed UVB-induced activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) activation, which are activated by ERK1/2 and Akt. Silibinin treatment under similar conditions also strongly inhibited EGF-induced ERK1/2, JNK1/2, and p38K as well as Akt phosphorylation, and also suppressed EGF-induced AP-1 and NF-κB activation. Because AP-1 and NF-κB are important nuclear transcription factors for tumor promotion, these results suggest that silibinin possibly prevents skin tumor promotion by inhibiting UVB- and EGF-induced mitogenic and cell survival signaling involving both AP-1 and NF-κB. [Mol Cancer Ther 2006;5(5):1145–53]
Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells
Authors: Zhang Qunzhou , Tang Xudong , Lu QingYi , Zhang ZuoFeng , Rao Jianyu , Le Anh D. 
Published: May 2006

Abstract
Green tea extract and its major component (−)-epigallocatechin-3-gallate (EGCG) exhibit antiangiogenic activities in various experimental tumor models. A growing body of evidence has established that hypoxia-inducible factor-1α (HIF-1α) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumor angiogenesis. In this study, we investigated the effect of green tea extract and EGCG on HIF-1α and VEGF expression in human cervical carcinoma (HeLa) and hepatoma (HepG2) cells. Our results showed that green tea extract and EGCG significantly inhibited hypoxia- and serum-induced HIF-1α protein accumulation in these cancer cells but had no effects on HIF-1α mRNA expression. Suppression of HIF-1α protein by green tea extract and EGCG also resulted in a drastic decrease in VEGF expression at both mRNA and protein levels. The mechanisms of green tea extract and EGCG inhibition of hypoxia-induced HIF-1α protein accumulation seem to involve the blocking of both phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling pathways and the enhancing of HIF-1α protein degradation through the proteasome system. In addition, green tea extract and EGCG inhibited serum-induced HIF-1α protein and VEGF expression by interfering with the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathways, which play a crucial role in the protein translational machinery cascade. Functionally, green tea extract and EGCG abolished both chemoattractant- and hypoxia-stimulated HeLa cell migration. Our data suggested that HIF-1α/VEGF function as therapeutic target for green tea extract and EGCG in the context of cancer chemoprevention and anticancer therapy. [Mol Cancer Ther 2006;5(5):1227–38]