bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer
Authors: Nahari Dorit , Satchi-Fainaro Ronit , Chen Ming , Mitchell Ian , Task Laurie B. , Liu Zijuan , Kihneman Jason , Carroll Allison B. , Terada Lance S. , Nwariaku Fiemu E. 
Published: April 2007

Abstract
Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO′90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor–induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation. [Mol Cancer Ther 2007;6(4):1329–37]
The RET oncogene is a critical component of transcriptional programs associated with retinoic acid–induced differentiation in neuroblastoma
Authors: Oppenheimer Orit , Cheung Nai-Kong , Gerald William L. 
Published: April 2007

Abstract
Differentiation is a key feature in pathologic classification and prognosis of neuroblastic tumors, although the underlying molecular mechanisms are not well defined. To identify key differentiation-related molecules and pathways, we evaluated gene expression during retinoic acid (RA)–induced differentiation of seven neuroblastic tumor cell lines. Transcriptional response to RA was highly variable among cell lines despite the fact that six of seven showed similar morphologic changes. RA consistently altered expression of a small set of genes, some of which are known to play a role in neurogenesis and differentiation. Expression of genes that were regulated by RA was associated with important clinical subgroups of neuroblastic tumors and were differentially expressed by stroma-rich and stroma-poor subtypes. RET, a receptor tyrosine kinase involved with differentiation, was consistently up-regulated throughout the time course of RA treatment in the majority of neuroblastic tumor cell lines. Interference with RET activation abrogated RA-induced transcriptional programs and differentiation, suggesting a key role of RET in this process. The core set of RA-regulated genes includes critical molecular components of pathways necessary for neuroblastic tumor differentiation and have potential as therapeutic targets and molecular markers of response to differentiating agents. [Mol Cancer Ther 2007;6(4):1300–9]
Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib
Authors: Pyrko Peter , Kardosh Adel , Liu Yen-Ting , Soriano Nathaniel , Xiong Wenyong , Chow Robert H. , Uddin Jasim , Petasis Nicos A. , Mircheff Austin K. , Farley Robert A. , Louie Stan G. , Chen Thomas C. , Schönthal Axel H. 
Published: April 2007

AbstractA drawback of extensive coxib use for antitumor purposes is the risk of life-threatening side effects that are thought to be a class effect and probably due to the resulting imbalance of eicosanoid levels. 2,5-Dimethyl-celecoxib (DMC) is a close structural analogue of the selective cyclooxygenase-2 inhibitor celecoxib that lacks cyclooxygenase-2–inhibitory function but that nonetheless is able to potently mimic the antitumor effects of celecoxib in vitro and in vivo. To further establish the potential usefulness of DMC as an anticancer agent, we compared DMC and various coxibs and nonsteroidal anti-inflammatory drugs with regard to their ability to stimulate the endoplasmic reticulum (ER) stress response (ESR) and subsequent apoptotic cell death. We show that DMC increases intracellular free calcium levels and potently triggers the ESR in various tumor cell lines, as indicated by transient inhibition of protein synthesis, activation of ER stress–associated proteins GRP78/BiP, CHOP/GADD153, and caspase-4, and subsequent tumor cell death. Small interfering RNA–mediated knockdown of the protective chaperone GRP78 further sensitizes tumor cells to killing by DMC, whereas inhibition of caspase-4 prevents drug-induced apoptosis. In comparison, celecoxib less potently replicates these effects of DMC, whereas none of the other tested coxibs (rofecoxib and valdecoxib) or traditional nonsteroidal anti-inflammatory drugs (flurbiprofen, indomethacin, and sulindac) trigger the ESR or cause apoptosis at comparable concentrations. The effects of DMC are not restricted to in vitro conditions, as this drug also generates ER stress in xenografted tumor cells in vivo, concomitant with increased apoptosis and reduced tumor growth. We propose that it might be worthwhile to further evaluate the potential of DMC as a non-coxib alternative to celecoxib for anticancer purposes. [Mol Cancer Ther 2007;6(4):1262–75]
1α,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells
Authors: Ben-Shoshan Moshe , Amir Sharon , Dang Duyen T. , Dang Long H. , Weisman Yosef , Mabjeesh Nicola J. 
Published: April 2007

Abstract
In vitro and in vivo studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits angiogenesis in cancer. We now examined whether the antiangiogenic effects of 1,25(OH)2D3 are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)2D3 reduces the protein expression of both the regulated HIF-1α subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)2D3 also inhibited HIF-1 transcriptional activity (measured by reporter gene assay) as well as HIF-1 target genes, including VEGF, ET-1, and Glut-1. We also showed that 1,25(OH)2D3 inhibits cell proliferation under hypoxia. Using HIF-1α knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)2D3 is mediated through a HIF-dependent pathway. Because HIF-1 is a major positive contributor in human tumorigenesis and angiogenesis, we believe that its inhibition by 1,25(OH)2D3 strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy. [Mol Cancer Ther 2007;6(4):1433–9]
Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer
Authors: Zhang Qing , Bhola Neil E. , Lui Vivian Wai Yan , Siwak Doris R. , Thomas Sufi M. , Gubish Christopher T. , Siegfried Jill M. , Mills Gordon B. , Shin Dong , Grandis Jennifer Rubin 
Published: April 2007

AbstractHead and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho–c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer. [Mol Cancer Ther 2007;6(4):1414–24]
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function
Authors: Schafer-Hales Katherine , Iaconelli Jon , Snyder James P. , Prussia Andrew , Nettles James H. , El-Naggar Adel , Khuri Fadlo R. , Giannakakou Paraskevi , Marcus Adam I. 
Published: April 2007

Abstract
Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed “lagging chromosomes”) were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENP-E and CENP-F, which mediate chromosomal capture and alignment. The data show that lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochore-microtubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with lonafarnib, providing support that lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. [Mol Cancer Ther 2007;6(4):1317–28]
Levels of p27kip1 determine Aplidin sensitivity
Authors: Moneo Victoria , Serelde Beatriz G. , Leal Juan F.M. , Blanco-Aparicio Carmen , Diaz-Uriarte Ramon , Aracil Miguel , Tercero Juan C. , Jimeno José , Carnero Amancio 
Published: April 2007

AbstractAplidin (plitidepsin) is a novel anticancer drug isolated from the marine tunicate Aplidium albicans. Aplidin shows potent antitumor activity in preclinical models against a wide variety of human tumors. Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies. Moreover, clinical studies of Aplidin in combination with other agents are ongoing because it generally lacks cross-resistance with other known cytotoxic drugs. The mode of action of Aplidin in tumor cells is only partially understood. Aplidin induces an early oxidative stress response, which results in a rapid and sustained activation of the epidermal growth factor receptor, the nonreceptor protein tyrosine kinase Src, and the serine threonine kinases c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase. Here, we show that sensitivity to Aplidin correlates inversely with the levels of expression of the cyclin-dependent kinase inhibitor p27kip1 (p27) in a panel of low passaged human sarcoma cell lines. Aplidin induces p27 through an oxidation-dependent mechanism and the reduction of p27 levels by specific short hairpin RNA increases Aplidin sensitivity. We confirmed these results in p27 null mouse embryonic fibroblasts corroborating the specificity of the p27 role in Aplidin response because p21waf1 null mouse embryonic fibroblasts do not show this increased sensitivity. We propose a mechanism of action of Aplidin involving p27 and support the analysis of p27 in the response to Aplidin in currently ongoing clinical trials to establish the levels of this protein as response predictor. [Mol Cancer Ther 2007;6(4):1310–6]
Seasonal and diurnal variation in the proportions of female morphs of the damselfly Enallagma cyathigerum
Authors: Bots Jessica , De Bruyn Luc , Adriaens Tim , Dumont Henri , Stoks Robby , Van Gossum Hans 
Published: April 2007

Abstract
In many damselfly species a female-limited colour polymorphism is encountered which is assumed to be the result of sexual conflict. Typically, one morph resembles the male's body colouration (andromorph), while the other is dissimilar (heteromorph). Little is known about the extent of temporal variation in female morph proportions at the water where mating occurs. Knowledge about such variation should help to identify the factors that affect female morph proportion and the scales at which these factors operate. The objective of this study is to assess the occurrence of diurnal and seasonal variation in female morph proportions at the water for the damselfly Enallagma cyathigerum. Diurnal variation was evaluated at six nearby populations, while seasonal variation was examined at one of these populations. Furthermore, we considered temporal variation in female morph proportion in relation to proxies of male harassment (i.e., male density and operational sex ratio). Our findings indicate that female morph proportion varies throughout a day but is uniform on a seasonal scale. Variation in female morph proportions could not be explained by concomitant variation in male density or operational sex ratio. We suggest future study of male mate choice may consider temporal variation in female morph proportions at the water.
Anti-predation behaviour of Dickerson's collared lizard, Crotaphytus dickersonae
Authors: Plasman Melissa , Duchateau Marie José , Macedonia Joseph 
Published: April 2007

Abstract
Males of Dickerson's collared lizard (Crotaphytus dickersonae) are conspicuously bright blue in colour and can be detected at great distances. In contrast, females are brown and much less conspicuous. Given the visibility of males to predators, the question arises how they avoid predation and whether the sexes differ in anti-predator behaviour. Using a slowly approaching human as a simulated predator, approach and flight distances were recorded, as were the presence of other anti-predation responses such as pursuit deterrence signalling, distraction behaviour and aggressive threat. The lizards were captured and physical data such as cloacal temperatures, weight and snout-vent length were obtained. To assess further the effect of coloration on predation pressure, test subjects were painted to make them inconspicuous (brown) or conspicuous (blue) and recaptured after a week. After shedding their painted skin, subjects were approached one final time. Few direct relationships were found between anti-predation displays and body weight, size or temperature. Exhibition of pursuit deterrence signalling or distraction behaviour was rare, and no subject displayed aggressive behaviour (except when caught). Interestingly, males fled sooner, and tended to use more refuge than females, which probably indicates stronger predation pressure on males. However, an overall low use of refuge, the observer's ability to approach most subjects closely before they fled, and few sightings of potential predators, suggest that weak local predation pressure helps to explain why sexually selected conspicuous male coloration has been able to evolve in C. dickersonae.
Aspects of body size and mate choice in the simultaneously hermaphroditic pond snail Lymnaea stagnalis
Authors: Koene Joris , Montagne-Wajer Kora , Maat Andries Ter 
Published: April 2007

Abstract
Body size can be a good indicator of the quality of a potential mate in terms of fecundity. In many hermaphrodites, egg production is positively correlated with body size. Especially when donating sperm is costly, a preference for larger partners might be expected. Here we test this prediction for the great pond snail Lymnaea stagnalis. As expected, we find a clear effect of body size on egg production, and show that shell height can be used as a reliable predictor of body size. Additionally, behavioural observations reveal that these snails are not physically limited in mating with a much larger or smaller partner. Nonetheless, both in a choice experiment as well as in spontaneous copulations, we find no evidence of mate choice based on body size. These results contribute to a growing field of research which attempts to understand the evolution of the wide variation in the ways that hermaphroditic species respond to the size of potential mating partners.
Tracking sperm of a donor in a recipient: an immunocytochemical approach
Authors: Schärer Lukas , Zaubzer Johanna , Salvenmoser Willi , Seifarth Christof , Ladurner Peter 
Published: April 2007

Abstract
In order to study the mechanisms of sperm competition and cryptic female choice we require an understanding of the patterns of sperm storage, sperm removal and sperm digestion. Current studies infer these patterns mainly from paternity data, which only reveal the ultimate outcomes of the interactions between male and female reproductive processes. However, only with a mechanistic understanding of the fate of received sperm, and the involved patterns of postcopulatory sexual selection, can we understand the evolution of male and female reproductive morphology and physiology. The currently available approaches for tracking donor sperm in a recipient are either very time consuming, spatially imprecise or limited to model organisms for which considerable genetic knowledge and molecular know-how is available. Using the free-living flatworm Macrostomum lignano we here present a novel sperm tracking approach that uses DNA-labelling with a halogenated pyrimidine and localisation of the label using immunocytochemistry. We first outline modifications to established protocols to allow visualisation of gametic cells, in addition to somatic cells, determine the duration and patterns of spermatogenesis, and then show that labelled sperm from labelled donors can be observed in unlabelled recipients. We further show that labelled worms have a mating behaviour that is comparable to that of unlabelled worms except in one parameter. We suggest ways in which this approach can be optimised, and that it should be readily transferable to other taxa. We conclude that this approach will be a valuable tool to study postcopulatory sexual selection.
Mating behaviour in the terrestrial slug Deroceras gorgonium: is extreme morphology associated with extreme behaviour?
Authors: Reise Heike , Visser Stefanie , Hutchinson John 
Published: April 2007

Abstract
Mating in Deroceras consists of an investigation phase (precourtship), then a long courtship involving mutual stroking with the extruded sarcobelum, then sperm exchange (copulation). The penial gland, if present, everts over the partner's skin during copulation: this is hypothesised to apply a secretion manipulating the partner to use received sperm. Deroceras gorgonium has a particularly large penial gland divided into many finger-like branches. We studied D. gorgonium mating behaviour in the hope of further indications of the gland's function. Precourtship and courtship together last longer than in other Deroceras (ca. 6 h to >9 h); precourtship is highly variable, often with many bouts of different behaviours, including seemingly inactive phases. During most of the courtship partners remain apart waving their particularly long, pointed sarcobela; only at a later stage do the tips of these contact the partner. This waving alternates with circling for half a turn. For the first time in Deroceras we observed the sarcobelum transferring a secretion. The copulation is amongst the fastest: genital eversion and sperm exchange occur within 1 s, and slugs separate 18-25 s later. The penial gland is everted immediately after sperm exchange, but, surprisingly, is often spread underneath the partner rather than over its back and, if on top, is not always fully spread over the partner's body. We discuss these observations with respect to penial gland morphology and in the light of possible sexual conflicts. The long courtship and distant sarcobelum waving might reflect attempts to transfer, but not receive, secretion, and the circling might serve for size assessment.
Store-refilling involves both L-type calcium channels and reverse-mode sodium–calcium exchange in airway smooth muscle
Authors: Hirota S. , Janssen L. J. 
Published: April 2007

The aim of the present study was to examine the relative contributions to store-refilling of the two following voltage-regulated calcium ion influx pathways: 1) L-type-Ca2+channels; and 2) the reverse-mode of the sodium–calcium exchanger (NCX).Successive acetylcholine-induced contractions, triggered in bovine tracheal smooth muscle strips, were measured to determine the effect of intervention on contractions as an indication of the extent of store-refilling.Pre-treating the tissues with cromakalim significantly reduced the magnitude of successive contractions. Zero-Ca2+bathing media abolished the contractions, an effect that was completely reversed upon reintroduction of Ca2+. Inhibition of L-type Ca2+channels, with nifedipine, significantly reduced the magnitude of the contractions. Similarly, inhibition of the reverse-mode of the NCX, with KB-R7943, significantly reduced the magnitude of the contractions. However, neither nifedipine nor KB-R7943 alone reduced contractions to the same extent as observed under zero-Ca2+conditions. Concurrent treatment with nifedipine and KB-R7943 almost abolished successive contractions. Furthermore, concurrent treatment with nifedipine and zero-Na+bathing media displayed a significantly greater effect than nifedipine alone. Probing the expression of NCX1 isoforms by Western blotting revealed the presence of three bands of 160, 120 and 110 kDa. The 120- and 110-kDa bands were identified as variably spliced NCX isoforms, NCX1.1 and NCX1.3, respectively.Taken together, these data suggest that influx of calcium ions through both L-type calcium channels and the reverse-mode of the sodium–calcium exchanger is necessary for complete store-refilling in airway smooth muscle.