bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non–small cell lung cancer
Authors: Bao Rudi , Lai Cheng-Jung , Wang Da-Gong , Qu Hui , Yin Ling , Zifcak Brian , Tao Xu , Wang Jing , Atoyan Ruzanna , Samson Maria , Forrester Jeffrey , Xu Guang-Xin , DellaRocca Steven , Borek Mylissa , Zhai Hai-Xiao , Cai Xiong , Qian Changgeng 
Published: December 2009

Abstract
CUDC-305 is a heat shock protein 90 (HSP90) inhibitor of the novel imidazopyridine class. Here, we report its activities in non–small cell lung cancer (NSCLC) cell lines with gene deregulations conferring primary or secondary resistance to epidermal growth factor receptor (EGFR) inhibitors. We show that CUDC-305 binds strongly to HSP90 extracted from erlotinib-resistant NSCLC cells (IC50 70 nmol/L). This result correlates well with the potent antiproliferative activity in erlotinib-resistant NSCLC cell lines (IC50 120–700 nmol/L) reported previously. Furthermore, it exhibits durable inhibition of multiple oncoproteins and induction of apoptosis in erlotinib-resistant NSCLC cells. CUDC-305 potently inhibits tumor growth in subcutaneous xenograft models of H1975 and A549, which harbor EGFR T790M mutation or K-ras mutations conferring acquired and primary erlotinib resistance, respectively. In addition, CUDC-305 significantly prolongs animal survival in orthotopic lung tumor models of H1975 and A549, which may be partially attributed to its preferential exposure in lung tissue. Furthermore, CUDC-305 is able to extend animal survival in a brain metastatic model of H1975, further confirming its ability to cross the blood-brain barrier. Correlating with its effects in various tumor models, CUDC-305 induces degradation of receptor tyrosine kinases and downstream signaling molecules of the PI3K/AKT and RAF/MEK/ERK pathways simultaneously, with concurrent induction of apoptosis in vivo. In a combination study, CUDC-305 enhanced the antitumor activity of a standard-of-care agent in the H1975 tumor model. These results suggest that CUDC-305 holds promise for the treatment of NSCLC with primary or acquired resistance to EGFR inhibitor therapy. [Mol Cancer Ther 2009;8(12):3296–306]
A novel two-step transcriptional activation system for gene therapy directed toward epithelial cells
Authors: Arendt Maja L. , Nasir Lubna , Morgan Iain M. 
Published: December 2009

Abstract
The two-step transcriptional activation (TSTA) mechanism in gene therapy amplifies cell type–specific promoter activity, allowing for increased levels of gene expression in target tissues. In this system, the specific promoter drives expression of a strong transcriptional activator that binds to DNA target sequences located upstream from a second promoter controlling the expression of the therapeutic gene. The majority of previous studies have exploited a fusion between the DNA binding domain of the yeast transcriptional activator Gal4 fused to the VP16 activation domain of herpes simplex virus 1 as the transcriptional activator. In this report, an alternative to this system is described based on a fusion protein containing the DNA binding domain of the bovine papillomavirus 1 transcriptional activator E2 fused to VP16 that induces target gene expression following binding to a minimal bovine papillomavirus 4 promoter containing upstream E2 binding sites and only 3 bp of promoter sequence upstream from the TATA box. VP16-E2 is superior to Gal4-VP16 as the transcriptional activator in a TSTA system driven by either of the two potentially cancer-specific promoters telomerase RNA and telomerase reverse transcriptase in several cell lines. Results also suggest that this new system has an advantage in epithelial cells and is therefore ideal for potential targeting of carcinomas. By incorporating the TRAIL gene as a transgene in the VP16-E2 TSTA system, selective killing of telomerase-positive cells occurs. We propose that our new system should be considered in future TSTA, particularly when targeting epithelial-derived cells. [Mol Cancer Ther 2009;8(12):3244–54]
The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activityin vivo
Authors: Douglas Mark , Lim Alice R. , Porter James R. , West Kip , Pink Melissa M. , Ge Jie , Wylie Andrew A. , Tibbits Thomas T. , Biggs Kurtis , Curtis Michael , Palombella Vito J. , Adams Julian , Fritz Christian C. , Normant Emmanuel 
Published: December 2009

AbstractIPI-504, a water-soluble ansamycin analogue currently being investigated in clinical trials, is a potent inhibitor of the protein chaperone heat shock protein 90 (Hsp90). Inhibition of Hsp90 by IPI-504 triggers the degradation of important oncogenic client proteins. In cells, the free base of IPI-504 hydroquinone exists in a dynamic redox equilibrium with its corresponding quinone (17-AAG); the hydroquinone form binding 50 times more tightly to Hsp90. It has been proposed recently that the NAD(P)H:quinone oxidoreductase NQO1 can produce the active hydroquinone and could be essential for the activity of IPI-504. Here, we have devised a method to directly measure the intracellular ratio of hydroquinone to quinone (HQ/Q) and have applied this measurement to correlate NQO1 enzyme abundance with HQ/Q ratio and cellular activity of IPI-504 in 30 cancer cell lines. Interestingly, the intracellular HQ/Q ratio was correlated with NQO1 levels only in a subset of cell lines and overall was poorly correlated with the growth inhibitory activity of IPI-504. Although artificial overexpression of NQO1 is able to increase the level of hydroquinone and cell sensitivity to IPI-504, it has little effect on the activity of 17-amino-17-demethoxy-geldanamycin, the major active metabolite of IPI-504. This finding could provide an explanation for the biological activity of IPI-504 in xenograft models of cell lines that are not sensitive to IPI-504 in vitro. Our results suggest that NQO1 activity is not a determinant of IPI-504 activity in vivo and, therefore, unlikely to become an important resistance mechanism to IPI-504 in the clinic. [Mol Cancer Ther 2009;8(12):3369–78]
Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D
Authors: Ballot Caroline , Kluza Jérome , Martoriati Alain , Nyman Ulrika , Formstecher Pierre , Joseph Bertrand , Bailly Christian , Marchetti Philippe 
Published: December 2009

Abstract
Lamellarin D, a potent cytotoxic marine alkaloid, exerts its antitumor action through two complementary pathways: a nuclear route via topoisomerase I inhibition and a mitochondrial targeting. The present study was designed to investigate the contribution of these two pathways for apoptosis in cancer cells. Lamellarin D promoted nuclear apoptosis in leukemia cells without prominent cell cycle arrest. Signals transmitted by lamellarin D initiated apoptosis via the intrinsic apoptotic pathway. The drug induced conformational activation of Bax and decreased the expression levels of antiapoptotic proteins Bcl-2 and cIAP2 in association with activation of caspase-9 and caspase-3. Upon lamellarin D exposure, Fas and Fas-L expression was not modified in leukemia cells. Moreover, leukemia cells deficient in caspase-8 or Fas-associated protein with death domain underwent apoptosis through the typical mitochondrial apoptotic cascade, indicating that cell death induced by lamellarin D was independent of the extrinsic apoptotic pathway. Lamellarin D also exerted a topoisomerase I–mediated DNA damage response resulting in H2AX phosphorylation, and the upregulation of the DNA repair protein Rad51 and of p53, as well as the phosphorylation of p53 at serine 15. However, lamellarin D killed efficiently mutated p53 or p53 null cancer cells, and sensitivity to lamellarin D was abrogated neither by cycloheximide nor in enucleated cells. Lamellarin D–induced cytochrome c release occurs independently of nuclear factors in a cell-free system. These results suggest that lamellarin D exerts its cytotoxic effects primarily by inducing mitochondrial apoptosis independently of nuclear signaling. Thus, lamellarin D constitutes a new proapoptotic agent that may bypass certain forms of apoptosis resistance that occur in tumor cells. [Mol Cancer Ther 2009;8(12):3307–17]
COMP-Ang1 Potentiates the Antitumor Activity of 5-Fluorouracil by Improving Tissue Perfusion in Murine Lewis Lung Carcinoma
Authors: Hwang Jeong-Ah , Lee Eun Hui , Kim Hyun-Woo , Park Jin Bong , Jeon Byeong Hwa , Cho Chung-Hyun 
Published: December 2009

Abstract
Chemotherapy is often hindered by abnormal tumor vascularity, which causes impaired delivery of drugs into the tumor. Angiopoietin-1 has potent roles in angiogenesis and vessel maturation. We report here that an angiopoietin-1 variant, COMP-Ang1, promotes vascular remodeling and pericyte coverage and thereby promotes the efficient delivery of a chemotherapeutic drug into tumors of murine Lewis lung carcinoma. The combination of COMP-Ang1 with the cytotoxic drug 5-fluorouracil potentiated the effect of 5-fluorouracil on tumor growth without increasing animal toxicity. Moreover, COMP-Ang1 increased perfusion into the tumor. Although COMP-Ang1 increased the functional vasculature in the tumor, COMP-Ang1 alone did not promote tumor growth, possibly due to its promotion of increased pericyte coverage. This study suggests that COMP-Ang1 may improve the microcirculation within a tumor by increasing functional vasculature and tissue perfusion and that the combination of chemotherapy together with COMP-Ang1 might be an advantageous therapeutic approach. (Mol Cancer Res 2009;7(12):1920–7)
A DNA Methyltransferase Inhibitor andAll-transRetinoic Acid Reduce Oral Cavity Carcinogenesis Induced by the Carcinogen 4-Nitroquinoline 1-Oxide
Authors: Tang Xiao-Han , Albert Martin , Scognamiglio Theresa , Gudas Lorraine J. 
Published: December 2009

AbstractThe transcriptional silencing of some cell cycle inhibitors and tumor suppressors, such as p16 and retinoic acid receptor β2, by DNA hypermethylation at CpG islands is commonly found in human oral squamous carcinoma cells. We examined the effects of the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza; 0.25 mg/kg body weight), all-trans retinoic acid (RA; given at 100 μg/kg body weight and 1 mg/kg body weight), and the combination of 5-Aza and the low-dose RA on murine oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model. All the drug treatments were done for 15 weeks after a 10-week 4-NQO treatment. Mice in all drug treatment groups showed decreases in the average numbers of neoplastic tongue lesions. The combination of 5-Aza and RA effectively attenuated tongue lesion severity. Although all drug treatments limited the increase in the percentage of proliferating cell nuclear antigen–positive cells and the decrease in the percentage of p16-positive cells caused by the 4-NQO treatment in mouse tongue epithelial regions without visible lesions and in the neoplastic tongue lesions, the combination of 5-Aza and RA was the most effective. Collectively, our results show that the combination of a DNA demethylating drug and RA has potential as a strategy to reduce oral cavity cancer in this 4-NQO model.
Gender Modifies the Effect of Ursodeoxycholic Acid in a Randomized Controlled Trial in Colorectal Adenoma Patients
Authors: Thompson Patricia A. , Wertheim Betsy C. , Roe Denise J. , Ashbeck Erin L. , Jacobs Elizabeth T. , Lance Peter , Martínez María Elena , Alberts David S. 
Published: December 2009

AbstractPurpose: Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk.Experimental Design: We conducted a secondary analysis of the efficacy of UDCA to prevent colorectal adenoma in men (n = 804) and women (n = 388).Results: We found no reduction in risk of any metachronous adenoma with UDCA treatment in men or women. However, UDCA treatment significantly lowered the odds of advanced lesions [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.43-0.89] in men, but not women. We also observed significantly higher odds of advanced lesions with UDCA treatment in women who were younger (age, &lt;65 years; OR, 3.24; 95% CI, 1.10-9.56), obese (body mass index, ≥30 kg/m2; OR, 5.45; 95% CI, 1.42-20.9), or in the highest tertile of total dietary fat (≥56.2 g/day; OR, 3.48; 95% CI, 1.35-8.95). In a multivariate model, the interactive effect of fat intake accounted for the modulating effects of age and body mass index in women.Conclusion: Our findings support the use of UDCA for preventing advanced colorectal adenomas in men. The increased odds of adenoma among women with high fat intake suggest a previously unrecognized harm that warrants further study, especially given the chronic exposure to UDCA in patients with primary biliary cirrhosis and the increasing investigational use of UDCA for several other conditions.
What Makes Shabti Slave?
Authors: Silver Morris 
Published: December 2009

AbstractThe first part of this paper considers why small funerary figures called shabtis, were willing to slave in the Beyond for deceased Egyptians. The proposed answer is that they agreed in return for being given "life" by the craftsman. It is well understood that ancient Egyptians were willing to utilize standard legal forms to mediate between the earthly and supernatural dimensions. However, consideration of the "contract" between craftsmen and shabtis casts new light on the nature of ancient Egypt's labor market and, more specifically, on the prevalence of resorting to contractual slavery. The second part of the paper uses economic analysis to reinforce the suggestion that temple ateliers probably earned a substantial profit by marketing shabtis. La première partie de cet article envisage les raisons pour lesquelles les figurines funéraires appelées oushebtis consentaient à servir les Egyptiens comme esclaves dans l'au-delà. Nous proposons que ces figurines acceptaient ce rôle en échange de la « vie » que leur insufflaient les artisans. Il est bien connu que les anciens Egyptiens employaient des formulaires juridiques comme mode de médiation entre le domaine terrestre et celui du surnaturel. L'examen du « contrat » passé entre artisans et oushebtis éclaire néanmoins d'un jour nouveau la nature du marché du travail dans l'Egypte ancienne, notamment le recours répandu à l'esclavage contractuel. Dans la seconde partie de l'article, une analyse économique confirme que la vente des oushebtis assurait vraisemblablement des profits substantiels aux ateliers des temples.
Ascertaining Living Standards in Erstwhile Mysore, Southern India, from Francis Buchanan's Journey of 1800-01: An Empirical Contribution to the Great Divergence Debate
Authors: Sivramkrishna Sashi 
Published: December 2009

AbstractIndia's position in the Great Divergence debate has remained tentative due to scanty data availability for the medieval and early modern periods. In the years 1800-01, Dr. Francis Buchanan conducted one of the first agricultural surveys in the erstwhile state of Mysore and its adjoining regions. His Journey contains a wealth of information, both quantitative and qualitative, which has not been studied systematically so far. This paper brings together the information scattered throughout his report to construct an aggregate welfare ratio in order to ascertain the overall living standard in Mysore at the turn of the nineteenth century, the eve of colonial intervention in the state. The results from this study have interesting and important implications for the Great Divergence debate. La place de l'Inde dans le débat sur la Grande Divergence est encore incertaine en raison de la rareté des données disponibles pour le Moyen Âge et le début de l'époque moderne. Dans les années 1800-'01, Francis Buchanan mena l'une des premières enquêtes agricoles dans l'ancien Etat de Mysore et les contrées avoisinantes. Son Voyage contient de nombreuses données relatives à cette région, tant quantitatives que qualitatives, qui n'ont jamais fait l'objet d'études systématiques. Cet article réunit les informations disponibles dans son rapport afin de restituer un taux global de bien-être. Il s'agit de déterminer le niveau de vie moyen au Mysore au tournant du XIXe siècle, à l'aube de l'intervention coloniale dans cet Etat. Les résultats de cette étude ont des implications importantes pour le débat sur la Grande Divergence.
Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils
Authors: Kang Elizabeth M. , Choi Uimook , Theobald Narda , Linton Gilda , Long Priel Debra A. , Kuhns Doug , Malech Harry L. 
Published: December 2009

Abstract
Chronic granulomatous disease (CGD) is associated with significant morbidity and mortality from infection. The first CGD gene therapy trial resulted in only short-term marking of 0.01% to 0.1% of neutrophils. A recent study, using busulfan conditioning and an SFFV retrovirus vector, achieved more than 20% marking in 2 patients with X-linked CGD. However, oxidase correction per marked neutrophil was less than normal and not sustained. Despite this, patients clearly benefited in that severe infections resolved. As such, we initiated a gene therapy trial for X-CGD to treat severe infections unresponsive to conventional therapy. We treated 3 adult patients using busulfan conditioning and an MFGS retroviral vector encoding gp91phox, achieving early marking of 26%, 5%, and 4% of neutrophils, respectively, with sustained long-term marking of 1.1% and 0.03% of neutrophils in 2 of the patients. Gene-marked neutrophils have sustained full correction of oxidase activity for 34 and 11 months, respectively, with full or partial resolution of infection in those 2 patients. Gene marking is polyclonal with no clonal dominance. We conclude that busulfan conditioning together with an MFGS vector is capable of achieving long-term correction of neutrophil oxidase function sufficient to provide benefit in management of severe infection. This study was registered at www.clinicaltrials.gov as #NCT00394316.
CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus
Authors: Zlotoff Daniel A. , Sambandam Arivazhagan , Logan Theodore D. , Bell J. Jeremiah , Schwarz Benjamin A. , Bhandoola Avinash 
Published: December 2009

AbstractT lymphopoiesis requires settling of the thymus by bone marrow–derived precursors throughout adult life. Progenitor entry into the thymus is selective, but the molecular basis of this selectivity is incompletely understood. The chemokine receptor CCR9 has been demonstrated to be important in this process. However, progenitors lacking CCR9 can still enter the thymus, suggesting a role for additional molecules. Here we report that the chemokine receptor CCR7 is also required for efficient thymic settling. CCR7 is selectively expressed on bone marrow progenitors previously shown to have the capacity to settle the thymus, and CCR7−/− progenitors are defective in settling the thymus. We further demonstrate that CCR7 sustains thymic settling in the absence of CCR9. Mice deficient for both CCR7 and CCR9 have severe reductions in the number of early thymic progenitors, and in competitive assays CCR7−/−CCR9−/− double knockout progenitors are almost completely restricted from thymic settling. However, these mice possess near-normal thymic cellularity. Compensatory expansion of intrathymic populations can account for at least a part of this recovery. Together our results illustrate the critical role of chemokine receptor signaling in thymic settling and help to clarify the cellular identity of the physiologic thymic settling progenitors.
Regulation of human NK-cell cytokine and chemokine production by target cell recognition
Authors: Fauriat Cyril , Long Eric O. , Ljunggren Hans-Gustaf , Bryceson Yenan T. 
Published: December 2009

AbstractNatural killer (NK)–cell recognition of infected or neoplastic cells can induce cytotoxicity and cytokine secretion. So far, it has been difficult to assess the relative contribution of multiple NK-cell activation receptors to cytokine and chemokine production upon target cell recognition. Using Drosophila cells expressing ligands for the NK-cell receptors LFA-1, NKG2D, DNAM-1, 2B4, and CD16, we studied the minimal requirements for secretion by freshly isolated, human NK cells. Target cell stimulation induced secretion of predominately proinflammatory cytokines and chemokines. Release of chemokines MIP-1α, MIP-1β, and RANTES was induced within 1 hour of stimulation, whereas release of TNF-α and IFN-γ occurred later. Engagement of CD16, 2B4, or NKG2D sufficed for chemokine release, whereas induction of TNF-α and IFN-γ required engagement of additional receptors. Remarkably, our results revealed that, upon target cell recognition, CD56dim NK cells were more prominent cytokine and chemokine producers than CD56bright NK cells. The present data demonstrate how specific target cell ligands dictate qualitative and temporal aspects of NK-cell cytokine and chemokine responses. Conceptually, the results point to CD56dim NK cells as an important source of cytokines and chemokines upon recognition of aberrant cells, producing graded responses depending on the multiplicity of activating receptors engaged.
The origin of bmp16, a novel Bmp2/4relative, retained in teleost fish genomes
Authors: Feiner Nathalie , Begemann Gerrit , Renz Adina J , Meyer Axel , Kuraku Shigehiro 
Published: December 2009

AbstractBackgroundWhole genome sequences have allowed us to have an overview of the evolution of gene repertoires. The target of the present study, the TGFβ superfamily, contains many genes involved in vertebrate development, and provides an ideal system to explore the relationships between evolution of gene repertoires and that of developmental programs.ResultsAs a result of a bioinformatic survey of sequenced vertebrate genomes, we identified an uncharacterized member of the TGFβ superfamily, designatedbmp16, which is confined to teleost fish species. Our molecular phylogenetic study revealed a high affinity ofbmp16to theBmp2/4subfamily. Importantly, further analyses based on the maximum-likelihood method unambiguously ruled out the possibility that this teleost-specific gene is a product of teleost-specific genome duplication. This suggests that the absence of abmp16ortholog in tetrapods is due to a secondary loss.In situhybridization showed embryonic expression of the zebrafishbmp16in the developing swim bladder, heart, tail bud, and ectoderm of pectoral and median fin folds in pharyngula stages, as well as gut-associated expression in 5-day embryos.ConclusionComparisons of expression patterns revealed (1) the redundancy ofbmp16expression with its homologs in presumably plesiomorphic expression domains, such as the fin fold, heart, and tail bud, which might have permitted its loss in the tetrapod lineage, and (2) the loss of craniofacial expression and gain of swim bladder expression ofbmp16after the gene duplication betweenBmp2,-4and-16. Our findings highlight the importance of documenting secondary changes of gene repertoires and expression patterns in other gene families.