bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
Authors: Pannequin Julie , Bonnans Caroline , Delaunay Nathalie , Ryan Joanne , Bourgaux Jean-François , Joubert Dominique , Hollande Frédéric 
Published: July 2009

Abstract
The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand Jagged-1, downstream of β-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of Jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Wnt signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC. [Cancer Res 2009;69(15):6065–73]
Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway
Authors: Crabtree Judy S. , Jelinsky Scott A. , Harris Heather A. , Choe Sung E. , Cotreau Monette M. , Kimberland Michelle L. , Wilson Ewa , Saraf Kathryn A. , Liu Wei , McCampbell Adrienne S. , Dave Bhuvanesh , Broaddus Russell R. , Brown Eugene L. , Kao Wenling , Skotnicki Jerauld S. , Abou-Gharbia Magid , Winneker Richard C. , Walker Cheryl L. 
Published: July 2009

Abstract
Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth. [Cancer Res 2009;69(15):6171–8]
CTLA4Variants, UV-Induced Tolerance, and Risk of Non-Melanoma Skin Cancer
Authors: Welsh Marleen M. , Applebaum Katie M. , Spencer Steven K. , Perry Ann E. , Karagas Margaret R. , Nelson Heather H. 
Published: July 2009

AbstractAlthough skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (Pinteraction = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States. [Cancer Res 2009;69(15):6158–63]
Complete Regression of Advanced Primary and Metastatic Mouse Melanomas following Combination Chemoimmunotherapy
Authors: Kohlmeyer Judith , Cron Mira , Landsberg Jennifer , Bald Tobias , Renn Marcel , Mikus Sandra , Bondong Sandra , Wikasari Diana , Gaffal Evelyn , Hartmann Gunther , Tüting Thomas 
Published: July 2009

Abstract
The development of therapeutic strategies which induce effective cellular antitumor immunity represents an important goal in cancer immunology. Here, we used the unique features of the genetically engineered Hgf-Cdk4R24C mouse model to identify a combination chemoimmunotherapy for melanoma. These mice develop primary cutaneous melanomas which grow progressively and metastasize in the absence of immunogenic foreign proteins such as oncogenes or antigens. Primary and metastatic tumors evade innate and adaptive immune defenses, although they naturally express melanocytic antigens which can be recognized by antigen-specific T cells. We found that primary melanomas continued to grow despite infiltration with adoptively transferred, in vivo–activated, tumor-specific CD8+ T cells. To promote tumor immune defense, we developed a treatment protocol consisting of four complementary components: (a) chemotherapeutic preconditioning prior to (b) adoptive lymphocyte transfer and (c) viral vaccination followed by (d) adjuvant peritumoral injections of immunostimulatory nucleic acids. Lymphocyte ablation and innate antiviral immune stimulation cooperatively enhanced the expansion and the effector cell differentiation of adoptively transferred lymphocytes. The efficacy of the different treatment approaches converged in the tumor microenvironment and induced a strong cytotoxic inflammatory response enabling preferential recognition and destruction of melanoma cells. This combination chemoimmunotherapy caused complete regression of advanced primary melanomas in the skin and metastases in the lung with minimal autoimmune side effects. Our results in a clinically highly relevant experimental model provide a scientific rationale to evaluate similar strategies which unleash the power of innate and adaptive immune defense in future clinical trials. [Cancer Res 2009;69(15):6265–74]
Dynamic Contrast-enhanced Magnetic Resonance Imaging as a Predictor of Clinical Outcome in Canine Spontaneous Soft Tissue Sarcomas Treated with Thermoradiotherapy
Authors: Viglianti Benjamin L. , Lora-Michiels Michael , Poulson Jeanie M. , Lan Lan , Yu Dahio , Sanders Linda , Craciunescu Oana , Vujaskovic Zeljko , Thrall Donald E. , MacFall James , Charles Cecil H. , Wong Terence , Dewhirst Mark W. 
Published: July 2009

AbstractPurpose: This study tests whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters obtained from canine patients with soft tissue sarcomas, treated with hyperthermia and radiotherapy, are predictive of therapeutic outcome.Experimental Design: Thirty-seven dogs with soft tissue sarcomas had DCE-MRI done before and following the first hyperthermia. Signal enhancement for tumor and reference muscle were fitted empirically, yielding a washin/washout rate for the contrast agent and tumor area under the signal enhancement curve (AUC) calculated from 0 to 60 seconds, 90 seconds, and the time of maximal enhancement in the reference muscle. These parameters were then compared with local tumor control, metastasis-free survival, and overall survival.Results: Pretherapy rate of contrast agent washout was positively predictive of improved overall and metastasis-free survival with hazard ratio of 0.67 (P = 0.015) and 0.68 (P = 0.012), respectively. After the first hyperthermia washin rate, AUC60, AUC90, and AUCt-max were predictive of improved overall and metastasis-free survival with hazard ratio ranging from 0.46 to 0.53 (P &lt; 0.002) and 0.44 to 0.55 (P &lt; 0.004), respectively. DCE-MRI parameters were compared with extracellular pH and 31P MR spectroscopy results (previously published) in the same patients showing a correlation. This suggested that an increase in perfusion after therapy was effective in eliminating excess acid from the tumor.Conclusions: This study shows that DCE-MRI has utility predicting overall and metastasis-free survival in canine patients with soft tissue sarcomas. To our knowledge, this is the first time that DCE-MRI parameters are predictive of clinical outcome for soft tissue sarcomas.
HER Family Receptor Abnormalities in Lung Cancer Brain Metastases and Corresponding Primary Tumors
Authors: Sun Menghong , Behrens Carmen , Feng Lei , Ozburn Natalie , Tang Ximing , Yin Guosheng , Komaki Ritsuko , Varella-Garcia Marileila , Hong Waun Ki , Aldape Kenneth D. , Wistuba Ignacio I. 
Published: July 2009

Abstract
Purpose: To compare the characteristics of deregulation of HER receptors and their ligands between primary tumor and corresponding brain metastases of non–small cell lung carcinoma (NSCLC).
Experimental Design: Fifty-five NSCLC primary tumors and corresponding brain metastases specimens were examined for the immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Her2, Her3, and phosphorylated Her3, and their ligands EGF, transforming growth factor-α, amphiregulin, epiregulin, betacellulin, heparin-binding EGFR-like growth factor, neuregulin (NRG) 1, and NRG2. Analysis of EGFR copy number using fluorescence in situ hybridization and mutation by PCR-based sequencing was also done.
Results: Metastases showed significantly higher immunohistochemical expression of EGF (membrane: brain metastases 66.0 versus primary tumors 48.5; P = 0.027; nucleus: brain metastases 92.2 versus 67.4; P = 0.008), amphiregulin (nucleus: brain metastases 53.7 versus primary tumors 33.7; P = 0.019), phosphorylated EGFR (membrane: brain metastases 161.5 versus primary tumors 76.0; P &lt; 0.0001; cytoplasm: brain metastases 101.5 versus primary tumors 55.9; P = 0.014), and phosphorylated Her3 (membrane: brain metastases 25.0 versus primary tumors 3.7; P = 0.001) than primary tumors did. Primary tumors showed significantly higher expression of cytoplasmic transforming growth factor-α(primary tumors 149.8 versus brain metastases 111.3; P = 0.008) and NRG1 (primary tumors 158.5 versus brain metastases 122.8; P = 0.006). In adenocarcinomas, a similar high frequency of EGFR copy number gain (high polysomy and amplification) was detected in primary (65%) and brain metastasis (63%) sites. However, adenocarcinoma metastases (30%) showed higher frequency of EGFR amplification than corresponding primary tumors (10%). Patients whose primary tumors showed EGFR amplification tended to develop brain metastases at an earlier time point.
Conclusions: Our findings suggest that NSCLC brain metastases have some significant differences in HER family receptor–related abnormalities from primary lung tumors.
Differential Genetic and Functional Markers of Second Neoplasias in Hodgkin's Disease Patients
Authors: Lorenzo Yolanda , Provencio Mariano , Lombardía Luís , Díaz Raquel , Silva Javier , Herrera Mercedes , García Jose M. , Peña Cristina , García Vanesa , Romero Jesús , Domínguez Gemma , Bonilla Félix 
Published: July 2009

AbstractPurpose: The mechanisms involved in the appearance of a second neoplasia in patients with Hodgkin's disease (HD) are probably related to the genomic damage induced by the treatments administered and its repair. Here, we searched for some constitutive molecular mechanisms that in a basal manner may influence the behavior of HD patients.Experimental Design: We aimed to evaluate with the Comet Assay whether baseline, induced, and unrepaired DNA damage differ between HD patients who did not develop a second neoplasia (HD-NST), HD patients who developed a second tumor (HD-ST), and healthy individuals; and to identify, through cDNA microarray hybridization, an expression signature of genes that could discriminate between the three groups.Results: Baseline, induced, and unrepaired DNA damage was higher in HD-ST than in HD-NST and higher in the second group than in healthy donors. The genomic approach revealed two sets of genes that discriminated between healthy subjects and patients and between the three sets of individuals. Hsp40, RAD50, TPMT, Rap2a, E2F2, EPHX2, TBX21, and BATF were validated by reverse transcription-PCR.Conclusions: Functional and genomic techniques revealed that alterations in cell cycle, repair, detoxification, and stress response pathways could be involved in the development of HD and in the occurrence of a primary second neoplasia in these patients. Both approaches may be useful as biological markers in the clinical setting.
Clinical and Immunologic Effects of Intranodal Autologous Tumor Lysate-Dendritic Cell Vaccine with Aldesleukin (Interleukin 2) and IFN-α2a Therapy in Metastatic Renal Cell Carcinoma Patients
Authors: Schwaab Thomas , Schwarzer Adrian , Wolf Benita , Crocenzi Todd S. , Seigne John D. , Crosby Nancy A. , Cole Bernard F. , Fisher Jan L. , Uhlenhake Jill C. , Mellinger Diane , Foster Cathy , Szczepiorkowski Zbigniew M. , Webber Susan M. , Schned Alan R. , Harris Robert D. , Barth Richard J. , Heaney John A. , Noelle Randolph J. , Ernstoff Marc S. 
Published: July 2009

Abstract
Purpose: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-α 2a in metastatic renal cell carcinoma patients.
Experimental Design: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 × 107 cells/1 mL Lactated Ringer's solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-α 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti–renal cell carcinoma antibody and cytokine levels.
Results: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4+ T regulatory cells had a strong association with outcome. Pre–IP-10 serum levels approached significance for predicting outcome.
Conclusions: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.
Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene
Authors: Fernandes Margret S. , Gomes Erica M. , Butcher Lindsay D. , Hernandez-Alcoceba Reuben , Chang Dongkun , Kansopon Joe , Newman Joseph , Stone Marvin J. , Tong Alex W. 
Published: July 2009

AbstractPurpose: The growth-inhibitory activity of recombinant CD40 ligand (CD40L) is well documented in human multiple myeloma (MM). We examined MM-targeted delivery of CD40L by a conditional replicative oncolytic adenovirus, AdEHCD40L.Experimental Design: The growth-regulatory activity of AdEHCD40L was determined in vitro and in vivo. Differential analysis with AdEHCD40L and parental virus (AdEHNull)–infected cultures allowed the identification of cellular and molecular pathways modulated by the CD40L transgene.Results: Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ. AdEHCD40L inhibited MM cell growth more effectively than AdEHNull. This enhanced growth-inhibitory activity was abrogated by cotreatment with a CD40L antibody. Chemoresistant MM lines (MR20 and LR5) were similarly susceptible to AdEHCD40L treatment. AdEHCD40L induced apoptosis and S-phase cell cycle blockade while uniquely up-regulating the previously described proapoptotic elements tumor necrosis factor–related apoptosis-inducing ligand, Fas, and IL-8. Intratumoral injections of AdEHCD40L reduced the growth of severe combined immunodeficient/hu RPMI 8226 xenografts by &gt;50% compared with 28% reduction by AdEHNull. Adenoviral hexon and CD40L were detected in AdEHCD40L-treated tumors at day 35 after infection primarily in necrotic areas, suggesting viral replicative activity.Conclusions: These findings show that CD40L acts in concert with viral oncolysis to produce MM growth inhibition through activation of cellular apoptosis. The direct growth-inhibitory activity of AdEHCD40L, together with the well-known immune-potentiating features of CD40L, may be clinically applicable for the experimental treatment of MM or plasma cell leukemia.
Adjuvant Trastuzumab Induces Ventricular Remodeling Despite Aerobic Exercise Training
Authors: Haykowsky Mark J. , Mackey John R. , Thompson Richard B. , Jones Lee W. , Paterson D. Ian 
Published: July 2009

Abstract
Purpose: To examine the effect of aerobic training in mitigating trastuzumab-mediated left ventricular (LV) remodeling in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
Experimental Design: Seventeen women (53 ± 7 years) with HER2-positive breast cancer did aerobic training during the first 4 months of adjuvant trastuzumab. Peak oxygen consumption and magnetic resonance imaging assessment of LV volumes, mass, and rest and peak (dobutamine stress) ejection fraction were assessed before and after 4 months of trastuzumab.
Results: Participants attended 59% ± 32% of prescribed exercise sessions at 78% ± 6% of peak heart rate. Peak exercise heart rate, systolic and diastolic blood pressure, power output, and oxygen consumption were not different after training (all P-values &gt; 0.05). Exercise adherence predicted change in peak oxygen consumption (r = 0.77; P = 0.000). Resting end-diastolic (pre: 120 ± 23 mL versus post: 133 ± 16 mL) and end-systolic volumes (pre: 44 ± 12 mL versus post: 55 ± 11 mL) and mass (pre: 108 ± 21 g versus post: 114 ± 18 g) increased, whereas ejection fraction (pre: 64% ± 4% versus post: 59% ± 4%) decreased from baseline to post-intervention (all P-values &lt; 0.05). Peak ejection fraction was lower after 4 months (pre: 79 ± 4 versus post: 76 ± 6%; P = 0.087).
Conclusion: Initiation of adjuvant trastuzumab therapy is associated with LV cavity dilation and reduced ejection fraction despite aerobic exercise training. The long-term consequences of trastuzumab-induced LV remodeling and the means to prevent LV dysfunction require further study.
Pitavastatin Fails to Lower Serum Lipid Levels or Inhibit Gastric Carcinogenesis in Helicobacter pylori–Infected Rodent Models
Authors: Toyoda Takeshi , Tsukamoto Tetsuya , Takasu Shinji , Hirano Naoki , Ban Hisayo , Shi Liang , Kumagai Toshiko , Tanaka Takuji , Tatematsu Masae 
Published: July 2009

Abstract
Statins are commonly used lipid-lowering drugs that reduce the risk of cardiovascular morbidity and mortality. Although recent studies have pointed to chemopreventive effects of statins against various cancers, their efficacy for gastric cancer is unclear. Here, we examined the effects of pitavastatin, a lipophilic statin, on Helicobacter pylori (H. pylori)–associated stomach carcinogenesis and gastritis using Mongolian gerbil and mouse models. The animals were allocated to H. pylori + N-methyl-N-nitrosourea administration (gerbils, 52 weeks) or H. pylori infection alone groups (gerbils and mice, 12 weeks). After H. pylori infection, they were fed basal diets containing 0 to 10 ppm of pitavastatin. The incidences of H. pylori–associated gastric adenocarcinomas and degrees of chronic gastritis were not decreased by pitavastatin compared with those of control values. Expression of interleukin-1β and tumor necrosis factor-α mRNAs in the pyloric mucosa was markedly up-regulated in pitavastatin-treated animals. Furthermore, in the H. pylori–infected groups, serum total cholesterol, triglyceride, and low-density lipoprotein levels were significantly increased by pitavastatin treatment, contrary to expectation. In the short-term study, H. pylori–infected gerbils and mice also showed significant up-regulation of serum triglyceride levels by pitavastatin, whereas total cholesterol was markedly reduced and low-density lipoprotein exhibited a tendency for decrease in noninfected animals. These findings indicate pitavastatin to be ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in H. pylori–infected gerbils. Our serologic results also suggest that the H. pylori infection and consequent severe chronic gastritis interfere with the cholesterol-lowering effects of pitavastatin.
Nematodes of the order Rhabditida from Andalucía Oriental, Spain. The genus Cephalobus Bastian, 1865 with description of C. harpagonis sp. n. and key to species
Authors: Abolafia Joaquín , Peña-Santiago Reyes 
Published: July 2009

AbstractA new species of the genus Cephalobus is described from natural areas in the south-eastern Iberian Peninsula. Cephalobus harpagonis sp. n. is characterised by female body length of 0.38-0.47 mm, lips amalgamated in pairs, labial probolae present as low ridges connecting tips of adjacent lips, ovary lacking flexures, spermatheca 11-12 μm long, postuterine sac very short (0.3-0.4 times corresponding body diam.), female tail conical or subcylindrical (22-31 μm, c = 13.2-17.1, c′ = 1.7-2.5) and ending in a tuberculate, often harpoon-like, mucro. Descriptions, measurements and illustrations, including SEM photographs, are also provided for C. persegnis and C. troglophilus from Spain. An identification key to Cephalobus species and a compendium of their measurements are also provided.