bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor Alkyl Ether Lipid Edelfosine: Tissue Distribution and Pharmacokinetic Behavior in Healthy and Tumor-Bearing Immunosuppressed Mice
Authors: de Mendoza Ander Estella-Hermoso , Campanero Miguel A. , de la Iglesia-Vicente Janis , Gajate Consuelo , Mollinedo Faustino , Blanco-Prieto María J. 
Published: February 2009

Abstract
Purpose: The present study investigates and compares the dose-dependent pharmacokinetics and oral bioavailability of edelfosine in healthy, immunodeficient, and tumor-bearing immunosuppressed mouse animal models, as well as edelfosine uptake and apoptotic activity in the Z-138 mantle cell lymphoma (MCL) cell line.
Experimental design: Biodistribution study of edelfosine was done in both BALB/c and severe combined immune deficiency (SCID) mice, and then the in vivo behavior of the drug after i.v. and oral administration was monitored.
Results: We found that edelfosine is incorporated and induces apoptosis in the Z-138 human mantle cell lymphoma cell line, whereas normal resting peripheral blood human lymphocytes were not affected. In vivo biodistribution studies revealed that accumulation of edelfosine in the tumor of a MCL-bearing mouse animal model was considerably higher (P &lt; 0.01) than in the other organs analyzed. Besides, no statistical differences were observed between the pharmacokinetic parameters of BALB/c and SCID mice. Edelfosine presented slow elimination and high distribution to tissues. Bioavailability for a single oral dose of edelfosine was &lt;10%, but a multiple-dose oral administration increased this value up to 64%.
Conclusion: Our results show that edelfosine is widely scattered across different organs, but it is preferentially internalized by the tumor both in vitro and in vivo. Our data, together with the apoptotic action of the drug on cancer cells, support a rather selective action of edelfosine in cancer treatment, and that multiple oral administration is required to increase oral bioavailability.
In vivoModel of Follicular Lymphoma Resistant to Rituximab
Authors: Dalle Stéphane , Dupire Sophie , Brunet-Manquat Stéphanie , Reslan Lina , Plesa Adriana , Dumontet Charles 
Published: February 2009

AbstractPurpose: Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Rituximab is widely used alone or in combination therapy for the treatment of FL. Despite its well-established clinical efficacy, a subpopulation of patients does not respond to rituximab and most patients will relapse after therapy. The mechanisms of action and resistance to rituximab are not fully understood.Experimental Design: To study these mechanisms we developed an in vivo model of FL resistant to rituximab. This model was developed using the human RL line, isolated from a patient with FL, grown as xenotransplants in severe combined immunodeficient mice, exposed weekly to rituximab in vivo, followed by serial reimplantation and reexposure to rituximab, until a resistant phenotype was obtained.Results: RL-derived tumors unexposed to rituximab were grown as controls and compared with the resistant tumors. Although the expression of CD46 and CD55 antigens were not differently expressed in the resistant cells, the complement inhibitor CD59 was overexpressed in a subpopulation and CD20 was found to be expressed at a lower level in a minority of cells. Bcl-XL and YY1 were also found more highly expressed in rituximab-resistant cells.Conclusion: This model provides insight on potential in vivo resistance mechanisms to rituximab and could help contribute to the development of novel therapies in rituximab-refractory diseases.
Genetic Variants and Family History Predict Prostate Cancer Similar to Prostate-Specific Antigen
Authors: Zheng S. Lilly , Sun Jielin , Wiklund Fredrik , Gao Zhengrong , Stattin Pär , Purcell Lina D. , Adami Hans-Olov , Hsu Fang-Chi , Zhu Yi , Adolfsson Jan , Johansson Jan-Erik , Turner Aubrey R. , Adams Tamara S. , Liu Wennuan , Duggan David , Carpten John D. , Chang Bao-Li , Isaacs William B. , Xu Jianfeng , Grönberg Henrik 
Published: February 2009

Abstract
Purpose: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk.
Experimental Design: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer.
Results: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 × 10−10).
Conclusion: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.
Associations of High-Grade Prostate Cancer withBRCA1andBRCA2Founder Mutations
Authors: Agalliu Ilir , Gern Robert , Leanza Suzanne , Burk Robert D. 
Published: February 2009

AbstractPurpose: Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers.Experimental Design: To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models.Results: Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of &lt;7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of ≥7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer.Conclusion: These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options.
Human-Like Mouse Models for Testing the Efficacy and Safety of Anti-β2-Microglobulin Monoclonal Antibodies to Treat Myeloma
Authors: Yang Jing , Cao Yabing , Hong Sungyongl , Li Haiyan , Qian Jianfei , Kwak Larry W. , Yi Qing 
Published: February 2009

AbstractPurpose: We showed recently that anti-β2-microglobulin (β2M) monoclonal antibodies (mAb) have remarkably strong apoptotic effects on myeloma cells in vitro and in SCID-hu mice. However, whether the mAbs will be therapeutic and safe in the treatment of myeloma patients, in whom every tissue expresses low densities of MHC class I molecules and elevated levels of soluble β2M are present, remains to be determined.Experimental Design: In this study, human-like myeloma mouse models (HLA-A2-transgenic NOD/SCID mice) were developed, which express mature and functional human MHC class I (HLA-A2 and human β2M) on murine organs and present high levels of circulating human β2M derived from human myeloma cells. Myeloma-bearing mice were treated intraperitoneally with anti-β2M mAbs, and the distribution and effects of the mAbs on normal organs and established tumors were examined.Results: Our results show that anti-β2M mAbs were effective in suppressing myeloma growth in treated mice. The therapeutic efficacy of the mAbs in these mice are comparable with those observed in myeloma-bearing nontransgenic NOD/SCID mice in which no human MHC class I is expressed on murine organs. Furthermore, although the mAbs can be detected on different organs, no tissue damage or cell apoptosis was observed in the mice.Conclusion: Based on the antimyeloma efficacy and low toxicity in the mice, our study suggests that anti-β2M mAbs may be safe and the tissue-expressing and soluble β2M may not compromise their therapeutic effects in myeloma patients. This study provides further support for the future application of the mAbs as therapeutic agents for multiple myeloma.
A Simple and Accurate Model for Prediction of Cancer-Specific Mortality in Patients Treated with Surgery for Primary Penile Squamous Cell Carcinoma
Authors: Zini Laurent , Cloutier Vincent , Isbarn Hendrik , Perrotte Paul , Capitanio Umberto , Jeldres Claudio , Shariat Shahrokh F. , Saad Fred , Arjane Philippe , Duclos Alain , Lattouf Jean-Baptiste , Montorsi Francesco , Karakiewicz Pierre I. 
Published: February 2009

Abstract
Purpose: Cancer-specific mortality (CSM) of patients with primary penile squamous cell carcinoma (PPSCC) may be quite variable. Recently, a nomogram was developed to provide standardized and individualized mortality predictions. Unfortunately, it relies on a large number (n = 8) of specific variables that are unavailable in routine clinical practice. We attempted to develop a simpler prediction rule with at least equal accuracy in predicting CSM after surgical removal of PPSCC.
Experimental Design: The predictive rule was developed on a cohort of 856 patients identified in the 1988 to 2004 Surveillance, Epidemiology and End Results (SEER) database. The predictors consisted of age, race, SEER stage (localized versus regional versus metastatic), tumor grade, type of surgery (excisional biopsy, partial penectomy, and radical penectomy), and of lymph node status (pN0 versus pN1-3 versus pNx). A look-up table based on Cox regression model-derived coefficients was used for prediction of 5-year CSM. The predictive rule accuracy was tested using the Harrell's modification of the area under the receiver operating characteristics curve.
Results: SEER stage and histologic grade achieved independent predictor status and qualified for inclusion in the model. The model achieved 73.8% accuracy for prediction of CSM at 5 years after surgery. Both predictors achieved independent predictor status in competing risk regression models addressing CSM, where other cause mortality was controlled for.
Conclusion: Despite equivalent accuracy, our predictive rule predicting 5-year CSM in patients with PPSCC is substantially less complex (2 versus 8 variables) than the previously published model.
Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer
Authors: Schwarzenbach Heidi , Alix-Panabières Catherine , Müller Imke , Letang Nicolas , Vendrell Jean-Pierre , Rebillard Xavier , Pantel Klaus 
Published: February 2009

Abstract
Purpose: Circulating cell-free DNA in the blood of cancer patients harbors tumor-specific aberrations. Here, we investigated whether this DNA might also reflect the presence of circulating tumor cells (CTC).
Experimental Design: To identify the source of cell-free DNA in blood, plasma derived from 81 patients with prostate cancer was examined for CTCs and cell-free DNA. An epithelial immunospot assay was applied for detection of CTCs, and a PCR-based fluorescence microsatellite analysis with a panel of 14 polymorphic markers was used for detection of allelic imbalances (AI).
Results: The plasma DNA levels significantly correlated with the diagnosis subgroups of localized (stage M0, n = 69) and metastasized prostate cancer (stage M1, n = 12; P = 0.03) and with the tumor stage of these patients (P &lt; 0.005). AI was found on cell-free DNA in plasma from 45.0% and 58.5% of M0 and M1 patients, respectively. Detection of CTCs showed that 71.0% or 92.0% of the M0 and M1 patients harbored 1 to 40 CTCs in their blood, respectively. The occurrence of CTCs correlated with tumor stage (P &lt; 0.03) and increasing Gleason scores (P = 0.04). Notably, significant associations of the number of CTCs with the AI frequencies at the markers D8S137 (P = 0.03), D9S171 (P = 0.04), and D17S855 (P = 0.02) encoding the cytoskeletal protein dematin, the inhibitor of the cyclin-dependent kinase CDKN2/p16 and BRCA1, respectively, were observed.
Conclusions: These findings show, for the first time, a relationship between the occurrence of CTCs and circulating tumor-associated DNA in blood, which, therefore, might become a valuable new source for monitoring metastatic progression in cancer patients.
Addition of S-1 to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Overcomes Gefitinib Resistance in Non–small cell Lung Cancer Cell Lines withMETAmplification
Authors: Okabe Takafumi , Okamoto Isamu , Tsukioka Sayaka , Uchida Junji , Hatashita Erina , Yamada Yuki , Yoshida Takeshi , Nishio Kazuto , Fukuoka Masahiro , Jänne Pasi A. , Nakagawa Kazuhiko 
Published: February 2009

AbstractPurpose: Most non–small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET proto-oncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines.Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice.Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-fluorouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, but not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification.Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.
A Novel Human Her-2/neu Chimeric Molecule Expressed byListeria monocytogenesCan Elicit Potent HLA-A2 Restricted CD8-positive T cell Responses and Impact the Growth and Spread of Her-2/neu-positive Breast Tumors
Authors: Seavey Matthew M. , Pan Zhen-Kun , Maciag Paulo C. , Wallecha Anu , Rivera Sandra , Paterson Yvonne , Shahabi Vafa 
Published: February 2009

AbstractPurpose: The aim of this study was to efficiently design a novel vaccine for human Her-2/neu-positive (hHer-2/neu) breast cancer using the live, attenuated bacterial vector Listeria monocytogenes.Experimental Design: Three recombinant L. monocytogenes–based vaccines were generated that could express and secrete extracellular and intracellular fragments of the hHer-2/neu protein. In addition, we generated a fourth construct fusing selected portions of each individual fragment that contained most of the human leukocyte antigen (HLA) epitopes as a combination vaccine (L. monocytogenes–hHer-2/neu chimera).Results: Each individual vaccine was able to either fully regress or slow tumor growth in a mouse model for Her-2/neu-positive tumors. All three vaccines could elicit immune responses directed toward human leukocyte antigen-A2 epitopes of hHer-2/neu. The L. monocytogenes–hHer-2/neu chimera was able to mimic responses generated by the three separate vaccines and prevent spontaneous outgrowth of tumors in an autochthonous model for Her-2/neu-positive breast cancer, induce tumor regression in transplantable models, and prevent seeding of experimental lung metastases in a murine model for metastatic breast cancer.Conclusion: This novel L. monocytogenes–hHer-2/neu chimera vaccine proves to be just as effective as the individual vaccines but combines the strength of all three in a single vaccination. These encouraging results support future clinical trials using this chimera vaccine and may be applicable to other cancer types expressing the Her-2/neu molecule such as colorectal and pancreatic cancer.
Genetically Targeted T Cells Eradicate Established Breast Cancer in Syngeneic Mice
Authors: Wang Hao , Wei Huafeng , Zhang Ruiping , Hou Sheng , Li Bohua , Qian Weizhu , Zhang Dapeng , Kou Gen , Dai Jianxin , Guo Yajun 
Published: February 2009

AbstractPurpose: The purpose of the present study was to evaluate the capacity and mechanisms of genetically modified erbB2-specific T cells to eradicate erbB2+ tumors in syngeneic mice.Experimental Design: Primary mouse T cells were modified to target the breast tumor–associated antigen erbB2 through retroviral-mediated transfer of a chimeric antigen receptor, termed single-chain antibody (scFv)–CD28–ζ. Antitumor efficacy of scFv-CD28-ζ–modified T cells was analyzed in mice bearing D2F2/E2 breast tumors.Results: The scFv-CD28-ζ–modified T cells were shown to specifically secrete T cytotoxic-1 cytokines and lyse erbB2+ breast tumor cells following receptor stimulation in vitro. Treatment with scFv-CD28-ζ–modified T cells was able to lead to long-term, tumor-free survival in mice bearing erbB2+ D2F2/E2 breast tumors. Importantly, the surviving mice developed a host memory response to D2F2/E2 tumor cells, and this host response was able to protect against a rechallenge with erbB2+ D2F2/E2 tumor cells and parental erbB2- D2F2 tumor cells. In addition, scFv-CD28-ζ T-cell expression of perforin and interferon-γ were essential for complete antitumor efficacy.Conclusions: Treatment with scFv-CD28-ζ–modified T cells was able to induce a host antitumor immunity in syngeneic mice. Complete tumor elimination by scFv-CD28-ζ–modified T cells required T cell–derived interferon-γ and perforin, indicating that cytotoxicity and cytokine secretion play a role in the in vivo response.
Overcoming Cancer Immune Tolerance and Escape
Authors: Clifton Guy T. , Peoples George E. 
Published: February 2009

Abstract
Although HER2/neu–targeted cancer vaccines have shown initial promise in the adjuvant setting, a therapeutic vaccine remains elusive due to the tumor escape mechanisms of established cancer. As described by Seavey et al. in this issue of CCR, a Listeria-delivered vaccine may help overcome immune tolerance, leading to an effective therapeutic vaccine.
Intragroup behavioral variation in white-fronted capuchin monkeys (Cebus albifrons): mixed evidence for social learning inferred from new and established analytical methods
Authors: Matthews Luke 
Published: February 2009

AbstractThe study of socially learned traditions in field settings has been complicated by the need to rule out alternative hypothesized causes of behavioral variation, including underlying genetic variation, and asocial reinforcement learning that shapes behavior in response to microecological variations. Intragroup associations of spatial proximity and behavioral similarity support the tradition hypothesis when the associations are predicted specifically by social learning and not by alternative hypotheses. This paper attempts to test for socially learned traditions by combining variations in multiple foraging techniques into pairwise behavioral similarity matrices. This method thereby avoids loss of power from conducting multiple statistical tests. These matrices are then compared through correlation and cluster analysis to a proximity association matrix. Cluster analysis enables very specific predictions to be made from the social learning hypothesis, predictions that are not particularly likely under alternative hypotheses that do not invoke social learning or traditions. The results are mixed, with binary behavioral variations being consistent with a traditional influence of social learning, and with variations in the frequency of technique use being inconsistent with traditions.
Conspicuousness and vestigial escape behaviour by two dendrobatid frogs, Dendrobates auratus and Oophaga pumilio
Authors: Caldwell Janalee , Vitt Laurie , Cooper William 
Published: February 2009

AbstractAposematic prey are thought to move slowly and openly near predators, but exhibit reduced escape behaviour. We studied conspicuousness and escape by aposematic poison frogs (Dendrobates auratus and Oophaga pumilio). In circles of leaf litter, observers detected poison frogs quickly. Flight initiation distance (FID, predator-prey distance when escape begins) increases with approach speed in non-cryptic palatable prey, but not for frogs in clearings, which permitted close approach. On trails frogs moved slowly into forest and FID in D. auratus increased with approach speed. Distance from cover and handling exposing predators to distastefulness may account for greater reliance on aposematism in clearings. We observed responses to a simulated predator (stick with painted face) in three conditions: not approached, approached, and touched. Latency to hop and time to exit circles decreased and exit from circles was directed further away from the approach path in the order not approached, approached, touched. Oophaga pumilio changed directions less when approached than not; many exhibited no escape behaviour. Aposematic dendrobatids move slowly near predators, but retain risk-assessment mechanisms due to occasional predation. Differences in escape between dendrobatids and palatable Craugastor frogs suggest that dendrobatid defensive behavior may have been molded to maximize the effectiveness of aposematism.