bluuebunny/crossref_metadata_2025_split huggingface dataset:
E2F7 Can Regulate Proliferation, Differentiation, and Apoptotic Responses in Human Keratinocytes: Implications for Cutaneous Squamous Cell Carcinoma Formation
Authors: Endo-Munoz Liliana , Dahler Alison , Teakle Ngari , Rickwood Danny , Hazar-Rethinam Mehlika , Abdul-Jabbar Ibtissam , Sommerville Scott , Dickinson Ian , Kaur Pritinder , Paquet-Fifield Sophie , Saunders Nicholas 
Published: February 2009

AbstractThe E2F family of transcription factors plays a crucial role in the regulation of genes involved in cell proliferation, differentiation, and apoptosis. In keratinocytes, the inhibition of E2F is a key step in the control and initiation of squamous differentiation. Because the product of the recently identified E2F7a/E2F7b gene has been shown to repress E2F-regulated promoters, and to be abundant in skin, we examined its role in the epidermis. Our results indicate that E2F7b mRNA expression is selectively associated with proliferation-competent keratinocytes. Moreover, E2F7 was able to antagonize E2F1-induced proliferation and apoptosis. In contrast, although E2F7 was able to inhibit proliferation and initiate differentiation, it was unable to antagonize the differentiation suppression induced by E2F1. These data indicate that E2F7-mediated suppression of proliferation and apoptosis acts through E2F1-dependent pathways, whereas E2F7-induced differentiation acts through an E2F1-independent pathway. These data also suggest that proliferation, differentiation, and survival of primary human keratinocytes can be controlled by the relative ratio of E2F1 to E2F7. Because deregulated proliferation, differentiation, and apoptosis are hallmarks of cancer, we examined the expression levels of E2F1 and E2F7 in cutaneous squamous cell carcinomas (CSCC). We found that both genes were overexpressed in CSCCs compared with normal epidermis. Furthermore, inhibition of E2F7 in a SCC cell line sensitized the cells to UV-induced apoptosis and doxorubicin-induced apoptosis. Combined, these data suggest that the selected disruption of E2F1 and E2F7 in keratinocytes is likely to contribute to CSCC formation and may prove to be a viable therapeutic target. [Cancer Res 2009;69(5):1800–9]
Down-regulation of Vascular Endothelial Growth Factor Receptor 2 Is a Major Molecular Determinant of Proteasome Inhibitor–Mediated Antiangiogenic Action in Endothelial Cells
Authors: Meissner Markus , Reichenbach Gabi , Stein Monika , Hrgovic Igor , Kaufmann Roland , Gille Jens 
Published: February 2009

Abstract
The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotic cells. This system controls a wide range of cellular regulatory proteins, including transcription factors and cell cycle regulatory proteins. Recent evidence also established the importance of the proteasome in tumor development, showing antitumor and antiangiogenic actions by using selective inhibitors in vivo. As signaling via the vascular endothelial growth factor receptor 2 (VEGFR2) pathway is critical for angiogenic responses to occur, we explored whether antiangiogenic effects due to proteasome inhibition were partly mediated through decreased endothelial VEGFR2 expression. This study shows that different proteasome inhibitors blocked VEGFR2 expression in a time-dependent and concentration-dependent manner. This blockade was paralleled by the respective inhibition of the formation of capillary-like structures and endothelial cell migration. In contrast, neither tie-2 nor VEGFR1 expression was significantly affected by proteasome inhibitor treatment. The suppressive effects on VEGFR2 expression were not conveyed by increased shedding or a decrease in protein half-life, suggesting that transcriptional mechanisms accounted for the observed effects. In line with this conclusion, proteasome inhibition significantly suppressed VEGFR2 mRNA accumulation. In addition, inhibitor treatment considerably decreased the transcriptional activity of 5′ deletional VEGFR2 promoter gene constructs. Proteasome inhibition–mediated repression was controlled by a GC-rich region that harbored one consensus Sp1-binding site. Subsequent EMSA analyses showed decreased constitutive Sp1-dependent DNA binding in response to proteasome inhibition. In addition, we could show that proteasome inhibitors reduced VEGFR2 mRNA stability. Therefore, VEGFR2 expression may constitute a critical molecular target of proteasome inhibitors that may mediate their antiangiogenic effects in vivo. [Cancer Res 2009;69(5):1976–84]
Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination
Authors: Schreiber Taylor H. , Deyev Vadim V. , Rosenblatt Joseph D. , Podack Eckhard R. 
Published: February 2009

AbstractEstablished tumors suppress antitumor immune responses and induce tolerance by incompletely characterized mechanisms, and this phenomenon is an important barrier to tumor immunotherapy. Single vaccination with tumor cells expressing gp96-Ig stimulates robust expansion of tumor-specific CTLs in tumor-naïve mice and this expansion is inhibited by established tumors. Interestingly, frequent vaccinations restore antitumor immune responses in the presence of established tumors. Syngeneic EG7 tumor-bearing mice have heterogeneous responses to frequent vaccination with EG7-gp96-Ig, with 32% complete responders and 68% partial responders. Comparison of responders to nonresponders revealed an inverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective antitumor immune responses, reverse transcription-PCR arrays were performed using cells isolated from the vaccination site. ELISAs, cellular phenotyping, and tumor immunohistochemistry were also performed comparing vaccine responders to nonresponders. These data show that up-regulation of T-bet, RORγt, IFNγ, CCL8, CXCL9, and CXCL10 at the vaccination site are associated with vaccine-induced antitumor immunity. These data correlate with increased CTL expansion in the peripheral blood of responders, increased infiltration of responder tumors by CD8+ cells and interleukin-17+ cells, and decreased infiltration of responder tumors by CD11b+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-β in nonresponders as compared with responders. Interestingly, CD8+ T cells isolated from responders and nonresponders have equivalent cytotoxic activity in vitro. Taken together, our data suggest that established tumors may escape immunosurveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy. [Cancer Res 2009;69(5):2026–33]
Polychlorinated Biphenyls and Risk of Testicular Germ Cell Tumors
Authors: McGlynn Katherine A. , Quraishi Sabah M. , Graubard Barry I. , Weber Jean-Philippe , Rubertone Mark V. , Erickson Ralph L. 
Published: February 2009

Abstract
Exposure to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCB), may alter hormonal balance and thereby increase risk of testicular germ cell tumors (TGCT). To study the relationship of PCBs to TGCT, prediagnostic serum samples from 736 cases and 913 controls in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Adjusted odds ratios and 95% confidence intervals were estimated using logistic regression. PCB levels were examined in association with all TGCT and, separately, with each histologic type (seminoma and nonseminoma). Risks associated with seven functional groupings of PCBs, as well as sum of PCBs, were also examined. There were significantly decreased risks of TGCT in association with eight PCBs (PCB-118, PCB-138, PCB-153, PCB-156, PCB-163, PCB-170, PCB-180, and PCB-187) and no association with the remaining three (PCB-99, PCB-101, and PCB-183). The same eight congeners were significantly associated with decreased risk of nonseminoma, whereas five (PCB-138, PCB-153, PCB-156, PCB-163, and PCB-170) were associated with decreased risk of seminoma. All functional groupings of PCBs were also associated with decreased risk of TGCT and of nonseminoma, whereas six of the seven functional groups were associated with decreased risk of seminoma. Sum of PCBs was significantly associated with decreased risk of TGCT (Ptrend = 0.006), nonseminoma (Ptrend = 0.007), and seminoma (Ptrend = 0.05). Overall, these data do not support the hypothesis that PCB exposure increases the risk of TGCT. [Cancer Res 2009;69(5):1901–9]
The Complex Relationship between BRCA1 and ERα in Hereditary Breast Cancer
Authors: Gorski Julia J. , Kennedy Richard D. , Hosey Alison M. , Harkin D. Paul 
Published: February 2009

Abstract
Breast cancer 1 (BRCA1) was initially identified as one of the genes conferring genetic predisposition to both breast and ovarian cancer. One of the interesting aspects of BRCA1-linked cancers is the observed specificity for estrogen-responsive tissues such as breast and ovary. Recent advances in our understanding of BRCA1-linked breast cancers have revealed a complex relationship between BRCA1 and estrogen receptor α (ERα) signaling. Estrogen stimulation increases expression of BRCA1 at the mRNA and protein level and conversely BRCA1 functions to both induce ERα mRNA expression and act as a negative regulator of ERα signaling. Here, we review the relationship between BRCA1 and ERα and discuss the use of antiestrogen therapies such as tamoxifen and aromatase inhibitors in the treatment of BRCA1 mutation carriers.
Involvement of FLIP in 2-Methoxyestradiol–Induced Tumor Regression in Transgenic Adenocarcinoma of Mouse Prostate Model
Authors: Ganapathy Manonmani , Ghosh Rita , Jianping Xie , Zhang Xiaoping , Bedolla Roble , Schoolfield John , Yeh I-Tien , Troyer Dean A. , Olumi Aria F. , Kumar Addanki P. 
Published: February 2009

AbstractPurpose: The purpose of this study is to investigate whether Fas-associated death domain interleukin-1 converting enzyme like inhibitory protein (FLIP) inhibition is a therapeutic target associated with 2-methoxyestradiol (2-ME2)–mediated tumor regression.Experimental Design: Expression and levels of FLIP were analyzed using (a) real-time PCR and immunoblot analysis in androgen-independent PC-3 cells treated with the newly formulated 2-ME2 and (b) immunohistochemistry in different Gleason pattern human prostate tumors. Transient transfections and chromatin immunoprecipitation (ChIP) assays were used to identify the transcription factors that regulate FLIP. Involvement of FLIP in 2-ME2–induced tumor regression was evaluated in transgenic adenocarcinoma mouse prostate (TRAMP) mice.Results: High Gleason pattern (5+5) human prostate tumors exhibit significant increase in FLIP compared with low Gleason pattern 3+3 (P = &lt;0.04). 2-ME2 reduced the levels and promoter activity of FLIP (P = 0.001) in PC-3 cells. Transient expression assays show sequences between −503/+242 being sufficient for 2-ME2–induced inhibition of FLIP promoter activity. Cotransfection experiments show that overexpression of Sp1 activated, whereas Sp3 inhibited, Sp1 transactivation of FLIP promoter activity (P = 0.0001). 2-ME2 treatment reduced binding of Sp1 to the FLIP promoter as evidenced by ChIP. Further, levels of FLIP associated with Fas or FADD decreased, whereas cleavage of caspase-8, levels of Bid, and apoptosis increased in response to 2-ME2 treatment in PC-3 cells. Administration of 2-ME2 regressed established prostate tumors in TRAMP mice that were associated with reduced expression of FLIP and Sp1.Conclusion: Targeting Sp1-mediated FLIP signaling pathway may provide a novel approach for prostate cancer management.
CD8 T-cell Responses against Cyclin B1 in Breast Cancer Patients with Tumors Overexpressing p53
Authors: Sørensen Rikke Bæk , Andersen Rikke Sick , Svane Inge Marie , Engell-Noerregaard Lotte , Hadrup Sine R. , Balslev Eva , Andersen Mads Hald , Straten Per thor 
Published: February 2009

Abstract
Purpose: This study aimed to examine CD8 T-cell reactivity in breast cancer patients against cyclin B1–derived peptides restricted by the human leukocyte antigen (HLA)-A2 molecule.
Experimental Design: Peripheral blood mononuclear cells from 36 breast cancer patients were analyzed by enzyme-linked immunosorbent spot (ELISPOT) for the presence of T cells recognizing the cyclin B1–derived peptides CB9 (AKYLMELTM) and CB-P4 (AKYLMELCC), in addition to modified versions of CB9, CB9L2 (ALYLMELTM) and CB9M2 (AMYLMELTM), both of which display higher affinity to HLA-A2.
Results: Twelve patients harbored a memory CD8 T-cell response against at least one of the peptides; strongest reactivity was detected against the CB9L2 peptide. Because the level of cyclin B1 has been shown to be influenced by the level of p53, which in turn is elevated in cancer cells because of point mutation, we analyzed the level of p53 protein in biopsies from the patients by immune histochemistry. Combined data showed that anti–cyclin B1 reactivity was predominantly detected in patients with tumors characterized by elevated expression of p53. Interestingly, no reactivity was detected against six peptides derived from the p53 protein.
Conclusions: Our data support the notion of cyclin B1 as a prominent target for immunologic recognition in cancer patients harboring p53-mutated cancer cells. Because mutation of p53 is one of the most frequent genetic alterations in human cancers, this suggests that immunotherapy based on targeting of cyclin B1 is broadly applicable in a large proportion of cancer patients.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for Prediction of Radiation-Induced Neurocognitive Dysfunction
Authors: Cao Yue , Tsien Christina I. , Sundgren Pia C. , Nagesh Vijaya , Normolle Daniel , Buchtel Henry , Junck Larry , Lawrence Theodore S. 
Published: February 2009

Abstract
Purpose: To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT).
Experimental Design: Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed.
Results: No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P &lt; 0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P &lt; 0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P &lt; 0.02) and frontal lobes (P &lt; 0.03), and changes in BBB permeability of left frontal lobes during RT (P &lt; 0.007). A similar correlation was found between recall scores and BBB permeability.
Conclusion: Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.
Genetic Signatures of HPV-related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications
Authors: Klussmann Jens P. , Mooren Jeroen J. , Lehnen Martin , Claessen Sandra M.H. , Stenner Markus , Huebbers Christian U. , Weissenborn Soenke J. , Wedemeyer Inga , Preuss Simon F. , Straetmans Jos M.J.A.A. , Manni Johannes J. , Hopman Anton H.N. , Speel Ernst-Jan M. 
Published: February 2009

AbstractPurpose: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer.Experimental Design: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16INK4A immunostaining. The results were correlated with HPV status and clinical data from patients.Results: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P = 0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P = 0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P = 0.002, 0.03; &lt;0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P = 0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P = 0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P = 0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P = 0.008; disease-free survival, P = 0.01) and none of these patients had a tumor recurrence.Conclusions: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.
Meta-analysis of Oncogenic Protein Kinase Cι Signaling in Lung Adenocarcinoma
Authors: Erdogan Eda , Klee Eric W. , Thompson E. Aubrey , Fields Alan P. 
Published: February 2009

Abstract
Purpose: Atypical protein kinase Cι (PKCι) is an oncogene in non–small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCι in lung adenocarcinoma (LAC), the most prominent form of NSCLC.
Experimental Design: Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCι in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediated knockdown of PKCι and the target genes was used to determine whether expression of the identified genes was regulated by PKCι, and whether these target genes play a role in anchorage-independent growth and invasion of LAC cells.
Results: Meta-analysis identified seven genes whose expression correlated with PKCι in primary LAC. Subsequent QPCR analysis confirmed coordinate overexpression of four genes (COPB2, ELF3, RFC4, and PLS1) in an independent set of LAC samples. RNAi-mediated knockdown showed that PKCι regulates expression of all four genes in LAC cells, and that the four PKCι target genes play an important role in the anchorage-independent growth and invasion of LAC cells. Meta-analysis of gene expression data sets from lung squamous cell, breast, colon, prostate, and pancreas carcinomas, as well as glioblastoma, revealed that a subset of PKCι target genes, particularly COPB2 and RFC4, correlate with PKCι expression in many tumor types.
Conclusion: Meta-analysis of public gene expression data are useful in identifying novel gene targets of oncogenic PKCι signaling. Our data indicate that both common and cell type–specific signaling mechanisms contribute to PKCι-dependent transformation.
Ductal Lavage Is an Inefficient Method of Biomarker Measurement in High-Risk Women
Authors: Khan Seema A. , Lankes Heather A. , Patil Deepa B. , Bryk Michele , Hou Nanjiang , Ivancic David , Nayar Ritu , Masood Shahla , Rademaker Alfred 
Published: February 2009

Abstract
Effective methods of serial epithelial sampling to measure breast-specific biomarkers will aid the rapid evaluation of new preventive interventions. We report here a proof-of-principle phase 2 study to assess the utility of ductal lavage (DL) to measure biomarkers of tamoxifen action. We enrolled women with a 5-year breast cancer risk estimate &gt;1.6% or the unaffected breast of women with T1a or T1b breast cancer. After entry DL, participants chose tamoxifen or observation and underwent repeat DL 6 months later. Samples were processed for cytology and immunohistochemistry for estrogen receptor α, Ki-67, and cyclooxygenase-2. Of 182 women recruited, 115 (63%) underwent entry and repeat DL; 85 (47%) had sufficient cells for analysis from ≥1 duct at both time points; in 78 (43%), cells were sufficient from ≥1 matched ducts. Forty-six women chose observation and 39 chose tamoxifen. We observed greater reductions in the tamoxifen group than in the observation group for Ki-67 (adjusted P = 0.03) and estrogen receptor α (adjusted P = 0.07), but not in cyclooxygenase-2 (adjusted P = 0.4) labeling. Cytologic findings showed a trend toward improvement in the tamoxifen group compared with the observation group. Interobserver variability for cytologic diagnosis between two observers showed good agreement (κ = 0.44). Using DL, we observed the expected changes in tamoxifen-related biomarkers; however, poor reproducibility of biomarkers in the observation group, the 53% attrition rate of subjects from recruitment to biomarker analyses, and the expense of DL are significant barriers to the use of this procedure for biomarker assessment over time.
On the Origin of the Ink of the Thanksgiving Scroll (1QHodayota)
Authors: Hahn Oliver , Weinberg Gisela , Rabin Ira , Wolff Timo , Masic Admir 
Published: February 2009

AbstractIn this study we demonstrate the possibility to identify the production area of the scrolls, coupling non-destructive quantitative analysis of trace elements to spectroscopic investigation of the inks. This approach, that allowed us to determine the Dead Sea area as origin of 1QHodayota, is of general validity.
A Qumran Composition of Sabbath Laws and Its Contribution to the Study of Early Halakah
Authors: Noam Vered , Qimron Elisha 
Published: February 2009

AbstractThis article presents a composite edition, with new reconstructions, notes, and translation, of a composition we title "Sabbath Laws" (4Q264a and 4Q421). Three of these Sabbath laws are treated at length in comparison to rabbinic halakah: carrying and playing musical instruments, reading a scroll, and leaving coals burning. Mutually beneficial, this comparison contributes to our understanding, and reconstruction, of the history of halakah.
On Pliny, the Essene Location and Kh. Qumran
Authors: Taylor Joan 
Published: February 2009

AbstractPliny wrote that the Essenes lived west of Lake Asphaltites, and that infra hos was En Gedi. Some scholars associate Pliny's reference with Qumran, others with a location above En Gedi. Given that Pliny writes about Judaea by following the course of the land's remarkable water, it would be most natural to read infra hos as "downstream from them." The Dead Sea itself has a current, and there was a belief that the lake had a subterranean exit in the south. From a survey of scholarship produced prior to the discovery of the Dead Sea Scrolls, it appears that Pliny's reference was usually believed to indicate a wide region of the Judaean wilderness, understood to stretch from En Gedi northwards and/or inland. When En Gedi was identified in the mid-19th century, the suggestion that Essenes occupied caves just north of and above the ancient settlement was made, but this was not seen as exclusive. If we again read Pliny appropriately, as referring to a region which the gens of the Essenes held, we can move away from either-or dichotomies of possible Essene sites.