bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Number of Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes Is Associated with the Absence of Lymph Node Metastases in Patients with Large Early-Stage Cervical Cancer
Authors: Piersma Sytse J. , Jordanova Ekaterina S. , van Poelgeest Mariëtte I.E. , Kwappenberg Kitty M.C. , van der Hulst Jeanette M. , Drijfhout Jan W. , Melief Cornelis J.M. , Kenter Gemma G. , Fleuren Gert Jan , Offringa Rienk , van der Burg Sjoerd H. 
Published: January 2007

AbstractIn a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16+)–induced or HPV18+-induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4+, CD8+, and regulatory T cells as well as by calculation of the ratio of CD8+/CD4+ T cells and CD8+/regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6- and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN−) or presence (LN+) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8+ T-cell tumor infiltration, a higher CD8+/CD4+ T-cell ratio, and higher CD8+/regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR+) or absence (IR−) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8+ T cells was found in the group of LN− patients displaying a concomitant systemic tumor-specific immune response (LN−IR+). CD8+ T-cell infiltration in LN−IR− patients was comparable with that of LN+ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN− patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis. [Cancer Res 2007;67(1):354–61]
hTERT Is Expressed in Cancer Cell Lines Despite Promoter DNA Methylation by Preservation of Unmethylated DNA and Active Chromatin around the Transcription Start Site
Authors: Zinn Rebekah L. , Pruitt Kevin , Eguchi Sayaka , Baylin Stephen B. , Herman James G. 
Published: January 2007

Abstract
hTERT, which encodes the catalytic subunit of telomerase and is expressed in most immortalized and cancer cells, has been reported to have increased DNA methylation in its promoter region in many cancers. This pattern is inconsistent with observations that DNA methylation of promoter CpG islands is typically associated with gene silencing. Here, we provide a comprehensive analysis of promoter DNA methylation, chromatin patterns, and expression of hTERT in cancer and immortalized cells. Methylation-specific PCR and bisulfite sequencing of the hTERT promoter in breast, lung, and colon cancer cells show that all cancer cell lines retain alleles with little or no methylation around the transcription start site despite being densely methylated in a region 600 bp upstream of the transcription start site. By real-time reverse transcription-PCR, all cancer cell lines express hTERT. Chromatin immunoprecipitation (ChIP) analysis reveals that both active (acetyl-H3K9 and dimethyl-H3K4) and inactive (trimethyl-H3K9 and trimethyl-H3K27) chromatin marks are present across the hTERT promoter. However, using a novel approach combining methylation analysis of ChIP DNA, we show that active chromatin marks are associated with unmethylated DNA, whereas inactive marks of chromatin are associated with methylated DNA in the region around the transcription start site. These results show that DNA methylation patterns of the hTERT promoter (−150 to +150 around the transcription start) are consistent with the usual dynamics of gene expression in that the absence of methylation in this region and the association with active chromatin marks allow for the continued expression of hTERT. [Cancer Res 2007;67(1):194–201]
Tumor-Targeted Enzyme/Prodrug Therapy Mediates Long-term Disease-Free Survival of Mice Bearing Disseminated Neuroblastoma
Authors: Danks Mary K. , Yoon K. Jin , Bush Rebecca A. , Remack Joanna S. , Wierdl Monika , Tsurkan Lyudmila , Kim Seung U. , Garcia Elizabeth , Metz Marianne Z. , Najbauer Joseph , Potter Philip M. , Aboody Karen S. 
Published: January 2007

Abstract
Neural stem cells and progenitor cells migrate selectively to tumor loci in vivo. We exploited the tumor-tropic properties of HB1.F3.C1 cells, an immortalized cell line derived from human fetal telencephalon, to deliver the cDNA encoding a secreted form of rabbit carboxylesterase (rCE) to disseminated neuroblastoma tumors in mice. This enzyme activates the prodrug CPT-11 more efficiently than do human enzymes. Mice bearing multiple tumors were treated with rCE-expressing HB1.F3.C1 cells and schedules of administration of CPT-11 that produced levels of active drug (SN-38) tolerated by patients. Both HB1.F3.C1 cells and CPT-11 were given i.v. None of the untreated mice and 30% of mice that received only CPT-11 survived long term. In contrast, 90% of mice treated with rCE-expressing HB1.F3.C1 cells and 15 mg/kg CPT-11 survived for 1 year without detectable tumors. Plasma carboxylesterase activity and SN-38 levels in mice receiving both rCE-expressing HB1.F3.C1 cells (HB1.F3.C1/AdCMVrCE) and CPT-11 were comparable with those in mice receiving CPT-11 only. These data support the hypothesis that the antitumor effect of the described neural stem/progenitor cell–directed enzyme prodrug therapy (NDEPT) is mediated by production of high concentrations of active drug selectively at tumor sites, thereby maximizing the antitumor effect of CPT-11. NDEPT approaches merit further investigation as effective, targeted therapy for metastatic tumors. We propose that the described approach may have greatest use for eradicating minimum residual disease. [Cancer Res 2007;67(1):22–5]
Human Monocytes, but not Dendritic Cells Derived from Them, Are Defective in Base Excision Repair and Hypersensitive to Methylating Agents
Authors: Briegert Manuela , Kaina Bernd 
Published: January 2007

Abstract
Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N′-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O6-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O6-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIα, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression. [Cancer Res 2007;67(1):26–31]
Akt1 Ablation Inhibits, whereas Akt2 Ablation Accelerates, the Development of Mammary Adenocarcinomas in Mouse Mammary Tumor Virus (MMTV)-ErbB2/Neu and MMTV-Polyoma Middle T Transgenic Mice
Authors: Maroulakou Ioanna G. , Oemler William , Naber Stephen P. , Tsichlis Philip N. 
Published: January 2007

Abstract
Ample evidence to date links the phosphatidylinositol 3-kinase–regulated protein kinase Akt with the induction and progression of human cancer, including breast cancer. However, there are three Akt isoforms with limited information about their specificity during oncogenesis. This study addresses the role of the three isoforms in polyoma middle T (PyMT) and ErbB2/Neu-driven mammary adenocarcinomas in mice. The effects of ablation of Akt1, Akt2, and Akt3 on the induction and the biology of these tumors were dramatically different, with ablation of Akt1 inhibiting, ablation of Akt2 accelerating, and ablation of Akt3 having a small, not statistically significant, inhibitory effect on tumor induction by both transgenes. Whereas PyMT-induced tumors are all invasive, Akt1−/−Neu–induced tumors are more invasive than Akt2−/−Neu–induced tumors. Invasiveness, however, does not always correlate with metastasis. Ablation of individual Akt isoforms does not affect the development of the mammary gland during puberty or the expression of the transgenes. Akt ablation, therefore, influences tumor induction by modulating transgene-induced oncogenic signaling. Immunostaining for Ki-67 and cyclin D1 and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assays on tissue sections revealed that the delay of tumor induction in Akt1 knockout mice is due to the inhibitory effects of Akt1 ablation on cell proliferation and survival. Given that these animal models exhibit significant similarities to human breast cancer, the results of the present study may have significant translational implications because they may influence how Akt inhibitors will be used in the treatment of human cancer. [Cancer Res 2007;67(1):167–77]
,,Wer Jesus Christus begegnet, begegnet dem Judentum". Das Verhältnis Benedikts XVI. zu Israel
Authors: Häring Hermann 
Published: January 2007

AbstractBenedict XVI's intention to intensify the relationship with Israel and Judaism is based on complex theological concepts. The new pope, initially a student of Augustine's teachings, understands Christianity as a religion of fulfillment in which Israel's heritage is fully integrated. Therefore Israel, as part of the ,,old alliance", has hardly anything new to offer to the Church. What exactly the content of any dialogue could be is even harder to determine as the new pope hardly recognizes the long history of previous dialogues and meetings. Faced with the current world crisis, Benedict XVI does try to bring together the world's different religious forces and to begin a dialogue with the representatives of secular reason. What role the Jewish heritage can play in this constellation remains unclear.
Alois Hudal – ein Anti-Pacelli? Zur Diskussion um die Haltung des Vatikans gegenüber dem Nationalsozialismus
Authors: Burkard Dominik 
Published: January 2007

AbstractThe files that have just recently been made available from Roman archives make it possible to shed new light on and relativize the often asserted ,,Pope's silence." It can be seen, that there was no agreement within the Vatican on how to deal with National Socialism. Recent publications have constructed an antagonism between Cardinal Secretary Eugenio Pacelli and Alois Hudal, the politically active principal of the Collegio Santa Maria dell'Anima and supposedly a representative of ,appeasement'. However, it can be shown that both men initially agreed in principle with their assessment of National Socialism, even though they pursued different strategies. Hudal insisted on the public denunciation of National Socialism, on a clear positioning of the school, yet without success. Pacelli, a diplomat by training, was the one who thwarted nearly all of the Vatican's public proclamations against National Socialism.
A newly established murine immature dendritic cell line can be differentiated into a mature state, but exerts tolerogenic function upon maturation in the presence of glucocorticoid
Authors: Bros Matthias , Jährling Frank , Renzing Andrea , Wiechmann Nadine , Dang Ngoc-Anh , Sutter Arne , Ross Ralf , Knop Jürgen , Sudowe Stephan , Reske-Kunz Angelika B. 
Published: January 2007

AbstractThe phenotype and function of murine dendritic cells (DCs) are primarily studied using bone-marrow–derived DCs (BM-DCs), but may be hampered by the heterogenous phenotype of BM-DCs due to their differential state of maturation. Here we characterize a newly established murine DC line (SP37A3) of myeloid origin. During maintainance in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and M-CSF, SP37A3 cells resemble immature DCs characterized by low expression of major histocompatibility complex (MHC) II and costimulatory molecules and low T-cell stimulatory capacity. Upon stimulation, SP37A3 cells acquire a mature phenotype and activate naive T cells as potently as BM-DCs. Similar to BM-DCs, SP37A3 cells activated in the presence of dexamethasone-induced regulatory T cells, which were anergic upon restimulation and suppressed proliferation of naive T cells. This tolerogenic state was reflected by lower expression levels of costimulatory molecules and proinflammatory cytokines compared with mature cells, as well as up-regulated expression of FcγRIIB and interleukin-1RA (IL-1RA). SP37A3 cells were responsive to dexamethasone even when applied at later time points during activation, suggesting functional plasticity. Thus, DC line SP37A3 represents a suitable model to study functions of immature and mature as well as tolerogenic myeloid DCs, circumventing restrictions associated with the use of primary DCs and BM-DCs.
Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome
Authors: Avet-Loiseau Hervé , Attal Michel , Moreau Philippe , Charbonnel Catherine , Garban Frédéric , Hulin Cyrille , Leyvraz Serge , Michallet Mauricette , Yakoub-Agha Ibrahim , Garderet Laurent , Marit Gérald , Michaux Lucienne , Voillat Laurent , Renaud Marc , Grosbois Bernard , Guillerm Gaelle , Benboubker Lotfi , Monconduit Mathieu , Thieblemont Catherine , Casassus Philippe , Caillot Denis , Stoppa Anne-Marie , Sotto Jean-Jacques , Wetterwald Marc , Dumontet Charles , Fuzibet Jean-Gabriel , Azais Isabelle , Dorvaux Véronique , Zandecki Marc , Bataille Régis , Minvielle Stéphane , Harousseau Jean-Luc , Facon Thierry , Mathiot Claire 
Published: January 2007

Abstract
Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with β2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.
Economics of New Oncology Drug Development
Authors: DiMasi Joseph A. , Grabowski Henry G. 
Published: January 2007

Purpose Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. Methods We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. Results We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. Conclusion The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.
Prevention of Bone Loss in Survivors of Breast Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Greenspan Susan L. , Bhattacharya Rajib K. , Sereika Susan M. , Brufsky Adam , Vogel Victor G. 
Published: January 2007

Abstract
Background: Few data are available on the safety and efficacy of once-weekly oral bisphosphonate therapy in breast cancer survivors.
Objective: Our objective was to determine whether risedronate, 35 mg weekly, is efficacious and safe in preventing bone loss associated with chemotherapy-induced menopause.
Design: The study was a randomized, double-blind, placebo-controlled clinical trial over 12 months.
Setting and Participants: Participants included 87 newly postmenopausal women with status post chemotherapy, recruited from a breast cancer clinic in an academic medical center.
Intervention: Participants were randomly assigned to receive risedronate 35 mg/wk or placebo.
Main Outcome Measures: The primary outcomes were the 12-month changes in spine and hip bone mineral density. Secondary outcomes included changes in markers of bone resorption (urine N-telopeptide cross-linked collagen type I) and formation (osteocalcin, N-terminal propeptide of type I procollagen, and bone-specific alkaline phosphatase).
Results: After 12 months, bone mineral density increased by 1.2% at the spine and 1.3% at the hip in women on risedronate vs. significant decreases for women in the placebo group of 0.9% at the spine and 0.8% at the hip (P &lt; 0.01, difference between groups). N-telopeptide cross-linked collagen type I, a marker of bone resorption, decreased by 19.3%, and N-terminal propeptide of type I procollagen, a marker of bone formation, decreased by 26.6% in participants on active therapy compared with increases in the control group. Risedronate was well tolerated, and the retention rate was 95% at 1 yr.
Conclusions: Risedronate once weekly prevented bone loss and reduced bone turnover in women with breast cancer treated with chemotherapy. Early measures to prevent bone loss should be considered in this cohort of breast cancer survivors.
Approach to the Patient with Subclinical Hyperthyroidism
Authors: Cooper David S. 
Published: January 2007

Abstract
Endogenous subclinical hyperthyroidism, defined by normal circulating levels of free T4 and T3 and low levels of TSH, is a common clinical entity and is typically caused by the same conditions that account for the majority of cases of overt hyperthyroidism: Graves’ disease, toxic multinodular goiter, and solitary autonomously functioning thyroid nodules. Subclinical hyperthyroidism has been associated with an increased risk of atrial fibrillation and mortality, decreased bone mineral density in postmenopausal women, and mild hyperthyroid symptoms. Treatment of subclinical hyperthyroidism remains controversial, given the lack of prospective randomized controlled trials showing clinical benefit with restoration of the euthyroid state. Nevertheless, it seems reasonable to treat older individuals whose serum TSH levels are less than 0.1 mU/liter and certain high-risk patients, even when the serum TSH is between 0.1 and the lower limit of the normal range.
Suppression of water loss during adult diapause in the northern house mosquito,Culex pipiens
Authors: Benoit Joshua B. , Denlinger David L. 
Published: January 2007

SUMMARYOne of the major challenges of overwintering in the mosquito, Culex pipiens, is prevention of dehydration. In this study, we compare the water balance requirements of nondiapausing and diapausing adult females of C. pipiens. Although their percentage water content is lower, diapausing females contain both higher initial and dry masses than nondiapausing individuals. Both nondiapausing and diapausing females tolerate a loss of up to 40% of their water mass before dying, but diapausing female C. pipiens reach this point after a longer period due to their lower rate of water loss. Males, which do not overwinter in diapause,showed no differences in their water balance characteristics when reared under diapausing or nondiapausing conditions. Likewise, no changes were noted in the water balance of pupae, indicating that diapause-related changes do not occur prior to adult eclosion. This mosquito does not replenish internal water stores by generating metabolic water or by absorbing vapor from the atmosphere, but instead relies on drinking liquid water (or blood feeding in the case of nondiapausing females). The critical transition temperature, a point where water loss increases rapidly with temperature, was the highest for females, then males, then pupae, but was not influenced by the diapause program. Females in diapause did not utilize common polyols (glycerol,trehalose and sorbitol) to retain water, but instead the presence of twice the amount of cuticular hydrocarbons in diapausing compared with nondiapausing females suggests that the deposition of hydrocarbons contribute to the reduced rates of water loss. The laboratory results were also verified in field-collected specimens: mosquitoes in the late fall and winter had a lower percentage water content and water loss rate, higher initial mass, dry mass and more cuticular hydrocarbons than individuals collected during the summer. Thus, the major features of diapause that contribute to the suppression of water loss are the large size of diapausing females (reduction of surface area to volume ratio lowers cuticular water loss), their low metabolic rate and the deposition of extra cuticular hydrocarbons.