bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal changes of under-reporting of cigarette consumption in population-based studies
Authors: Gallus Silvano , Tramacere Irene , Boffetta Paolo , Fernandez Esteve , Rossi Silvia , Zuccaro Piergiorgio , Colombo Paolo , La Vecchia Carlo 
Published: September 2010

ObjectivesTo monitor trends in under-reporting of smoking in Italy over the last two decades.MethodsA total of 9 representative population-based surveys on smoking conducted in Italy in 1990 and annually between 2001 and 2008, covering 26 397 individuals, were studied. The number of cigarettes per day per person aged 15 years or over, obtained from these interview-based surveys, was compared with official data from legal sales.ResultsOver the last two decades, self-reported smoking prevalence progressively decreased from 32% in 1990 to 22% in 2008. Self-reported daily per capita consumption of cigarettes also showed a reduction between 1990 and 2008, notably so over the last few years (from 5.2 in 1990 to 4.0 in 2004 to 3.2 in 2008). According to data from legal sales, number of cigarettes per day per person decreased from 5.3 in 1990 to 5.0 in 1992, levelled off from 1992 to 1997, subsequently increased from 5.0 in 1997 to 5.8 in 2002 (likely due to control of smuggling), and decreased over the last 6 years (to 4.9 in 2008). These figures correspond to an under-reporting of approximately 1% in 1990, 25% in 2001 and up to 35% in 2008.ConclusionsThe difference in cigarette consumption between legal sale and self-reported data has substantially increased over the last two decades in Italy, reflecting increasing under-reporting of cigarette consumption mainly due to a decreasing social acceptability of smoking. Comparisons between interview-based and legal sale data are complicated by factors such as smuggling control and changes in the population (eg, increased proportion of immigrants); however these are able to justify only a small proportion of the gap found in Italy.
PML-RARα and Dnmt3a1 Cooperate in vivo to Promote Acute Promyelocytic Leukemia
Authors: Subramanyam Deepa , Belair Cassandra D. , Barry-Holson Keegan Q. , Lin Haijiang , Kogan Scott C. , Passegué Emmanuelle , Blelloch Robert 
Published: September 2010

Abstract
The PML-RARα oncogene is the central effector of acute promyelocytic leukemia (APL). PML-RARα physically interacts with epigenetic-modifying enzymes including DNA methyltransferases (Dnmt) to suppress critical downstream targets. Here, we show that increased expression of Dnmt3a1 cooperates with PML-RARα in vivo to promote early lethality secondary to myeloid expansion and dysfunction in primary mice. Bone marrow cells from these mice cause leukemogenesis with a shortened latency and a higher penetrance on transplantation into irradiated recipients. Furthermore, leukemic cells overexpressing PML-RARα and Dnmt3a1 display increased methylation at a target promoter compared with PML-RARα or Dnmt3a1 controls. Our findings show a cooperation between the PML-RARα oncogene and the Dnmt3a1 enzyme in vivo and that Dnmt levels can be rate limiting in APL progression. Cancer Res; 70(21); 8792–801. ©2010 AACR.
Histone Methyltransferase MLL1 Regulates MDR1 Transcription and Chemoresistance
Authors: Huo Hairong , Magro Pellegrino G. , Pietsch E. Christy , Patel Brijesh B. , Scotto Kathleen W. 
Published: September 2010

Abstract
The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC2(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance. Cancer Res; 70(21); 8726–35. ©2010 AACR.
Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer
Authors: Huang Qin Miao , Tomida Shuta , Masuda Yuji , Arima Chinatsu , Cao Ke , Kasahara Taka-aki , Osada Hirotaka , Yatabe Yasushi , Akashi Tomohiro , Kamiya Kenji , Takahashi Takashi , Suzuki Motoshi 
Published: September 2010

Abstract
Genomic instability is an important factor in cancer susceptibility, but a mechanistic understanding of how it arises remains unclear. We examined hypothesized contributions of the replicative DNA polymerase δ (pol δ) subunit POLD4 to the generation of genomic instability in lung cancer. In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle- and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). A fraction of non–small cell lung cancer patients also showed low expression comparable with that in SCLC, which was associated with poor prognosis. The lung cancer cell line ACC-LC-48 was found to have low POLD4 expression, with higher histone H3K9 methylation and lower acetylation in the POLD4 promoter, as compared with the A549 cell line with high POLD4 expression. In the absence of POLD4, pol δ exhibited impaired in vitro DNA synthesis activity. Augmenting POLD4 expression in cells where it was attenuated altered the sensitivity to the chemical carcinogen 4-nitroquinoline-1-oxide. Conversely, siRNA-mediated reduction of POLD4 in cells with abundant expression resulted in a cell cycle delay, checkpoint activation, and an elevated frequency of chromosomal gap/break formation. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. Furthermore, POLD4 overexpression reduced intrinsically high induction of γ-H2AX, a well-accepted marker of double-stranded DNA breaks. Together, our findings suggest that reduced expression of POLD4 plays a role in genomic instability in lung cancer. Cancer Res; 70(21); 8407–16. ©2010 AACR.
Tyrosine Phosphorylation Profiling Reveals the Signaling Network Characteristics of Basal Breast Cancer Cells
Authors: Hochgräfe Falko , Zhang Luxi , O'Toole Sandra A. , Browne Brigid C. , Pinese Mark , Porta Cubas Ana , Lehrbach Gillian M. , Croucher David R. , Rickwood Danny , Boulghourjian Alice , Shearer Robert , Nair Radhika , Swarbrick Alexander , Faratian Dana , Mullen Peter , Harrison David J. , Biankin Andrew V. , Sutherland Robert L. , Raftery Mark J. , Daly Roger J. 
Published: September 2010

Abstract
To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry–based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup. Cancer Res; 70(22); 9391–401. ©2010 AACR.
DLC1 Negatively Regulates Angiogenesis in a Paracrine Fashion
Authors: Shih Yi-Ping , Liao Yi-Chun , Lin Yuan , Lo Su Hao 
Published: September 2010

Abstract
The Rho GTPase-activating protein DLC1 is a tumor suppressor that is often deleted in liver cancer and downregulated in other cancers. DLC1 regulates the actin cytoskeleton, cell shape, adhesion, migration, and proliferation through its Rho GTPase-activating protein activity and focal adhesion localization. In this study, we silenced DLC1 in nonmalignant prostate epithelial cells to explore its tumor suppression functions. Small hairpin RNA-mediated silencing of DLC1 was insufficient to promote more aggressive phenotypes associated with tumor cell growth. In contrast, DLC1 silencing promoted pro-angiogenic responses through vascular endothelial growth factor (VEGF) upregulation, accompanied by the accumulation of hypoxia-inducible factor 1α and its nuclear localization. Notably, modulation of VEGF expression by DLC1 was dependent on epidermal growth factor receptor–MAP/ERK kinase–hypoxia-inducible factor 1 signaling but on RhoA pathways. Clinically, VEGF upregulation is a highly significant event in prostate cancers in which DLC1 is downregulated. Thus, our results strongly suggest that loss of DLC1 may serve as a “second hit” in promoting angiogenesis in a paracrine fashion during tumorigenesis. Cancer Res; 70(21); 8270–5. ©2010 AACR.
Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo
Authors: Hebbard Lionel W. , Maurer Jochen , Miller Amber , Lesperance Jacqueline , Hassell John , Oshima Robert G. , Terskikh Alexey V. 
Published: September 2010

Abstract
Maternal embryonic leucine zipper kinase (MELK) is expressed in several developing tissues, in the adult germ line, and in adult neural progenitors. MELK expression is elevated in aggressive undifferentiated tumors, correlating with poor patient outcome in human breast cancer. To investigate the role of MELK in mammary tumorigenesis in vivo, we used a MELK-green fluorescent protein (GFP) reporter mouse, which allows prospective isolation of MELK-expressing cells based on GFP fluorescence. We found that in the normal mammary gland, cells expressing high levels of MELK were enriched in proliferating cells that express markers of mammary progenitors. The isolation of cells with high levels of MELK in mammary tumors from MMTV-Wnt1/MELK-GFP bitransgenic mice resulted in a significant enrichment of tumorsphere formation in culture and tumor initiation after transplantation into mammary fat pads of syngeneic mice. Furthermore, using lentiviral delivery of MELK-specific shRNA and limiting dilution cell transplantations, we showed that MELK function is required for mammary tumorigenesis in vivo. Our findings identify MELK as a potential target in breast tumor-initiating cells. Cancer Res; 70(21); 8863–73. ©2010 AACR.
Tumor-Reactive CD8+ Early Effector T Cells Identified at Tumor Site in Primary and Metastatic Melanoma
Authors: Anichini Andrea , Molla Alessandra , Vegetti Claudia , Bersani Ilaria , Zappasodi Roberta , Arienti Flavio , Ravagnani Fernando , Maurichi Andrea , Patuzzo Roberto , Santinami Mario , Pircher Hanspeter , Di Nicola Massimo , Mortarini Roberta 
Published: September 2010

Abstract
CD8+ T cells at the earliest stage of effector generation have not been identified at tumor site of melanoma patients. Such early effectors, if present, should be characterized by a specific phenotype, distinct from that expressed at later stages of the antigen-induced differentiation program, by short-lived effector cells, memory precursors, and terminal effectors. Here, we show that neoplastic tissues from primary and metastatic lesions of melanoma patients contain a subset of CD8+ T cells expressing FOXP3. CD8+ FOXP3+ CD25+ T lymphocytes were found in tumor-invaded lymph nodes (TILN), s.c. metastases, and advanced primary lesions. Their frequency was significantly higher in TILN compared with tumor-free lymph nodes or with peripheral blood and in primary tumors compared with TILN. CD8+ FOXP3+ T cells did not express markers of regulatory [CTLA-4, CCL4, interleukin-10 (IL-10), transforming growth factor-β1], exhausted (PD-1), or senescent (CD57) CD8+ T lymphocytes. Instead, this subset showed an antigen-experienced “EM1” phenotype (CCR7− CD45RA− CD28+ CD27+) and exhibited a CD127−, KLRG1−, HLA-DR+, CD38+, T-bet+, perforin+ “early effector” profile predicted by current models. CD8+ FOXP3+ T cells produced IFN-γ on short in vitro activation, recognized autologous tumor by CD107a mobilization, and expressed Ki-67 on ex vivo analysis. In response to autologous tumor plus IL-2/IL-15, the CD8+ FOXP3+ T cells proliferated promptly and showed competence for differentiation (downregulation of CD27 and upregulation of T-bet). These results suggest development of early phases of antitumor immunity even in advanced melanoma. Moreover, the CD8+ FOXP3+ “early effector” subset may be an invaluable tool for monitoring immunity at tumor site. Cancer Res; 70(21); 8378–87. ©2010 AACR.
The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia
Authors: Curtis David J. , McCormack Matthew P. 
Published: September 2010

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell–like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche. Clin Cancer Res; 16(23); 5618–23. ©2010 AACR.
Macrophage Migration Inhibitory Factor Is Secreted by Rhabdomyosarcoma Cells, Modulates Tumor Metastasis by Binding to CXCR4 and CXCR7 Receptors and Inhibits Recruitment of Cancer-Associated Fibroblasts
Authors: Tarnowski Maciej , Grymula Katarzyna , Liu Rui , Tarnowska Joanna , Drukala Justyna , Ratajczak Janina , Mitchell Robert A. , Ratajczak Mariusz Z. , Kucia Magda 
Published: September 2010

Abstract
The overexpression of macrophage migration inhibitory factor (MIF) has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors and, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)–binding receptor CXCR4. Here, we report that human rhabdomyosarcoma (RMS) cell lines secrete MIF and that this chemokine (a) induces phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT, (b) stimulates RMS cell adhesion, (c) enhances tumor vascularization, but surprisingly (d) decreases recruitment of cancer-associated fibroblasts (CAF). Because RMS cells used in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4, and as we report here for the first time, MIF may also engage another SDF-1–binding receptor (CXCR7) as well. Interestingly, downregulation of MIF in RMS cells inoculated into immunodeficient mice led to formation of larger tumors that displayed higher stromal cell support. Based on these observations, we postulate that MIF is an important autocrine/paracrine factor that stimulates both CXCR4 and CXCR7 receptors to enhance the adhesiveness of RMS cells. We also envision that when locally secreted by a growing tumor, MIF prevents responsiveness of RMS to chemoattractants secreted outside the growing tumor (e.g., SDF-1) and thereby prevents release of cells into the circulation. On the other hand, despite its obvious proangiopoietic effects, MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. Our data indicate that therapeutic inhibition of MIF in RMS may accelerate metastasis and tumor growth. Mol Cancer Res; 8(10); 1328–43. ©2010 AACR.
Forecast Impact of Targeted Observations: Sensitivity to Observation Error and Proximity to Steep Orography
Authors: Irvine E. A. , Gray S. L. , Methven J. , Renfrew I. A. 
Published: September 2010

Abstract
For a targeted observations case, the dependence of the size of the forecast impact on the targeted dropsonde observation error in the data assimilation is assessed. The targeted observations were made in the lee of Greenland; the dependence of the impact on the proximity of the observations to the Greenland coast is also investigated. Experiments were conducted using the Met Office Unified Model (MetUM), over a limited-area domain at 24-km grid spacing, with a four-dimensional variational data assimilation (4D-Var) scheme. Reducing the operational dropsonde observation errors by one-half increases the maximum forecast improvement from 5% to 7%–10%, measured in terms of total energy. However, the largest impact is seen by replacing two dropsondes on the Greenland coast with two farther from the steep orography; this increases the maximum forecast improvement from 5% to 18% for an 18-h forecast (using operational observation errors). Forecast degradation caused by two dropsonde observations on the Greenland coast is shown to arise from spreading of data by the background errors up the steep slope of Greenland. Removing boundary layer data from these dropsondes reduces the forecast degradation, but it is only a partial solution to this problem. Although only from one case study, these results suggest that observations positioned within a correlation length scale of steep orography may degrade the forecast through the anomalous upslope spreading of analysis increments along terrain-following model levels.
Joint Kinetics and Muscle Activity While Walking on Ballast
Authors: Wade Chip , Redfern Mark S. , Andres Robert O. , Breloff Scott P. 
Published: September 2010

Objective: This study examined the impact of two common sizes of ballast on gait biomechanics. The terrain was designed to simulate a railroad work setting to investigate the variation in gait kinetics and muscle activation while walking. Background: Research and epidemiology suggest a potential link between walking surface characteristics and injury. However, few studies have investigated the impact of ballast surfaces, which is a surface of interest in the railroad and construction industries, on gait dynamics. Method: For this study, 20 healthy adult men walked along three distinct pathways (no ballast [NB], walking ballast [WB], and mainline ballast [MB]). WB and MB consisted of rock with an average size of 0.75 to 1 in. and 1.25 to 1.5 in., respectively. Full-body motion, ground reaction forces, and electromyographic (EMG) signals from lower extremity muscles were collected, and three dimensional joint moments were calculated. Parameters of interest were moment trajectories and ranges, EMG activity, and temporal gait measures. Results: Joint-specific differences indicate significant variations between surface conditions. Joint moment ranges were generally smaller for MB and WB compared with NB. EMG activity, in particular, co-contraction levels, was found to be significantly greater on ballast compared with NB. Temporal gait parameters were significantly different for MB than for either WB or NB. Conclusion: Walking on ballast increases muscle activation to control the moments of the lower extremity joints. Application: The results suggest that ballast has an effect on muscles and joints; thus, the findings provide insight to improve and develop new work practices and methods for injury prevention.
Animals in the administrative zoo: organizational change and agency autonomy in Germany
Authors: Bach Tobias , Jann Werner 
Published: September 2010

Although Germany does not figure among the ‘forerunners’ of managerial reforms of the public sector, it has a long tradition of agencies and non-departmental bodies at the federal level. Over time, the federal administration has developed into a highly differentiated ‘administrative zoo’ with a large number of species, questioning the image of a well-ordered German bureaucracy. The article addresses organizational changes among non-ministerial agencies during the past 20 years and ministry—agency relations, drawing on data from a comprehensive survey of the federal administration. The structural changes we observe are neither comprehensive nor planned; they are much more evolutionary than revolutionary, driven by sectoral policies and not by any overall agency policy, supported more by regulatory than by managerial reforms, and most of the changes are horizontal mergers or successions of existing organizations, while we find almost no evidence for hiving-off from ministries to agencies. At the same time, federal agencies report a lot of bureaucratic discretion, whereas they perceive substantial levels of ‘red tape’ due to administrative regulations. We also find that traditional, hierarchical modes of ministerial oversight are still dominating; only few agencies have performance agreements with measurable goals. Points for practitioners The article will be of interest to practitioners concerned about the nature and direction of organizational change within government, especially about processes of horizontal and vertical differentiation and steering. It demonstrates that even in a highly developed and classical bureaucratic administrative system such as Germany there is and has for a long time been a large variety of governmental agencies that enjoy a considerable amount of autonomy. At the same time there is continuous change and adaptation to new circumstances, even though all this has very little to do with international modernization trends such as New Public Management or comprehensive agencification.