bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Wild-Type and Mutant p53 with Small Molecule CP-31398 Blocks the Growth of Rhabdomyosarcoma by Inducing Reactive Oxygen Species–Dependent Apoptosis
Authors: Xu Jianmin , Timares Laura , Heilpern Clay , Weng Zhiping , Li Changzhao , Xu Hui , Pressey Joseph G. , Elmets Craig A. , Kopelovich Levy , Athar Mohammad 
Published: August 2010

Abstract
Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma of childhood in need of more effective therapeutic options. The expression of p53 in RMS is heterogeneous such that some tumors are wild-type whereas others are p53 mutant. The small molecule CP-31398 modulates both the wild-type and the mutant p53 proteins. Here, we show that CP-31398 blocks the growth of RMS cells that have either wild-type or mutant p53 status. In wild-type A204 cells, CP-31398 increased the expression of p53 and its downstream transcriptional targets, p21 and mdm2; enhanced the expression of apoptosis-related proteins; and reduced proliferation biomarkers. Flow profiling of CP-31398–treated cells indicated an enhancement in sub-G0 and G1 populations. CP-31398 inhibited proliferation in a manner associated with co-induction of SOX9 and p21. Apoptosis induced by CP-31398 occurred with translocation of p53 to mitochondria, leading to altered mitochondrial membrane potential, cytochrome c release, and reactive oxygen species release. In vivo, CP-31398 decreased the growth of tumor xenografts composed of wild-type or mutant p53 tumor cells, increasing tumor-free host survival. Our findings indicate that the ability of CP-31398 to modulate wild-type and mutant p53 results in the inhibition of RMS growth and invasiveness. Cancer Res; 70(16); 6566–76. ©2010 AACR.
Decreased Survival of Human Breast Cancer Cells Expressing HER2/neuonIn vitroIncubation with an Anti-HER2/neuAntibody Fused to C5a or C5adesArg
Authors: Fuenmayor Jaheli , Perez-Vazquez Karin , Perez-Witzke Daniel , Penichet Manuel L. , Montano Ramon F. 
Published: August 2010

AbstractTreatment of human epidermal growth factor receptor 2 (HER2/neu)-expressing breast cancer patients with a monoclonal antibody (mAb) directed against HER2/neu improves the outcome of chemotherapy. In cases in which remission is observed, antibody-dependent cell-mediated cytotoxicity (ADCC) seems to be one of the main mechanisms of anti-HER2/neu mAb action, implicating Fcγ receptors (FcγRs) in this tumoricidal activity. In vitro and in vivo studies have revealed that anti-HER2/neu-mediated ADCC is mainly accomplished by polymorphonuclear granulocytes (PMN). C5a, a cleavage product of the complement component C5, modulates FcγR expression via upregulation of activating and downregulation of inhibitory FcγRs. C5a also recruits PMNs to sites of inflammation and increases PMN survival. To enhance the recruitment and activation of C5a receptor–bearing cells into the tumor microenvironment, we developed antibody fusion proteins composed of a human IgG3 anti-HER2/neu antibody genetically fused to C5a [anti-HER2/neu IgG3-(C5a)] or to its derivative, C5adesArg [anti-HER2/neu IgG3-(C5adesArg)]. Both fusion proteins were expressed, properly assembled, and secreted by murine myeloma cells, and displayed chemotactic activity on human PMN. Under comparable conditions, anti-HER2/neu IgG3-(C5adesArg) increased the survival of PMN more efficiently than anti-HER2/neu IgG3-(C5a) or C5adesArg. Surprisingly, incubation of the fusion proteins with breast cancer cells that overexpress HER2/neu (SK-BR-3) induced cell death at a dose at which the anti-HER2/neu IgG3 antibody was innocuous. In the presence of human peripheral blood leukocytes as effector cells, both fusion proteins induced tumor cell death more efficiently than anti-HER2/neu IgG3. These data suggest that anti-HER2/neu IgG3-(C5a) and anti-HER2/neu IgG3-(C5adesArg) fusion proteins possess novel properties that could be useful in cancer immunotherapy. Mol Cancer Ther; 9(8); 2175–85. ©2010 AACR.
Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis
Authors: Chen Ying , Hao Hua , He Songqing , Cai Lei , Li Yongsheng , Hu Shunze , Ye Duyun , Hoidal John , Wu Ping , Chen Xiaoping 
Published: August 2010

AbstractTumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A4 (LXA4) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164–74. ©2010 AACR.
Cisplatin Treatment Induces a Transient Increase in Tumorigenic Potential Associated with High Interleukin-6 Expression in Head and Neck Squamous Cell Carcinoma
Authors: Poth Kim J. , Guminski Alexander D. , Thomas Gethin P. , Leo Paul J. , Jabbar Ibtissam A. , Saunders Nicholas A. 
Published: August 2010

Abstract
Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of ∼50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited &gt;99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6–positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment. Mol Cancer Ther; 9(8); 2430–9. ©2010 AACR.
Dual Inhibition of Both the Epidermal Growth Factor Receptor and erbB2 Effectively Inhibits the Promotion of Skin Tumors during Two-Stage Carcinogenesis
Authors: Kiguchi Kaoru , Kitamura Takuya , Moore Tricia , Rumi Mohammad , Chang Hsiang-Chun , Treece Devon , Ruffino Lynnsie , Connolly Kevin , DiGiovanni John 
Published: August 2010

Abstract
The erbB family of receptor tyrosine kinases are known to play important roles in normal epithelial development and epithelial neoplasia. Considerable evidence also suggests that signaling through the epidermal growth factor receptor (EGFR) plays an important role in multistage skin carcinogenesis in mice; however, less is known about the role of erbB2. In this study, to further examine the role of both erbB2 and EGFR in epithelial carcinogenesis, we examined the effect of a dual erbB2/EGFR tyrosine kinase inhibitor, GW2974, given in the diet on skin tumor promotion during two-stage carcinogenesis in wild-type and BK5.erbB2 mice. In BK5.erbB2 mice, erbB2 is overexpressed in the basal layer of epidermis and leads to heightened sensitivity to skin tumor development. GW2974 effectively inhibited skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in wild-type and BK5.erbB2 mice, although a more marked effect was seen in BK5.erbB2 mice. In addition, this inhibitory effect was reversible when GW2974 treatment was withdrawn. GW2974 inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperproliferation, which correlated with reduced activation of both the EGFR and erbB2. These results support the hypothesis that both the EGFR and erbB2 play an important role in the development of skin tumors during two-stage skin carcinogenesis, especially during the tumor promotion stage. Furthermore, the marked sensitivity of BK5.erbB2 mice to the inhibitory effects of GW2974 during tumor promotion suggest greater efficacy for this compound when erbB2 is overexpressed or amplified as an early event in the carcinogenic process. Cancer Prev Res; 3(8); 940–52. ©2010 AACR.
Characterization of Static and Dynamic Left Ventricular Diastolic Function in Patients With Heart Failure With a Preserved Ejection Fraction
Authors: Prasad Anand , Hastings Jeffrey L. , Shibata Shigeki , Popovic Zoran B. , Arbab-Zadeh Armin , Bhella Paul S. , Okazaki Kazunobu , Fu Qi , Berk Martin , Palmer Dean , Greenberg Neil L. , Garcia Mario J. , Thomas James D. , Levine Benjamin D. 
Published: August 2010

Background—
Congestive heart failure in the setting of a preserved left ventricular (LV) ejection fraction is increasing in prevalence among the senior population. The underlying pathophysiologic abnormalities in ventricular function and structure remain unclear for this disorder. We hypothesized that patients with heart failure with preserved ejection fraction (HFPEF) would have marked abnormalities in LV diastolic function with increased static diastolic stiffness and slowed myocardial relaxation compared with age-matched healthy controls.

Methods and Results—
Eleven highly screened patients (4 men, 7 women) aged 73±7 years with HFPEF were recruited to participate in this study. Thirteen sedentary healthy controls (7 men, 6 women) aged 70±4 years also were recruited. All subjects underwent pulmonary artery catheterization with measurement of cardiac output, end-diastolic volumes, and pulmonary capillary wedge pressures at baseline; cardiac unloading (lower-body negative pressure or upright tilt); and cardiac loading (rapid saline infusion). The data were used to define the Frank-Starling and LV end-diastolic pressure-volume relationships. Doppler echocardiographic data (tissue Doppler velocities, isovolumic relaxation time, propagation velocity of early mitral inflow , E/A-wave ratio) were obtained at each level of cardiac preload. Compared with healthy controls, patients with HFPEF had similar LV contractile function and static LV compliance but reduced LV chamber distensibility with elevated filling pressures and slower myocardial relaxation as assessed by tissue Doppler imaging.

Conclusions—
In this small, highly screened patient population with hemodynamically confirmed HFPEF, increased end-diastolic static ventricular stiffness relative to age-matched controls was not a universal finding. Nevertheless, patients with HFPEF, even when well compensated, had elevated filling pressures, reduced distensibility, and increased diastolic wall stress compared with controls. In contrast, LV relaxation as assessed by tissue Doppler variables appeared consistently impaired in patients with HFPEF.
Interhospital Transfers Among Medicare Beneficiaries Admitted for Acute Myocardial Infarction at Nonrevascularization Hospitals
Authors: Iwashyna Theodore J. , Kahn Jeremy M. , Hayward Rodney A. , Nallamothu Brahmajee K. 
Published: August 2010

Background—
Patients with acute myocardial infarction (AMI) who are admitted to hospitals without coronary revascularization are frequently transferred to hospitals with this capability, yet we know little about the basis for how such revascularization hospitals are selected.

Methods and Results—
We examined interhospital transfer patterns in 71 336 AMI patients admitted to hospitals without revascularization capabilities in the 2006 Medicare claims using network analysis and regression models. A total of 31 607 (44.3%) AMI patients were transferred from 1684 nonrevascularization hospitals to 1104 revascularization hospitals. Median time to transfer was 2 days. Median transfer distance was 26.7 miles, with 96.1% within 100 miles. In 45.8% of cases, patients bypassed a closer hospital to go to a farther hospital that had a better 30-day risk standardized mortality rates. However, in 36.8% of cases, another revascularization hospital with lower 30-day risk-standardized mortality was actually closer to the original admitting nonrevascularization hospital than the observed transfer destination. Adjusted regression models demonstrated that shorter transfer distances were more common than transfers to the hospitals with lowest 30-day mortality rates. Simulations suggest that an optimized system that prioritized the transfer of AMI patients to a nearby hospital with the lowest 30-day mortality rate might produce clinically meaningful reductions in mortality.

Conclusions—
More than 40% of AMI patients admitted to nonrevascularization hospitals are transferred to revascularization hospitals. Many patients are not directed to nearby hospitals with the lowest 30-day risk-standardized mortality, and this may represent an opportunity for improvement.
Neighborhood-Based Verification of Precipitation Forecasts from Convection-Allowing NCAR WRF Model Simulations and the Operational NAM
Authors: Clark Adam J. , Gallus William A. , Weisman Morris L. 
Published: August 2010

Abstract
Since 2003 the National Center for Atmospheric Research (NCAR) has been running various experimental convection-allowing configurations of the Weather Research and Forecasting Model (WRF) for domains covering a large portion of the central United States during the warm season (April–July). In this study, the skill of 3-hourly accumulated precipitation forecasts from a large sample of these convection-allowing simulations conducted during 2004–05 and 2007–08 is compared to that from operational North American Mesoscale (NAM) model forecasts using a neighborhood-based equitable threat score (ETS). Separate analyses were conducted for simulations run before and after the implementation in 2007 of positive-definite (PD) moisture transport for the NCAR-WRF simulations. The neighborhood-based ETS (denoted 〈ETS〉r) relaxes the criteria for “hits” (i.e., correct forecasts) by considering grid points within a specified radius r. It is shown that 〈ETS〉r is more useful than the traditional ETS because 〈ETS〉r can be used to diagnose differences in precipitation forecast skill between different models as a function of spatial scale, whereas the traditional ETS only considers the spatial scale of the verification grid. It was found that differences in 〈ETS〉r between NCAR-WRF and NAM generally increased with increasing r, with NCAR-WRF having higher scores. Examining time series of 〈ETS〉r for r = 100 and r = 0 km (which simply reduces to the “traditional” ETS), statistically significant differences between NCAR-WRF and NAM were found at many forecast lead times for 〈ETS〉100 but only a few times for 〈ETS〉0. Larger and more statistically significant differences occurred with the 2007–08 cases relative to the 2004–05 cases. Because of differences in model configurations and dominant large-scale weather regimes, a more controlled experiment would have been needed to diagnose the reason for the larger differences that occurred with the 2007–08 cases. Finally, a compositing technique was used to diagnose the differences in the spatial distribution of the forecasts. This technique implied westward displacement errors for NAM model forecasts in both sets of cases and in NCAR-WRF model forecasts for the 2007–08 cases. Generally, the results are encouraging because they imply that advantages in convection-allowing relative to convection-parameterizing simulations noted in recent studies are reflected in an objective neighborhood-based metric.
An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation
Authors: MacDonald Kelli P. A. , Palmer James S. , Cronau Stephen , Seppanen Elke , Olver Stuart , Raffelt Neil C. , Kuns Rachel , Pettit Allison R. , Clouston Andrew , Wainwright Brandon , Branstetter Dan , Smith Jeffrey , Paxton Raymond J. , Cerretti Douglas Pat , Bonham Lynn , Hill Geoffrey R. , Hume David A. 
Published: August 2010

AbstractThe development of the mononuclear phagocyte system requires macrophage colony-stimulating factor (CSF-1) signaling through the CSF-1 receptor (CSF1R, CD115). We examined the effect of an antibody against CSF1R on macrophage homeostasis and function using the MacGreen transgenic mouse (csf1r-enhanced green fluorescent protein) as a reporter. The administration of a novel CSF1R blocking antibody selectively reduced the CD115+Gr-1neg monocyte precursor of resident tissue macrophages. CD115+Gr-1+ inflammatory monocytes were correspondingly increased, supporting the view that monocytes are a developmental series. Within tissue, the antibody almost completely depleted resident macrophage populations in the peritoneum, gastrointestinal tract, liver, kidney, and skin, but not in the lung or female reproductive organs. CSF1R blockade reduced the numbers of tumor-associated macrophages in syngeneic tumor models, suggesting that these cells are resident type macrophages. Conversely, it had no effect on inflammatory monocyte recruitment in models, including lipopolysaccharide-induced lung inflammation, wound healing, peritonitis, and severe acute graft-versus-host disease. Depletion of resident tissue macrophages from bone marrow transplantation recipients actually resulted in accelerated pathology and exaggerated donor T-cell activation. The data indicate that CSF1R signaling is required only for the maturation and replacement of resident-type monocytes and tissue macrophages, and is not required for monocyte production or inflammatory function.
In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells
Authors: Courties Gabriel , Seiffart Virginia , Presumey Jessy , Escriou Virginie , Scherman Daniel , Zwerina Jochen , Ruiz Gisela , Zietara Natalia , Jablonska Jadwiga , Weiss Siegfried , Hoffmann Andrea , Jorgensen Christian , Apparailly Florence , Gross Gerhard 
Published: August 2010

Abstract
Cells from the mononuclear phagocyte system (MPS) act as systemic and local amplifiers that contribute to the progression of chronic inflammatory disorders. Transforming growth factor-β–activated kinase 1 (TAK1) is a pivotal upstream mitogen-activated protein kinase-kinase-kinase acting as a mediator of cytokine expression. It remains critical to determine in vivo the implication of TAK1 in controlling the innate immune system. Here, we describe a vehicle tailored to selectively deliver siRNAs into MPS cells after intravenous administration, and validate in vivo the potential of the RNAi-mediated TAK1 knock down for immunomodulation. In a mouse model of immune-mediated inflammatory disorder, we show that anti-TAK1 siRNA lipoplexes efficiently alleviate inflammation, severely impair the downstream c-Jun N-terminal kinase and nuclear factor-κB signaling pathways, and decrease the expression of proinflammatory mediators. Importantly, the systemic TAK1 gene silencing decreases the frequency of Th1 and Th17 cells, both mediating autoimmunity in experimental arthritis, demonstrating the immunomodulatory potential of TAK1. Finally, in vitro inhibition of TAK1 in myeloid cells decreases interferon-γ–producing T cells, suggesting that a delivery sys-tem able to target MPS cells and to silence TAK1 impacts on pathogenic T effector cells in autoimmunity.
Development and validation of a questionnaire to identify severe maternal morbidity in epidemiological surveys
Authors: Souza Joao P , Cecatti Jose G , Pacagnella Rodolfo C , Giavarotti Thaís M , Parpinelli Mary A , Camargo Rodrigo S , Sousa Maria H 
Published: August 2010

Abstract

Objective
to develop and validate a questionnaire on severe maternal morbidity and to evaluate the maternal recall of complications related to pregnancy and childbirth. Design: validity of a questionnaire as diagnostic instrument. Setting: a third level referral maternity in Campinas, Brazil. Population: 386 survivors of severe maternal complications and 123 women that delivered without major complications between 2002 and 2007.

Methods
eligible women were traced and interviewed by telephone on the occurrence of obstetric complications and events related to their treatment. Their answers were compared with their medical records as gold standard. Sensitivity, specificity and likelihood ratios plus their correspondent 95% confidence intervals were used as main estimators of accuracy. Main outcomes: diagnosis of severe maternal morbidity associated with past pregnancies, including hemorrhage, eclampsia, infections, jaundice and related procedures (hysterectomy, admission to ICU, blood transfusion, laparotomy, inter-hospital transfer, mechanical ventilation and post partum stay above seven days).

Results
Women did not recall accurately the occurrence of obstetric complications, especially hemorrhage and infection. The likelihood ratios were < 5 for hemorrhage and infection, while for eclampsia it almost reached 10. The information recalled by women regarding hysterectomy, intensive care unit admission and blood transfusion were found to be highly correlated with finding evidence of the event in the medical records (likelihood ratios ranging from 12.7-240). The higher length of time between delivery and interview was associated with poor recall.

Conclusion
Process indicators are better recalled by women than obstetric complication and should be considered when applying a questionnaire on severe maternal morbidity.