bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of a father's presence during newborn resuscitation: a qualitative interview study with healthcare professionals
Authors: Harvey Merryl E , Pattison Helen M 
Published: March 2013

ObjectiveTo explore healthcare professionals’ experiences around the time of newborn resuscitation in the delivery room, when the baby's father was present.DesignA qualitative descriptive, retrospective design using the critical incident approach. Tape-recorded semistructured interviews were undertaken with healthcare professionals involved in newborn resuscitation. Participants recalled resuscitation events when the baby's father was present. They described what happened and how those present, including the father, responded. They also reflected upon the impact of the resuscitation and the father's presence on themselves. Participant responses were analysed using thematic analysis.SettingA large teaching hospital in the UK.ParticipantsPurposive sampling was utilised. It was anticipated that 35–40 participants would be recruited. Forty-nine potential participants were invited to take part. The final sample consisted of 37 participants including midwives, obstetricians, anaesthetists, neonatal nurse practitioners, neonatal nurses and paediatricians.ResultsFour themes were identified: ‘whose role?’ ‘saying and doing’ ‘teamwork’ and ‘impact on me’. While no-one was delegated to support the father during the resuscitation, midwives and anaesthetists most commonly took on this role. Participants felt the midwife was the most appropriate person to support fathers. All healthcare professional groups said they often did not know what to say to fathers during prolonged resuscitation. Teamwork was felt to be of benefit to all concerned, including the father. Some paediatricians described their discomfort when fathers came to the resuscitaire. None of the participants had received education and training specifically on supporting fathers during newborn resuscitation.ConclusionsThis is the first known study to specifically explore the experiences of healthcare professionals of the father's presence during newborn resuscitation. The findings suggest the need for more focused training about supporting fathers. There is also scope for service providers to consider ways in which fathers can be supported more readily during newborn resuscitation.
PARALLEL CONSTRUCTION OF DATA CUBES ON MULTI-CORE MULTI-DISK PLATFORMS
Authors: DEHNE FRANK , ZABOLI HAMIDREZA 
Published: March 2013

On-line Analytical Processing (OLAP) has become one of the most powerful and prominent technologies for knowledge discovery in VLDB (Very Large Database) environments. Central to the OLAP paradigm is the data cube, a multi dimensional hierarchy of aggregate values that provides a rich analytical model for decision support. Various sequential algorithms for the efficient generation of the data cube have appeared in the literature. However, given the size of contemporary data warehousing repositories, multi-processor solutions are crucial for the massive computational demands of current and future OLAP systems. In this paper we discuss the development of MCMD-CUBE, a new parallel data cube construction method for multi-core processors with multiple disks. We present experimental results for a Sandy Bridge multi-core processor with four parallel disks. Our experiments indicate that MCMD-CUBE achieves very close to linear speedup. A critical part of our MCMD-CUBE method is parallel sorting. We developed a new parallel sorting method termed MCMD-SORT for multi-core processors with multiple disks which outperforms other previous methods.
High-Throughput Tyrosine Kinase Activity Profiling Identifies FAK as a Candidate Therapeutic Target in Ewing Sarcoma
Authors: Crompton Brian D. , Carlton Anne L. , Thorner Aaron R. , Christie Amanda L. , Du Jinyan , Calicchio Monica L. , Rivera Miguel N. , Fleming Mark D. , Kohl Nancy E. , Kung Andrew L. , Stegmaier Kimberly 
Published: March 2013

Abstract
Limited progress has been made in the treatment of advanced-stage pediatric solid tumors despite the accelerated pace of cancer discovery over the last decade. Tyrosine kinase inhibition is one tractable therapeutic modality for treating human malignancy. However, little is known about the kinases critical to the development or maintenance of many pediatric solid tumors such as Ewing sarcoma. Using a fluorescent, bead-based technology to profile activated tyrosine kinases, we identified focal adhesion kinase (FAK, PTK2) as a candidate target in Ewing sarcoma. FAK is a tyrosine kinase critical for cellular adhesion, growth, and survival. As such, it is a compelling target for cancer-based therapy. In this study, we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK-selective kinase inhibitor, PF-562271, impaired growth and colony formation in Ewing sarcoma cell lines. Moreover, treatment of Ewing sarcoma cell lines with PF-562271 induced apoptosis and led to downregulation of AKT/mTOR and CAS activity. Finally, we showed that small-molecule inhibition of FAK attenuated Ewing sarcoma tumor growth in vivo. With FAK inhibitors currently in early-phase clinical trials for adult malignancies, these findings may bear immediate relevance to patients with Ewing sarcoma. Cancer Res; 73(9); 2873–83. ©2013 AACR.
Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis
Authors: Teitz Tal , Inoue Madoka , Valentine Marcus B. , Zhu Kejin , Rehg Jerold E. , Zhao Wei , Finkelstein David , Wang Yong-Dong , Johnson Melissa D. , Calabrese Christopher , Rubinstein Marcelo , Hakem Razqallah , Weiss William A. , Lahti Jill M. 
Published: March 2013

Abstract
Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblasoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model. Cancer Res; 73(13); 4086–97. ©2013 AACR.
Tumor–Immune Dynamics Regulated in the Microenvironment Inform the Transient Nature of Immune-Induced Tumor Dormancy
Authors: Wilkie Kathleen P. , Hahnfeldt Philip 
Published: March 2013

Abstract
Cancer in a host induces responses that increase the ability of the microenvironment to sustain the growing mass, for example, angiogenesis, but cancer cells can have varying sensitivities to these sustainability signals. Here, we show that these sensitivities are significant determinants of ultimate tumor fate, especially in response to treatments and immune interactions. We present a mathematical model of cancer–immune interactions that modifies generalized logistic growth with both immune-predation and immune-recruitment. The role of a growing environmental carrying capacity is discussed as a possible regulatory mechanism for tumor growth, and this regulation is shown to modify cancer–immune interactions and the possibility of achieving immune-induced tumor dormancy. This mathematical model qualitatively matches experimental observations of immune-induced tumor dormancy as it predicts dormancy as a transient period of growth that necessarily ends in either tumor elimination or tumor escape. As dormant tumors may exist asymptomatically and may be easier to treat with conventional therapy, an understanding of the mechanisms behind tumor dormancy may lead to new treatments aimed at prolonging the dormant state or converting an aggressive cancer to the dormant state. Cancer Res; 73(12); 3534–44. ©2013 AACR.
NIK Controls Classical and Alternative NF-κB Activation and Is Necessary for the Survival of Human T-cell Lymphoma Cells
Authors: Odqvist Lina , Sánchez-Beato Margarita , Montes-Moreno Santiago , Martín-Sánchez Esperanza , Pajares Raquel , Sánchez-Verde Lydia , Ortiz-Romero Pablo L. , Rodriguez Jose , Rodríguez-Pinilla Socorro M. , Iniesta-Martínez Francisca , Solera-Arroyo Juan Carlos , Ramos-Asensio Rafael , Flores Teresa , Palanca Javier Menarguez , Bragado Federico García , Franjo Purificación Domínguez , Piris Miguel A. 
Published: March 2013

Abstract
Purpose: Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB–inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas.
Experimental Design: We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability.
Results: We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors.
Conclusions: The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies. Clin Cancer Res; 19(9); 2319–30. ©2013 AACR.
Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer
Authors: Xu Ye , Xu Qinghua , Yang Li , Ye Xun , Liu Fang , Wu Fei , Ni Shujuan , Tan Cong , Cai Guoxiang , Meng Xia , Cai Sanjun , Du Xiang 
Published: March 2013

AbstractPurpose: The early detection of colorectal cancer (CRC) is crucial for successful treatment and patient survival. However, compliance with current screening methods remains poor. This study aimed to identify an accurate blood-based gene expression signature for CRC detection.Experimental Design: Gene expression in peripheral blood samples from 216 patients with CRC tumors and 187 controls was investigated in the study. We first conducted a microarray analysis to select candidate genes that were significantly differentially expressed between patients with cancer and controls. A quantitative reverse transcription PCR assay was then used to evaluate the expression of selected genes. A gene expression signature was identified using a training set (n = 200) and then validated using an independent test set (n = 160).Results: We identified an 18-gene signature that discriminated the patients with CRC from controls with 92% accuracy, 91% sensitivity, and 92% specificity. The signature performance was further validated in the independent test set with 86% accuracy, 84% sensitivity, and 88% specificity. The area under the receiver operating characteristics curve was 0.94. The signature was shown to be enriched in genes related to immune functions.Conclusions: This study identified an 18-gene signature that accurately discriminated patients with CRC from controls in peripheral blood samples. Our results prompt the further development of blood-based gene expression biomarkers for the diagnosis and early detection of CRC. Clin Cancer Res; 19(11); 3039–49. ©2013 AACR.
Suppression of Survivin Induced by a BCR-ABL/JAK2/STAT3 Pathway Sensitizes Imatinib-Resistant CML Cells to Different Cytotoxic Drugs
Authors: Stella Stefania , Tirrò Elena , Conte Enrico , Stagno Fabio , Di Raimondo Francesco , Manzella Livia , Vigneri Paolo 
Published: March 2013

Abstract
The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) displays exclusive cytoplasmic localization and constitutive tyrosine kinase activity leading to the activation of different pathways that favor cell proliferation and survival. BCR-ABL induces survivin expression at both the mRNA and protein level, thus inhibiting the apoptotic machinery of CML cells and contributing to the expansion of the leukemic clone. We report that, in human CML cell lines, BCR-ABL–mediated upregulation of survivin involves the JAK2/STAT3 pathway since silencing of either protein caused a consistent reduction in survivin expression. Cell lines unresponsive to imatinib mesylate (IM) because of BCR-ABL gene amplification were not resensitized to the drug after survivin downregulation. However, cells insensitive to IM because of point mutations in the BCR-ABL kinase domain were highly responsive to hydroxyurea (HU) after survivin silencing. To address the possible clinical applications of our results, we used shepherdin, a cell-permeable peptidomimetic compound that downregulates survivin expression by preventing its interaction with Hsp90. Incubation with shepherdin of immortalized cell lines both sensitive and resistant to IM enhanced cell death induced by HU and doxorubicin. Similarly, the combination of shepherdin with first- and second-generation tyrosine kinase inhibitors reduced the colony-forming potential of human progenitors derived from both patients with IM-sensitive and IM-resistant CML. These results suggest that strategies aimed at reducing survivin levels may represent a potential therapeutic option for patients with CML unresponsive to IM. Mol Cancer Ther; 12(6); 1085–98. ©2013 AACR.
Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis
Authors: Petruccelli Luca A. , Pettersson Filippa , del Rincón Sonia V. , Guilbert Cynthia , Licht Jonathan D. , Miller Wilson H. 
Published: March 2013

Abstract
Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repair–deficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARα, PML-RARα, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19INK4D and p21WAF1 and triggered a G2–M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZF-RARα–expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs. Mol Cancer Ther; 12(8); 1591–604. ©2013 AACR.
HGF as a Circulating Biomarker of Onartuzumab Treatment in Patients with Advanced Solid Tumors
Authors: Penuel Elicia , Li Congfen , Parab Vaishali , Burton Luciana , Cowan Kyra J. , Merchant Mark , Yauch Robert L. , Patel Premal , Peterson Amy , Hampton Garret M. , Lackner Mark R. , Hegde Priti S. 
Published: March 2013

Abstract
The objective of this study was to evaluate circulating hepatocyte growth factor (cHGF) as a pharmacodynamic biomarker of Met inhibition for onartuzumab (MetMAb, OA5D5v2) in a phase I trial in patients with advanced cancers and a phase II trial in non–small cell lung cancer (NSCLC). The phase I study was a dose escalation trial with onartuzumab administered i.v. once every three weeks. The phase II study was a randomized two-arm trial in which onartuzumab or placebo was administered in combination with erlotinib in 137 patients with second and third line (2/3L) NSCLC. cHGF levels were evaluated by ELISA at multiple time points over the treatment period. Onartuzumab administration resulted in an acute and sustained rise in cHGF in both the phase I and phase II studies. Elevation in cHGF was independent of dose or drug exposure and was restricted to onartuzumab treatment. Neither higher baseline nor elevated change in cHGF levels upon treatment could simply be attributed to tumor burden or number of liver metastasis. We have shown that elevated cHGF can consistently and reproducibly be measured as a pharmacodynamic biomarker of onartuzumab activity. The elevation in cHGF is independent of tumor type, dose administered, or dose duration. Although these studies were not powered to directly address the contribution of cHGF as a predictive, on-treatment, circulating biomarker, these data suggest that measurement of cHGF in future expanded studies is warranted. Mol Cancer Ther; 12(6); 1122–30. ©2013 AACR.
Canonical Wnt/β-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance
Authors: Watson Adrienne L. , Rahrmann Eric P. , Moriarity Branden S. , Choi Kwangmin , Conboy Caitlin B. , Greeley Andrew D. , Halfond Amanda L. , Anderson Leah K. , Wahl Brian R. , Keng Vincent W. , Rizzardi Anthony E. , Forster Colleen L. , Collins Margaret H. , Sarver Aaron L. , Wallace Margaret R. , Schmechel Stephen C. , Ratner Nancy , Largaespada David A. 
Published: March 2013

Abstract
Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.
Significance: We show canonical Wnt/β-catenin signaling is a novel genetic driver of Schwann cell tumor development and progression, due to downregulation of β-catenin destruction complex members and overexpression of RSPO2. Inhibitors of Wnt signaling alone, or in combination with RAD-001, may have therapeutic value for patients with MPNSTs or neurofibromas. Cancer Discov; 3(6); 674–89. ©2013 AACR.
See related commentary by Reilly, p. 610
This article is highlighted in the In This Issue feature, p. 591
Nobiletin, a polymethoxyflavone in citrus fruits, reduces TAFI expression in HepG2 cells through transcriptional inhibition
Authors: Takada Kimihiko , Seike Toru , Sasaki Tomoyuki , Masuda Yutaka , Ito Akira , Ishii Hidemi 
Published: March 2013

SummaryThrombin-activatable fibrinolysis inhibitor (TAFI, carboxypeptidase B2) is a 58-kDa plasma glycoprotein secreted by hepatocytes as an inactive form. TAFI is activated by the thrombin-thrombomodulin complex, and activated TAFI (TAFIa) plays an important role in regulating the balance between coagulation and fibrinolysis through inhibition of fibrinolysis. It has been suggested that high levels of TAFI in circulating plasma increase the risks of cardiovascular death and acute phase in ischaemic stroke. However, the mechanisms of regulating TAFI expression have been unclear. The present study investigated the effects of nobiletin (a polymethoxy flavonoid contained in the rind of citrus fruits) on TAFI gene (CPB2) and TAFI antigen expression in cultured human hepatoma HepG2 cells. Nobiletin decreased the release of TAFI antigen from HepG2 cells into conditioned medium in parallel with decreased levels of CPB2 mRNA and antigen. The half-life time of CPB2 mRNA in nobiletin-treated cells was unchanged compared to that of untreated control cells. Using nobiletin-treated cells that were transfected with a luciferase CPB2 promoter reporter plasmid, activity decreased to half of that in untreated control cells. A series of luciferase reporter constructs containing 5´-flanking region deletions of the human CPB2 gene showed that the sequences from –150 bp to –50 bp were essential for transcription of CPB2 and contained an AP-1 binding sequence at ∼ –119 bp to – 99 bp in the CPB2 promoter. The amount of complexed nuclear protein and sequences from ∼ –119 bp to –99 bp was decreased in nobiletin-treated cells. ChIP assays showed that c-Jun bound to the ∼ –119 bp to –99 bp region of the CPB2 promoter and that the amount of the immunocomplex decreased after nobiletin treatment. Therefore, nobiletin-induced repression of CPB2 transcription might involve AP-1 inhibition and/or prevention of AP-1 binding in a specific region on the CPB2 gene in HepG2 cells.