bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secular trend, seasonality and effects of a community-based intervention on neonatal mortality: follow-up of a cluster-randomised trial in Quang Ninh province, Vietnam
Authors: Eriksson Leif , Nga Nguyen T , Hoa Dinh T Phuong , Duc Duong M , Bergström Anna , Wallin Lars , Målqvist Mats , Ewald Uwe , Huy Tran Q , Thuy Nguyen T , Do Tran Thanh , Lien Pham T L , Persson Lars-Åke , Selling Katarina Ekholm 
Published: May 2018

BackgroundLittle is know about whether the effects of community engagement interventions for child survival in low-income and middle-income settings are sustained. Seasonal variation and secular trend may blur the data. Neonatal mortality was reduced in a cluster-randomised trial in Vietnam where laywomen facilitated groups composed of local stakeholders employing a problem-solving approach for 3 years. In this analysis, we aim at disentangling the secular trend, the seasonal variation and the effect of the intervention on neonatal mortality during and after the trial.MethodsIn Quang Ninh province, 44 communes were allocated to intervention and 46 to control. Births and neonatal deaths were assessed in a baseline survey in 2005, monitored during the trial in 2008–2011 and followed up by a survey in 2014. Time series analyses were performed on monthly neonatal mortality data.ResultsThere were 30 187 live births and 480 neonatal deaths. The intervention reduced the neonatal mortality from 19.1 to 11.6 per 1000 live births. The reduction was sustained 3 years after the trial. The control areas reached a similar level at the time of follow-up. Time series decomposition analysis revealed a downward trend in the intervention areas during the trial that was not found in the control areas. Neonatal mortality peaked in the hot and wet summers.ConclusionsA community engagement intervention resulted in a lower neonatal mortality rate that was sustained but not further reduced after the end of the trial. When decomposing time series of neonatal mortality, a clear downward trend was demonstrated in intervention but not in control areas.Trial registration numberISRCTN44599712, Post-results.
Ultrahigh-pressure metamorphic rocks in the Dabie–Sulu orogenic belt: compositional inheritance and metamorphic modification
Authors: Zheng Yong-Fei , Zhao Zi-Fu , Chen Ren-Xu 
Published: May 2018

Abstract

The Dabie–Sulu orogenic belt in east-central China contains one of the largest ultrahigh-pressure (UHP) metamorphic terranes in the world. The UHP eclogites are associated with gneiss, peridotite and marble. But all these rocks underwent
in situ
UHP metamorphism during the continental collision in the Triassic. Although fluid action is not significant during cold subduction, it becomes prominent during hot exhumation of UHP slices. Whereas the composition of UHP metamorphic rocks is primarily inherited from their protoliths, they were locally modified by partial melting to varying extents. The partial melting of UHP rocks is highly heterogeneous along the collisional orogen, and achieves a maximum during rifting orogeny at the post-collisional stage. This paper outlines the petrographical features and geochemical compositions of UHP metamorphic rocks, and presents an overview of collisional modification and post-collisional reworking of the subducted continental crust. Further discussions are devoted to continental subduction tectonics, as well as to subduction style, subduction polarity and exhumation mechanism. The results also provide insights into the initiation of continental rifting in a Wilson cycle. Consequently, studies of the Dabie–Sulu orogenic belt have contributed greatly to our understanding of tectonic processes, fluid regime and chemical geodynamics in continental subduction zones.
HP1γ Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A
Authors: Alam Hunain , Li Na , Dhar Shilpa S. , Wu Sarah J. , Lv Jie , Chen Kaifu , Flores Elsa R. , Baseler Laura , Lee Min Gyu 
Published: May 2018

Abstract
Lung adenocarcinoma is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma–promoting histone methylation reader protein show that heterochromatin protein 1γ (HP1γ; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human lung adenocarcinoma, and that high HP1γ mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. In vivo depletion of HP1γ reduced K-RasG12D–driven lung adenocarcinoma and lengthened survival of mice bearing K-RasG12D–induced lung adenocarcinoma. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma cells. HP1γ directly repressed expression of the transcription-repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1γ-depleted lung adenocarcinoma cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high HP1γ mRNA levels in lung adenocarcinoma samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1γ and its reader activity in lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma–promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes.
Significance: Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1γ leads to activation of protumorigenic genes in lung adenocarcinoma. Cancer Res; 78(14); 3834–48. ©2018 AACR.
Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors
Authors: Von Hoff Daniel D. , Rasco Drew W. , Heath Elisabeth I. , Munster Pamela N. , Schellens Jan H.M. , Isambert Nicolas , Tourneau Christophe Le , O'Neil Bert , Mathijssen Ron H.J. , Lopez-Martin Jose A. , Edenfield W. Jeff , Martin Miguel , LoRusso Patricia M. , Bray Gordon L. , DiMartino Jorge , Nguyen Aaron , Liu Kejian , Laille Eric , Bendell Johanna C. 
Published: May 2018

Abstract
Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.
Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.
Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.
Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.
Abstract A06: Automated, high-throughput 3D desorption electrospray ionization (DESI) mass spectrometry imaging of a xenograft model of glioblastoma
Authors: Henderson Fiona , Jones Emrys , Denbeigh Joanna , Christie Lidan , Batey Michael A. , Claude Emmanuelle , Williams Kaye J. , McMahon Adam 
Published: May 2018

Abstract
Glioblastomas are a highly aggressive brain tumor, which are commonly resistant to chemotherapy and radiotherapy. The heterogeneity of these tumors can cause major problems for diagnosis and therapy. It is therefore important to study these local variations in glioblastoma metabolism, in order to understand tumor development and to guide treatment. Desorption electrospray ionization mass spectrometry (DESI MS) imaging is a technique that can image hundreds of molecules in a 2D tissue section in a single scan, making it an ideal tool for imaging heterogeneity in tumors. Here, 3D DESI-MS imaging has been implemented to reveal lipid heterogeneity in a whole xenograft glioblastoma. In addition, immunofluorescence staining has been used to elucidate the role of hypoxia in lipid heterogeneity.
Fifteen sections were taken from a xenograft glioblastoma at 120-um increments for DESI-MS imaging. DESI-MS imaging was carried out in both negative and positive ion mode, using the spatial resolution of 120um, to allow even-sized voxels. An automatic slide loader was used to allow high-throughput imaging. Recently written software at Waters, UK was used to automatically reconstruct a 3D image from the 2D DESI-MS images. Serial sections were used for immunofluorescence staining of carbonic anhydrase-9 (a marker for hypoxia). Sections also underwent H&E staining.
High-throughput 3D DESI-MS imaging has been carried out to reveal lipid heterogeneity in a xenograft glioblastoma. Here, 3D DESI-MS imaging reveals segmentation of the tumor based on local lipid expression, which correlates with the histologic mapping of normoxia, hypoxia, and necrosis. Hypoxia is a key contributor to tumor heterogeneity and, importantly, is associated with aggressive tumor development. This work highlights that lipids are playing an important role in glioblastoma heterogeneity. Furthermore, DESI-MS imaging can be used for 3D lipid imaging in an automated fashion, to reveal heterogeneity that is not apparent in H&E stains alone.
Citation Format: Fiona Henderson, Emrys Jones, Joanna Denbeigh, Lidan Christie, Michael A. Batey, Emmanuelle Claude, Kaye J. Williams, Adam McMahon. Automated, high-throughput 3D desorption electrospray ionization (DESI) mass spectrometry imaging of a xenograft model of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A06.
Abstract A37: SB insertional mutagenesis identifies new metastasis-promoting tumor suppressor genes in pancreatic cancer
Authors: Maurin Michelle , Jones Devin J. , Black Mik A. , Newberg Justin Y. , Jenkins Nancy A. , Copeland Neal G. , Mann Karen M. 
Published: May 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with poor patient outcome. While acquired oncogenic activation of KRAS is an initiating event, disease progression requires functional perturbation of additional genes and cellular pathways. Identifying key molecular events that cooperate with oncogenic KRAS in human tumors to drive disease progression is a challenge due in part to the high degree of inter- and intratumor heterogeneity in PDAC genomes. We have taken a comparative genomics approach to identify progression drivers using a mouse model of metastatic PDAC driven by Sleeping Beauty (SB) insertional mutagenesis in the context of oncogenic Kras. Statistical enrichment analysis of SB insertions defined hundreds of cooperating tumor-suppressor genes in SB PDAC tumors. We hypothesized that recurrently mutated TSGs in pancreatic tumors drive metastatic disease. Enrichment analysis of high-read depth insertions from SB PDAC tumors defined 48 drivers predicted to contribute to disease progression. Thirty-two of these genes were statistically enriched in a population-based analysis of SB insertions in metastases isolated from a subset of the animals from the primary cohort. We demonstrated significant increases in primary tumor burden and metastatic spread by single-gene knockdown of novel TSGs TCF12, FNDC3B, or RBFOX2 in orthotopic human PDAC mouse models. TCF12 encodes a basic Helix-loop-helix (bHLH) transcription factor that partners with other bHLH transcription factors in different cellular contexts, including TWIST, a transcription factor involved in epithelial-to-mesenchymal transition (EMT); PTF1A, a pancreas-specific transcription factor with essential roles in pancreas development and cancer; and SMAD3, a TGFβ-related transcription factor involved in cellular migration. TCF12 resides in a chromosomal region (15q21) frequently lost in pancreatic cancer, and decreased TCF12 expression is associated with poor patient prognosis. Using human PDAC expression data from ICGC, we identified 209 genes that exhibit coregulated gene expression with TCF12. A subset of these genes function in Wnt or TGF-Beta signaling pathways and show consistent decreases in expression upon TCF12 knockdown in orthotopic tumors. Ongoing experiments aim to define the TCF12 transcriptional targets involved in metastatic progression.
Citation Format: Michelle Maurin, Devin J. Jones, Mik A. Black, Justin Y. Newberg, Nancy A. Jenkins, Neal G. Copeland, Karen M. Mann. SB insertional mutagenesis identifies new metastasis-promoting tumor suppressor genes in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A37.
Abstract B04: Activating K-RasA146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium
Authors: Poulin Emily , Gierut Jessica , Haigis Kevin 
Published: May 2018

Abstract
Ras is the most commonly mutated oncogene in human cancer, and is highly mutated in pancreatic, lung, and colorectal cancer. The most commonly reported canonical activating point mutations occur in codons 12, 13, and 61. Colorectal cancer, in particular, harbors a number of noncanonical K-Ras mutations, including mutations at codon 146, which occur in ~4% of patients. To understand the biologic effects of K-RasA146T expression in the intestinal epithelium and other tissues, we engineered a conditional Cre recombinase-dependent mutant allele (K-RasLSL-A146T), expressed from the endogenous KRas locus. We crossed K-RasLSL-A146T mice to Fabpl-Cre mice, which express Cre recombinase in the colonic and distal small intestinal epithelium, and compared the phenotype of Fabpl-Cre; K-RasLSL-A146T/+ mice to that of Fabpl-Cre; K-RasLSL-G12D/+ mice. Compared to K-RasG12D, expression of K-RasA146T results in a mild hyperplastic and hyperproliferative phenotype, while expression of K-RasG12D causes drastic hyperplasia and hyperproliferation. Additionally, we found that K-RasA146T expression activates Mapk signaling and that K-RasA146T-induced hyperproliferation is Mapk-dependent. Interestingly, unlike Fabpl-Cre; K-RasLSL-G12D mice, which lack Paneth cells in the small intestine, Fabpl-Cre; K-RasLSL-A146T/+ mice have intact Paneth cells. Finally, we found that although K-RasG12D expression in the pancreas causes neoplastic transformation, K-RasA146T expression has no detectable effect on pancreatic homeostasis, even after one year. Together, our results suggest that compared to the canonical K-RasG12D mutation, activating K-RasA146T mutations have a similar but milder effect on colonic homeostasis. Additionally, consistent with human data, we found that K-RasA146T mutations have tissue-specific effects on neoplastic transformation.
Citation Format: Emily Poulin, Jessica Gierut, Kevin Haigis. Activating K-RasA146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B04.
Abstract B12: The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis
Authors: Hill Kristen S. , Wang Xue , Roberts Evan R. , Kim Youngchul , Messina Jane , Kim Minjung 
Published: May 2018

Abstract
The Ras family of small GTP-binding proteins is frequently activated by mutations, including NRAS (20%), KRAS (2%), and HRAS (1%), in melanoma. In addition to mutations, Ras isoforms can also be activated by the inactivation of Ras GTPase activating proteins (RasGAPs), such as NF1, RASA1, and RASA2. In our recent study, we observed that the inactivation of RASA1 (RAS p21 protein activator 1, also called p120RasGAP) suppressed melanoma via its RasGAP activity toward the R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. We hypothesized that, although not mutated, R-Ras is activated in melanoma through the inactivation of RasGAPs and that RasGAP/R-Ras pathway activation cooperates with BRAF activation in melanoma tumorigenesis.
In this study, we addressed the importance of R-Ras, a previously less-appreciated member of the Ras family, in melanoma tumorigenesis and investigated the molecular mechanisms underlying R-Ras signaling in BRAF mutant melanoma. We observed frequent activation of R-Ras in BRAF mutant human melanoma cell lines. In addition, RNAi-mediated reduced expression of R-Ras suppressed anchorage-independent colony growth and tumor growth. Moreover, among the three major RAS effector pathways, reduced R-Ras expression suppressed Ral-A activation, which may explain the mechanism of Ral-A activation in BRAF mutant melanoma. Interestingly, anchorage-independent growth driven by RASA1 inactivation and subsequent R-Ras activation was suppressed by both genetic (siRNA targeting Ral-A) and pharmacologic (Ral inhibitor BQU57) inhibition of Ral-A. To further investigate the impact of RASA1 loss, and thus R-Ras activation, on BRAF mutant melanoma development in vivo, we generated a RASA1 L/L; BRAF CA/CA; Tyr-CreERT2 mouse model in which treatment with 4OHT results in the expression of constitutively activated mutant BRAF and the deletion of RASA1 in melanocytic lineage cells. Preliminary analysis shows hyperpigmentation of the ear, tail, and foot pad in RASA1 L/L BRAF CA/CA mice compared to RASA1 +/+ BRAF CA/CA littermates and the development of melanoma in RASA1 mutant mice. This study demonstrates the importance of the RASA1/R-Ras/Ral-A signaling pathway in BRAF mutant melanoma and supports the possible combinatorial treatment strategy targeting both the BRAF/MAPK and Ral signaling pathways.
Citation Format: Kristen S. Hill, Xue Wang, Evan R. Roberts, Youngchul Kim, Jane Messina, Minjung Kim. The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B12.
Abstract B35: An innovative in vivo model of metastasizing prostate cancer using orthotopic xenografts
Authors: Linxweiler Johannes , Körbel Christina , Müller Andreas , Hammer Markus , Stöckle Michael , Junker Kerstin , Menger Michael D. 
Published: May 2018

Abstract
Introduction: In this study, we aimed to develop a versatile in vivo model of prostate cancer using orthotopic xenografts, which adequately represents intraprostatic tumor growth as well as the natural routes of metastatic spread.
Materials and Methods: 5x105 VCaP-, LuCaP136-, and LuCaP147 cells were injected into the prostate of male CB17-SCID mice (n=8 for each cell line; VCaP cultured as monolayer, LuCaP136 and LuCaP147 as three-dimensional spheroid culture). During 12 weeks of follow-up, orthotopic tumor growth and the development of metastases was monitored by repetitive serum-PSA measurements and imaging studies (ultrasonography, CT, MRI). At autopsy, primary tumors and metastases were harvested and examined by conventional histology (H&E) and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, PSA). From the results of the imaging studies and PSA measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated for each cell line.
Results: All 24 mice developed orthotopic tumors, whose growth could be reliably monitored by ultrasonography, CT, MRI, and serum-PSA measurements. 4 animals died during follow-up (1 in the VCaP group, 1 in the LuCaP136 group, 2 in the LuCaP147 group). Mean PSA-density was 433.9 ng/ml per ml tumor in the VCaP group, 6.5 ng/ml per ml tumor in the LuCaP136 group, and 11.2 ng/ml per ml tumor in the LuCaP147 group. Tumor-specific growth rate and tumor volume doubling time were 3.87% per day and 21.24 days in the VCaP group, 3.11% and 27.57 days in the LuCaP136 group, and 4.47% and 16.2 days in the LuCaP147 group, respectively. In up to 100% of animals, lymph node metastases could be detected after 12 weeks (5/7 in the VCaP group, 6/7 in the LuCaP136 group, 6/6 in the LuCaP147 group). These could also be visualized by ultrasonography and MRI. Immunohistochemistry showed positive CK8, AR, and AMACR as well as negative CK5 reactions in all tumors. ERG-straining was positive in VCaP and negative in both LuCaP tumors, Ki67 proliferation indices were &gt;90% in all groups.
Conclusions: By using different monolayer as well as 3D spheroid cell cultures in an orthotopic xenograft model, we could establish an innovative, versatile in vivo model of prostate cancer, which enables the study of both intraprostatic tumor growth as well as metastatic spread to regional lymph nodes.
Citation Format: Johannes Linxweiler, Christina Körbel, Andreas Müller, Markus Hammer, Michael Stöckle, Kerstin Junker, Michael D. Menger. An innovative in vivo model of metastasizing prostate cancer using orthotopic xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B35.