bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic inflammation inhibits serotonin receptor 2-induced phrenic motor facilitation upstream from BDNF/TrkB signaling
Authors: Agosto-Marlin Ibis M. , Nichols Nicole L. , Mitchell Gordon S. 
Published: March 2018

Although systemic inflammation induced by even a low dose of lipopolysaccharide (LPS, 100 μg/kg) impairs respiratory motor plasticity, little is known concerning cellular mechanisms giving rise to this inhibition. Phrenic motor facilitation (pMF) is a form of respiratory motor plasticity elicited by pharmacological agents applied to the cervical spinal cord, or by acute intermittent hypoxia (AIH; 3, 5-min hypoxic episodes); when elicited by AIH, pMF is known as phrenic long-term facilitation (pLTF). AIH consisting of moderate hypoxic episodes (mAIH, arterial Po2 = 35–55 mmHg) elicits pLTF via the Q pathway to pMF, a mechanism that requires spinal serotonin (5HT2) receptor activation and new brain-derived neurotrophic factor (BDNF) protein synthesis. Although mild systemic inflammation attenuates mAIH-induced pLTF via spinal p38 MAP kinase activation, little is known concerning how p38 MAP kinase activity inhibits the Q pathway. Here, we confirmed that 24 h after a low LPS dose (100 μg/kg ip), mAIH-induced pLTF is greatly attenuated. Similarly, pMF elicited by intrathecal cervical injections of 5HT2A(DOI; 100 μM; 3 × 6 μl) or 5HT2Breceptor agonists (BW723C86; 100 μM; 3 × 6 μl) is blocked 24 h post-LPS. When pMF was elicited by intrathecal BDNF (100 ng, 12 μl), pMF was actually enhanced 24 h post-LPS. Thus 5HT2A/2Breceptor-induced pMF is impaired downstream from 5HT2receptor activation, but upstream from BDNF/TrkB signaling. Mechanisms whereby LPS augments BDNF-induced pMF are not yet known.NEW & NOTEWORTHY These experiments give novel insights concerning mechanisms whereby systemic inflammation undermines serotonin-dependent, spinal respiratory motor plasticity, yet enhances brain-derived neurotrophic factor (BDNF)/TrkB signaling in phrenic motor neurons. These insights may guide development of new strategies to elicit functional recovery of breathing capacity in patients with respiratory impairment by reducing (or bypassing) the impact of systemic inflammation characteristic of clinical disorders that compromise breathing.
Meridian interference reveals neural locus of motion-induced position shifts
Authors: Liu Sirui , Tse Peter U. , Cavanagh Patrick 
Published: March 2018

When a Gabor patch moves along a path in one direction while its internal texture drifts orthogonally to this path, it can appear to deviate from its physical path by 45° or more. This double-drift illusion is different from other motion-induced position shift effects in several ways: it has an integration period of over a second; the illusory displacement that accumulates over a second or more is orthogonal to rather than along the motion path; the perceptual deviations are much larger; and they have little or no effect on eye movements to the target. In this study we investigated the underlying neural mechanisms of the motion integration and position processing for this double-drift stimulus by testing possible anatomical constraints on its magnitude. We found that the illusion was reduced at the vertical and horizontal meridians when the perceptual path would cross or be driven toward the meridian, but not at other locations or other motion directions. The disruption of the accumulation of the position error at both the horizontal and vertical meridians suggests a central role of quadrantic areas in the generation of this type of motion-induced position shift.NEW & NOTEWORTHY The remarkably strong double-drift illusion is disrupted at both the vertical and horizontal meridians. We propose that this finding is the behavioral consequence of the anatomical gaps at both meridians, suggesting that neural areas with quadrantic representations (e.g., V2, V3) are the initial locus of this motion-induced position shift. This result rules out V1 as the source of the illusion because it has an anatomical break only at the vertical meridian.
Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFβRIII–p38MAPK–pS249/T252RB Pathway
Authors: Yu-Lee Li-Yuan , Yu Guoyu , Lee Yu-Chen , Lin Song-Chang , Pan Jing , Pan Tianhong , Yu Kai-Jie , Liu Bin , Creighton Chad J. , Rodriguez-Canales Jaime , Villalobos Pamela A. , Wistuba Ignacio I. , de Nadal Eulalia , Posas Francesc , Gallick Gary E. , Lin Sue-Hwa 
Published: March 2018

AbstractBone metastasis from prostate cancer can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTCs are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 prostate cancer cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single-cell level revealed that conditioned medium from differentiated, but not undifferentiated, osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to prostate cancer cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating prostate cancer tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates retinoblastoma (RB) at the novel N-terminal S249/T252 sites to block prostate cancer cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 prostate cancer cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in patients with prostate cancer correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTCs are induced into a dormant state through TGFβRIII–p38MAPK–pS249/pT252–RB signaling and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone.Significance: These findings provide mechanistic insights into the dormancy of metastatic prostate cancer in the bone and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Cancer Res; 78(11); 2911–24. ©2018 AACR.
The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis
Authors: Deel Michael D. , Slemmons Katherine K. , Hinson Ashley R. , Genadry Katia C. , Burgess Breanne A. , Crose Lisa E.S. , Kuprasertkul Nina , Oristian Kristianne M. , Bentley Rex C. , Linardic Corinne M. 
Published: March 2018

Abstract
Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. Five-year survival for aRMS is &lt;50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.
Experimental Design: After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo. Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.
Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2–M phase of the cell cycle. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.
Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS. Clin Cancer Res; 24(11); 2616–30. ©2018 AACR.
COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment
Authors: Dong Xiao-Feng , Liu Tian-Qi , Zhi Xu-Ting , Zou Jie , Zhong Jing-Tao , Li Tao , Mo Xiang-Lan , Zhou Wei , Guo Wen-Wen , Liu Xia , Chen Yuan-Yuan , Li Meng-Yang , Zhong Xiao-Gang , Han Ya-Min , Wang Zhong-Hao , Dong Zhao-Ru 
Published: March 2018

Abstract
Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.
Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.
Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2–specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.
Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2–specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204–16. ©2018 AACR.
Genome-wide Discovery and Identification of a Novel miRNA Signature for Recurrence Prediction in Stage II and III Colorectal Cancer
Authors: Kandimalla Raju , Gao Feng , Matsuyama Takatoshi , Ishikawa Toshiaki , Uetake Hiroyuki , Takahashi Naoki , Yamada Yasuhide , Becerra Carlos , Kopetz Scott , Wang Xin , Goel Ajay 
Published: March 2018

Abstract
Purpose: The current tumor–node–metastasis (TNM) staging system is inadequate at identifying patients with high-risk colorectal cancer. Using a systematic and comprehensive biomarker discovery and validation approach, we aimed to identify an miRNA recurrence classifier (MRC) that can improve upon the current TNM staging as well as is superior to currently offered molecular assays.
Experimental Design: Three independent genome-wide miRNA expression profiling datasets were used for biomarker discovery (N = 158) and in silico validation (N = 109 and N = 40) to identify an miRNA signature for predicting tumor recurrence in patients with colorectal cancer. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh-frozen (N = 127, cohort 1) and formalin-fixed paraffin-embedded (FFPE; N = 165, cohort 2 and N = 139, cohort 3) specimens.
Results: We identified an 8-miRNA signature that significantly predicted recurrence-free interval (RFI) in the discovery (P = 0.002) and two independent publicly available datasets (P = 0.00006 and P = 0.002). The RT-PCR–based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in patients with stage II and III colorectal cancer [cohort 1: hazard ratio (HR), 3.44 (1.56–7.45), P = 0.001; cohort 2: HR, 6.15 (3.33–11.35), P = 0.001; and cohort 3: HR, 4.23 (2.26–7.92), P = 0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence and achieved superior predictive accuracy over the currently available molecular assays. The RT-PCR–based MRC risk score = (−0.1218 × miR-744) + (−3.7142 × miR-429) + (−2.2051 × miR-362) + (3.0564 × miR-200b) + (2.4997 × miR-191) + (−0.0065 × miR-30c2) + (2.2224 × miR-30b) + (−1.1162 × miR-33a).
Conclusions: This novel MRC is superior to currently used clinicopathologic features, as well as National Comprehensive Cancer Network (NCCN) criteria, and works regardless of adjuvant chemotherapy status in identifying patients with high-risk stage II and III colorectal cancer. This can be readily deployed in clinical practice with FFPE specimens for decision-making pending further model testing and validation. Clin Cancer Res; 24(16); 3867–77. ©2018 AACR.
See related commentary by Rodriguez et al., p. 3787
Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model
Authors: Nguyen Ferro , Alferiev Ivan , Guan Peng , Guerrero David T. , Kolla Venkatadri , Moorthy Ganesh S. , Chorny Michael , Brodeur Garrett M. 
Published: March 2018

Abstract
Purpose: Currently, &lt;50% of high-risk pediatric solid tumors like neuroblastoma can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature.
Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles. Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance nanoparticle retention. We treated neuroblastomas with SN38-TOA nanoparticles and compared the efficacy with the parent prodrug CPT-11 using a mouse xenograft model.
Results: Nanoparticle treatment induced prolonged event-free survival (EFS) in most mice, compared with CPT-11. This was shown for both SH-SY5Y and IMR-32 neuroblastoma xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared with conventional CPT-11 delivery. Interestingly, when recurrent CPT-11–treated tumors were re-treated with SN38-TOA nanoparticles, the tumors transformed from undifferentiated neuroblastomas to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology.
Conclusions: Nanoparticle delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in nanoparticles during circulation should decrease toxicity. We propose that nanoparticle-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors. Clin Cancer Res; 24(11); 2585–93. ©2018 AACR.
Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without Helicobacter Pylori Eradication
Authors: Kodama Masaaki , Okimoto Tadayoshi , Mizukami Kazuhiro , Abe Hisanori , Ogawa Ryo , Okamoto Kazuhisa , Shuto Mitsutaka , Matsunari Osamu , Hirashita Yuka , Sato Ryugo , Abe Takashi , Nagai Takayuki , Arita Tsuyoshi , Murakami Kazunari 
Published: March 2018

Background/Aims: The rate of gastric cancer (GC) after Helicobacter pylori eradication has gradually increased; therefore, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. Methods: This study included 50 subjects with GC after eradication (GCE) and 151 patients with GC with H. pylori infection (GCI). Clinicopathological factors were assessed. The manifestation of GC was further evaluated using immunohistochemical analysis and in situ hybridization. Results: Macroscopic analysis revealed a significantly higher ratio of depressed type /elevated type in the GCE compared with the GCI (30/19 vs. 61/77, p = 0.041). The gastric phenotype was more common in the GCE compared with the GCI, and the proportion of CDX2-positive cases was lower in the GCE (8 out of 18; 44.4%) compared with the GCI (18 out of 19; 94.7%; p = 0.00082). Ki-67 labeling index was significantly lower in the GCE (32.03 ± 22.15) compared with the GCI (79.20 ± 14.87, p < 0.0001). No patient in the GCE showed evidence of Epstein-Barr virus infection. Conclusion: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in terms of morphology, mucin phenotype, and proliferation rate.
Long-Term Follow-Up after Paediatric Kidney Transplantation and Influence Factors on Graft Survival: A Single-Centre Experience of 16 years
Authors: Friedersdorff Frank , Koch Therese-Marie , Banuelos-Marco Beatriz , Gonzalez Ricardo , Fuller Tom Florian , von Mechow Stefanie , Müller Dominik , Lingnau Anja 
Published: March 2018

<b><i>Introduction:</i></b> To evaluate graft- and patient survival after paediatric kidney transplantation and detecting influence factors, which affect the post-transplant time. <b><i>Materials and Methods:</i></b> We analysed long-term survival rates and complications after paediatric kidney transplantation and searched for predictive parameters for graft function. <b><i>Results:</i></b> In 132 patients, 143 kidney transplantations were performed. Graft failure occurred in 25%. Chronic rejections were the leading cause of graft loss (42.9%). Graft survival rates were 92.2% after 1 year, 85.5% after 5 years, 71.1% after 10 years and 62.1% after 15 years. The following parameters strongly influenced graft survival: number of transplants (<i>p</i> = 0.014), year of transplant (<i>p</i> &#x3c; 0.0001 for 1997–2005), Epo-therapy post-transplant (<i>p</i> = 0.001), hypotension donor (<i>p</i> = 0.027), cold ischemia time (<i>p</i> = 0.023), anastomosis time &#x3e;50 min (<i>p</i> = 0.008), delayed graft function (<i>p</i> = 0.003) and deceased donation (<i>p</i> = 0.039). The percentage of patients who died was 5.6%. Overall patient survival rates were 99.3% after 1 year, 95.2% after 5 years, 94.2% after 10 years and 90.7% after 15 years. Various types of infections (42.9%) were the main causes of death. <b><i>Conclusions:</i></b> The main causes of death after kidney transplantations in paediatric recipients are malignancy and infections. To avoid vascular complications especially in young recipients (&#x3c;9 years), the cold ischemia time should be as short as possible.
Evolution of the East Central Eurasian Hydrocarbon Energy Complex
Authors: Cutler Robert M. 
Published: March 2018

Abstract
This article analyzes the evolution of the East Central Eurasian energy triangle China-Kazakhstan-Russia. It treats in depth the behavior of Chinese national oil companies (nocs) regarding foreign direct investment (fdi) in Kazakhstan and Russia. The first section sets out the framework of geo-economics in a complexity-science perspective, in particular the key analytical categories of the ‘emergent coherence’ approach, and it defines a ‘hydrocarbon energy complex’ (hec). The second section analyzes the formation of the East Central Eurasian hec by examining Chinese energy investment in Kazakhstan and Russia since 1991, using the ‘emergent coherence’ framework as explained. The third section examines the geo-economics of Sino-Russian competition for energy resources in Central Asia, specifically in Kazakhstan and Turkmenistan, over the same timeframe. The fourth section presents conclusions about changes over time in the behavior of Chinese nocs regarding investment in Kazakhstan and Russia and cooperation with them in the energy sector. The fifth section, the conclusion, summarizes the findings, gives them geopolitical perspective, and concludes on the criteria determining the delimitation of the distinct chronological periods emerging from application of the ‘emergent coherence’ framework.
China’s Statist Energy Relations with Turkmenistan and Kazakhstan
Authors: Amineh Mehdi P. , van Driel Melanie 
Published: March 2018

Abstract
During the last decade, China’s diplomatic, economic, security and multilateral relations with Resource-Rich Countries (rrcs) in general, and with Central Asia and the Caspian Region (cacr) in particular, created a regional web of complementarity connecting states and societies. This trend reflects a dimension of the “statist globalization” of the Chinese economy. Chinese National Oil Companies (cnocs) are powerful actors within this emerging network. This comes as no surprise, as China’s domestic power-wealth structure relies on uninterrupted foreign (energy) supplies. The main aim of this paper will be to present a geopolitical economic reflection on China’s post-Cold War energy relations with the rrcs of Turkmenistan and Kazakhstan. Our theoretical framework, which stems from critical geopolitics, tries to conceptualize the geopolitical economic policy tools used by China’s ruling class in rrcs in general and the two cases in particular.
Inclusive Development and Climate Change: The Geopolitics of Fossil Fuel Risks in Developing Countries
Authors: Gupta Joyeeta , Chu Eric 
Published: March 2018

Abstract
This conceptual paper brings together two previously disparate strands of scholarship on climate change and development together with emerging studies of stranded assets. It addresses the question: What are the lessons learnt from this literature for the way developing countries should ‘develop’ in a post-Paris Agreement world? The paper argues that instead of a blind neo-colonial process of rapidly replicating the development paths of already industrialized countries – especially in the context of the fossil fuel sector – developing countries must adopt their own unique development strategies that are more inclusive and transformative. The foregone economic gains from not investing in fossil fuels maybe compensated by the reduced risks of stranded assets and climate change impacts in the future – as well as the reduced risks of climate change impacts on, for example, the agricultural sector – which may facilitate their own unique paths toward inclusive development.
The “Others” Coming to John the Baptist and the Text of Josephus
Authors: Rotman Marco 
Published: March 2018

Abstract
Josephus’s passage on John the Baptist (Ant. 18.116-119) contains a much-discussed crux interpretum: who are the “others” that are inspired by John’s words and ready to do everything he said (§118), and who are distinguished from those who gave heed to his message and were baptized (§117)? After a brief discussion of the textual witnesses, text, and translation of the passage in question, various interpretations of “the others” are discussed, none of which is entirely satisfactory. In this article a case will be made for accepting the conjecture originally proposed by Benedikt Niese, who assumed that Josephus originally wrote ἀνθρώπων “people” instead of ἄλλων “others.”