bluuebunny/crossref_metadata_2025_split huggingface dataset:
Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis
Authors: Bramswig Kira H. , Poettler Marina , Unseld Matthias , Wrba Friedrich , Uhrin Pavel , Zimmermann Wolfgang , Zielinski Christoph C. , Prager Gerald W. 
Published: October 2013

Abstract
Carcinoembryonic antigen (CEA, CD66e, CEACAM-5) is a cell-surface–bound glycoprotein overexpressed and released by many solid tumors that has an autocrine function in cancer cell survival and differentiation. Soluble CEA released by tumors is present in the circulation of patients with cancer, where it is used as a marker for cancer progression, but whether this form of CEA exerts any effects in the tumor microenvironment is unknown. Here, we present evidence that soluble CEA is sufficient to induce proangiogenic endothelial cell behaviors, including adhesion, spreading, proliferation, and migration in vitro and tumor microvascularization in vivo. CEA-induced activation of endothelial cells was dependent on integrin β-3 signals that activate the focal-adhesion kinase and c-Src kinase and their downstream MAP–ERK kinase/extracellular signal regulated kinase and phosphoinositide 3-kinase/Akt effector pathways. Notably, while interference with VEGF signaling had no effect on CEA-induced endothelial cell activation, downregulation with the CEA receptor in endothelial cells attenuated CEA-induced signaling and tumor angiogenesis. Corroborating these results clinically, we found that tumor microvascularization was higher in patients with colorectal cancer exhibiting higher serum levels of soluble CEA. Together, our results elucidate a novel function for soluble CEA in tumor angiogenesis. Cancer Res; 73(22); 6584–96. ©2013 AACR.
Maintenance of Androgen Receptor Inactivation by S-Nitrosylation
Authors: Qin Yu , Dey Anindya , Purayil Hamsa Thayele , Daaka Yehia 
Published: October 2013

Abstract
Antiandrogens target ligand-binding domain of androgen receptor (AR) and are used as first-line therapeutics to treat patients diagnosed with locally advanced and metastatic prostate cancer. Although initially beneficial as judged with actual tumor mass shrinkage, this therapy invariably fails and the cancer reappears as castration-resistant disease. Here, we report that increased intracellular nitric oxide (NO) levels lead to growth inhibition of both androgen-dependent and castration-resistant prostate tumors through a mechanism that involves AR function inactivation by S-nitrosylation of a single C601 residue present in the DNA-binding domain. AR S-nitrosylation does not impact its subcellular distribution but attenuates its ability to bind AR-responsive elements in promoter region of target genes. Mechanistically, AR is transnitrosylated by its partner HSP90 protein. Ubiquitous small-molecule NO donors promote the AR S-nitrosylation and inhibit growth of castration-resistant prostate tumors. These findings reveal a new mechanism of regulating AR function and suggest that sequential targeting of distinct domains of AR may extend therapeutic efficacy for patients with advanced prostate cancer. Cancer Res; 73(22); 6690–9. ©2013 AACR.
Carbon Monoxide Expedites Metabolic Exhaustion to Inhibit Tumor Growth
Authors: Wegiel Barbara , Gallo David , Csizmadia Eva , Harris Clair , Belcher John , Vercellotti Gregory M. , Penacho Nuno , Seth Pankaj , Sukhatme Vikas , Ahmed Asif , Pandolfi Pier Paolo , Helczynski Leszek , Bjartell Anders , Persson Jenny Liao , Otterbein Leo E. 
Published: October 2013

Abstract
One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. Cancer Res; 73(23); 7009–21. ©2013 AACR.
The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models
Authors: Miyajima Naoto , Tsutsumi Shinji , Sourbier Carole , Beebe Kristin , Mollapour Mehdi , Rivas Candy , Yoshida Soichiro , Trepel Jane B. , Huang Ying , Tatokoro Manabu , Shinohara Nobuo , Nonomura Katsuya , Neckers Len 
Published: October 2013

Abstract
The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers. Cancer Res; 73(23); 7022–33. ©2013 AACR.
TERT Promoter Mutations Occur Early in Urothelial Neoplasia and Are Biomarkers of Early Disease and Disease Recurrence in Urine
Authors: Kinde Isaac , Munari Enrico , Faraj Sheila F. , Hruban Ralph H. , Schoenberg Mark , Bivalacqua Trinity , Allaf Mohamad , Springer Simeon , Wang Yuxuan , Diaz Luis A. , Kinzler Kenneth W. , Vogelstein Bert , Papadopoulos Nickolas , Netto George J. 
Published: October 2013

Abstract
Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade transitional cell carcinomas (TCC), 31 pTa high-grade TCCs, and 17 pTis carcinoma in situ lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine whether urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). In addition, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur (P &lt; 0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and seem to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker for both early detection and monitoring of bladder neoplasia. Cancer Res; 73(24); 7162–7. ©2013 AACR.
Autotaxin–Lysophosphatidic Acid Signaling Axis Mediates Tumorigenesis and Development of Acquired Resistance to Sunitinib in Renal Cell Carcinoma
Authors: Su Shih-Chi , Hu Xiaoxiao , Kenney Patrick A. , Merrill Megan M. , Babaian Kara N. , Zhang Xiu-Ying , Maity Tapati , Yang Shun-Fa , Lin Xin , Wood Christopher G. 
Published: October 2013

Abstract
Purpose: Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance.
Experimental Design: Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo.
Results: Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC.
Conclusions: Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib. Clin Cancer Res; 19(23); 6461–72. ©2013 AACR.
Identification of a Glutamic Acid Repeat Polymorphism of
ALMS1
as a Novel Genetic Risk Marker for Early-Onset Myocardial Infarction by Genome-Wide Linkage Analysis
Authors: Ichihara Sahoko , Yamamoto Ken , Asano Hiroyuki , Nakatochi Masahiro , Sukegawa Mayo , Ichihara Gaku , Izawa Hideo , Hirashiki Akihiro , Takatsu Fumimaro , Umeda Hisashi , Iwase Mitsunori , Inagaki Haruo , Hirayama Haruo , Sone Takahito , Nishigaki Kazuhiko , Minatoguchi Shinya , Cho Myeong-Chan , Jang Yangsoo , Kim Hyo-Soo , Park Jeong E. , Tada-Oikawa Saeko , Kitajima Hidetoshi , Matsubara Tatsuaki , Sunagawa Kenji , Shimokawa Hiroaki , Kimura Akinori , Lee Jong-Young , Murohara Toyoaki , Inoue Ituro , Yokota Mitsuhiro 
Published: October 2013

Background—
Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention.

Methods and Results—

We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (
ALMS1
) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the
ALMS1
promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the
ALMS1
coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI.

Conclusions—

The glutamic acid repeat polymorphism of
ALMS1
identified in the present study may provide insight into the pathogenesis of early-onset MI.
Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s)
Authors: Oksala Niku , Pärssinen Jenita , Seppälä Ilkka , Raitoharju Emma , Ivana Kholova , Hernesniemi Jussi , Lyytikäinen Leo-Pekka , Levula Mari , Mäkelä Kari-Matti , Sioris Thanos , Kähönen Mika , Laaksonen Reijo , Hytönen Vesa , Lehtimäki Terho 
Published: October 2013

Background—
Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.

Methods and Results—

The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (−2.9-fold;
P
<0.0001) and UNC5B upregulated (2.2-fold;
P
<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (
P
=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.

Conclusions—
Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques.
Introduction: Conversion Narratives in the Early Modern World
Authors: Mazur Peter , Shinn Abigail 
Published: October 2013

Abstract
In the early modern world the process of describing a conversion experience was often as important, and problematic, as the conversion itself, and the resulting texts illustrate the extent to which conversion and its effects permeated cultural forms. Charting the discursive nature of conversion narratives, which were frequently translated into foreign languages and crossed international boundaries, this introduction discusses the problems inherent in narrating religious change, considers the current historiography, and outlines the premise for this collection.
Fortunetellers and Sorcerers in the Service of a Russian Aristocrat of the Eighteenth Century: The Case of Chamberlain Petr Saltykov
Authors: Smilianskaia Elena B. 
Published: October 2013

The case of Petr Saltykov, which stretched on between 1758 and 1765, with a surprising coda in 1796, is noteworthy in many respects. The material collected in connection with Saltykov’s crime is useful for an investigation into magic belief as such, offering parallels and supplementary information to the dozens of “magic trials” of the 18th century. However, what makes the Saltykov case unique is how the chancellor’s “superstition” managed so compellingly to bring together two cultures – traditional folk culture and the “Europeanized” culture of the imperial court.
The case of Saltykov’s “sorcery” brought the diametrically opposed cultures of the court elite and the masses into confrontation. But even opposites can come together. As it turned out, the magic beliefs of the masses and medical practices of archaic traditional culture continued to attract adherents at court, getting along just fine in a high-culture, “Europeanized” environment. The chasm that lay between the culture of the aristocratic court elite and popular culture in the 18th century was not unbridgeable, although possible intersections of these two cultures sometimes took on rather strange configurations.
Differentiation of myxoid liposarcoma by magnetic resonance imaging: a histopathologic correlation
Authors: Löwenthal D , Zeile M , Niederhagen M , Fehlberg S , Schnapauff D , Pink D , Tunn PU , Reichardt P , Hamm B , Dudeck O 
Published: October 2013

Background Myxoid liposarcomas represent a heterogeneous group of soft tissue tumors in which prognosis is dependent on differentiation. Purpose To identify magnetic resonance imaging (MRI) criteria to distinguish low-grade from high-grade myxoid liposarcomas. Material and Methods MR images of 30 histologically proven myxoid liposarcomas were retrospectively reviewed. Tumors were evaluated according to size, localization, tumor border, and structure as well as tumor composition. These imaging criteria were correlated with histopathological findings. Results Nineteen myxoid liposarcomas were histologically classified as low-grade myxoid liposarcomas, whereas 11 were considered high-grade myxoid liposarcomas. Mean tumor volume of low-grade myxoid liposarcomas (710.1 ± 960.1 ccm) was significantly smaller as compared to high-grade myxoid liposarcomas (2737.0 ± 3423.7 ccm; P = 0.04). In addition to necrotic areas, three tumor components – fatty, myxoid, as well as contrast-enhancing non-fatty, non-myxoid – could be identified. The mean fraction of fatty tumor areas in low-grade myxoid liposarcomas was 10 ± 11% as compared to 6 ± 4% for high-grade myxoid liposarcomas ( P = 0.66). Myxoid components accounted for 88 ± 16% in low-grade myxoid liposarcomas, but only for 45 ± 25% in high-grade myxoid liposarcomas ( P < 0.0001). The non-fatty, non-myxoid tumor fraction was significantly higher in high-grade myxoid liposarcomas (50 ± 25%) as compared to low-grade myxoid liposarcomas (2 ± 9%; P < 0.0001). A proportion of > 5% of this tumor fraction was found to be a precise unique predictor for high-grade myxoid liposarcomas with a sensitivity of 100% and a specificity of 95%. Conclusion Tumor components with contrast-enhancing non-fatty, non-myxoid imaging features were predominantly found in high-grade myxoid liposarcomas, which may histologically resemble round cell clusters.
Febrile Illness in the Athlete
Authors: Dick Natalie A. , Diehl Jason J. 
Published: October 2013

Context: Acute febrile illnesses are common in athletes over the course of training and competition seasons. Complete recovery and rapid yet safe return to participation are critical for competitive athletes. Alterations in thermoregulation, metabolism, fluid homeostasis, muscle strength, and endurance, as well as potential complications for the athlete and others, must be considered. Evidence Acquisition: The PubMed database was searched (1970-2013) for all English-language articles related to febrile illness in sport, using the keywords fever, febrile, body temperature, thermoregulation, infection, illness, disease, exercise, athlete, sport, performance, return to play, metabolism, hydration, and dehydration. Study Design: Clinical review. Level of Evidence: Level 4. Results: Limited data confirm that febrile illness is correlated with alterations in the body’s thermoregulatory system, with increases in metabolic rate, and with effects in fluid homeostasis. Human and animal studies demonstrate a decrease in muscle strength and endurance secondary to muscle catabolism in febrile illness. However, indirect evidence suggests that regular exercise enhances the immune response. No strong clinical research has been published on return to play during or following acute febrile illness, excluding mononucleosis and myocarditis. Conclusion: Fever is correlated with an increase in insensible fluid losses, dehydration, metabolic demands, and dysregulation of body temperature. Fever can have detrimental effects on the musculoskeletal system, including decreasing strength and endurance, generalized muscle catabolism, and increase in perceived fatigue. Participating in strenuous exercise during febrile illness can worsen the illness and has demonstrated increased lethality in animal models. No consensus recommendations support return to activity before resolution of fever, and training should be resumed gradually once fever and dehydration have resolved.
Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up
Authors: Salviato Balbão Marina , Cecílio Hallak Jaime Eduardo , Arcoverde Nunes Emerson , Homem de Mello Mauricio , Triffoni-Melo Andresa de Toledo , Ferreira Flavia Isaura de Santi , Chaves Cristiano , Durão Ana Maria Sertori , Ramos Adriana Pelegrino Pinho , de Souza Crippa José Alexandre , Queiroz Regina Helena Costa 
Published: October 2013

Objective: Olanzapine is an atypical antipsychotic drug used to treat schizophrenia. Some of the adverse effects related to its use are obesity, hyperlipidemia, type 2 diabetes and hypertension, which may result in development of metabolic syndrome. This study aimed to investigate a possible increase in some anthropometric and biochemical parameters, and the existence of any correlation between them in Brazilian patients with schizophrenia treated with olanzapine in the mid term. Methods: Thirty subjects with schizophrenia were evaluated, 16 women and 14 men, aged between 18 and 47 years. All patients underwent blood collection and anthropometric measurements at four different times during 12 months of follow up; thus each patient was his or her own control. Results: Evaluation of some anthropometric measurements showed significant differences when comparing the mean values obtained in each of the different data collection times ( p < 0.05). However, the biochemical indicators of development of metabolic syndrome measured in our study did not show the same rate of increment, with only the total cholesterol and glucose levels presenting statistically significant changes ( p < 0.05), but without the same magnitude of weight change. Conclusion: We conclude that medium-term treatment with olanzapine promoted a substantial weight gain and increased visceral fat, while the metabolic profile did not show the same magnitude of change, suggesting a dissociation between weight gain and blood parameters, despite the severe weight gain observed among subjects evaluated.