bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical properties of the airway tree: heterogeneous and anisotropic pseudoelastic and viscoelastic tissue responses
Authors: Eskandari Mona , Arvayo Alberto L. , Levenston Marc E. 
Published: May 2018

Airway obstruction and pulmonary mechanics remain understudied despite lung disease being the third cause of death in the United States. Lack of relevant data has led computational pulmonary models to infer mechanical properties from available material data for the trachea. Additionally, the time-dependent, viscoelastic behaviors of airways have been largely overlooked, despite their potential physiological relevance and utility as metrics of tissue remodeling and disease progression. Here, we address the clear need for airway-specific material characterization to inform biophysical studies of the bronchial tree. Specimens from three airway levels (trachea, large bronchi, and small bronchi) and two orientations (axial and circumferential) were prepared from five fresh pig lungs. Uniaxial tensile tests revealed substantial heterogeneity and anisotropy. Overall, the linear pseudoelastic modulus was significantly higher axially than circumferentially (30.5 ± 3.1 vs. 8.4 ± 1.1 kPa) and significantly higher among circumferential samples for small bronchi than for the trachea and large bronchi (12.5 ± 1.9 vs. 6.0 ± 0.6 and 6.6 ± 0.9 kPa). Circumferential samples exhibited greater percent stress relaxation over 300 s than their axial counterparts (38.0 ± 1.4 vs. 23.1 ± 1.5%). Axial and circumferential trachea samples displayed greater percent stress relaxation (26.4 ± 1.6 and 42.5 ± 1.7%) than corresponding large and small bronchi. This ex vivo pseudoelastic and viscoelastic characterization reveals novel anisotropic and heterogeneous behaviors and equips us to construct airway-specific constitutive relations. Our results establish necessary fundamentals for airway mechanics, laying the groundwork for future studies to extend to clinical questions surrounding lung injury, and further directly enables computational tools for lung disease obstruction predictions. NEW & NOTEWORTHY Understanding the mechanics of the lung is necessary for investigating disease progression. Trachea mechanics comprises the vast majority of ex vivo airway tissue characterization despite distal airways being the site of disease manifestation and occlusion. Furthermore, viscoelastic studies are scarce, whereas time-dependent behaviors could be potential physiological metrics of tissue remodeling. In this study, the critical need for airway-specific material properties is addressed, reporting bronchial tree anisotropic and heterogeneous material properties.
miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway
Authors: Salem Mohamed , O'Brien Jacob A. , Bernaudo Stefanie , Shawer Heba , Ye Gang , Brkić Jelena , Amleh Asma , Vanderhyden Barbara C. , Refky Basel , Yang Burton B. , Krylov Sergey N. , Peng Chun 
Published: May 2018

Abstract
miRNAs play important roles in gene regulation, and their dysregulation is associated with many diseases, including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared with low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in patients with EOC than in subjects with benign gynecologic disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3′ UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, whereas knockout of FOXA2 increased VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2–VCAN pathway.
Significance: Low FOXA2/high VCAN levels mediate the tumor-promoting effects of miR-590-3p and negatively correlate with ovarian cancer survival. Cancer Res; 78(15); 4175–90. ©2018 AACR.
A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening
Authors: Beshiri Michael L. , Tice Caitlin M. , Tran Crystal , Nguyen Holly M. , Sowalsky Adam G. , Agarwal Supreet , Jansson Keith H. , Yang Qi , McGowen Kerry M. , Yin JuanJuan , Alilin Aian Neil , Karzai Fatima H. , Dahut William L. , Corey Eva , Kelly Kathleen 
Published: May 2018

AbstractPurpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis.Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested &gt;20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin.Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2−/− organoids, similar to responses observed in patients.Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. Clin Cancer Res; 24(17); 4332–45. ©2018 AACR.
Clonal Hematopoiesis: A New Layer in the Liquid Biopsy Story in Lung Cancer
Authors: Bauml Joshua , Levy Benjamin 
Published: May 2018

Abstract
Cell-free DNA (cfDNA) is a unique biospecimen that contains multiple sources of DNA, including tumor, germline, fetal, and others. Clonal hematopoiesis, a process that leads to expansion of mutations in peripheral blood cells, is an additional source of DNA that adds a layer of complexity when interpreting results. Clin Cancer Res; 24(18); 4352–4. ©2018 AACR.
See related article by Hu et al., p. 4437
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy
Authors: Yano Wakako , Yokogawa Tatsushi , Wakasa Takeshi , Yamamura Keisuke , Fujioka Akio , Yoshisue Kunihiro , Matsushima Eiji , Miyahara Seiji , Miyakoshi Hitoshi , Taguchi Junko , Chong Khoon Tee , Takao Yayoi , Fukuoka Masayoshi , Matsuo Kenichi 
Published: May 2018

Abstract
5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment. Mol Cancer Ther; 17(8); 1683–93. ©2018 AACR.
Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors
Authors: Marzi Laetitia , Agama Keli , Murai Junko , Difilippantonio Simone , James Amy , Peer Cody J. , Figg William D. , Beck Daniel , Elsayed Mohamed S.A. , Cushman Mark , Pommier Yves 
Published: May 2018

Abstract
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (γH2AX) compared with their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and γH2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (http://discover.nci.nih.gov/cellminercdb) were used to investigate the following: (i) the correlations of fluoroindenoisoquinolines activity with other drugs, and (ii) genomic determinants of response in the NCI-60. The activity of the fluoroindenoisoquinolines was mostly correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. Genomic analyses and activity assays in CCRF-CEM SLFN11–deleted cells showed that SLFN11 expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1. Mol Cancer Ther; 17(8); 1694–704. ©2018 AACR.
Interleukin 10 Treatment Ameliorates High-Fat Diet–Induced Inflammatory Atrial Remodeling and Fibrillation
Authors: Kondo Hidekazu , Abe Ichitaro , Gotoh Koro , Fukui Akira , Takanari Hiroki , Ishii Yumi , Ikebe Yuki , Kira Shintaro , Oniki Takahiro , Saito Shotaro , Aoki Kohei , Tanino Tomomi , Mitarai Kazuki , Kawano Kyoko , Miyoshi Miho , Fujinami Mami , Yoshimura Seiichiro , Ayabe Reika , Okada Norihiro , Nagano Yasuko , Akioka Hidefumi , Shinohara Tetsuji , Akiyoshi Kumiko , Masaki Takayuki , Teshima Yasushi , Yufu Kunio , Nakagawa Mikiko , Takahashi Naohiko 
Published: May 2018

Background:
Obesity, characterized by systemic low-grade inflammation, is considered a well-known risk for atrial fibrillation. In fact, IL-10 (interleukin 10), which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypotheses forwarding that genetic deletion of IL-10 exacerbates high-fat diet (HFD)–induced obesity-caused atrial inflammation, lipidosis, fibrosis, and fibrillation and that IL-10 therapy inhibits this pathology.

Methods:
Eight- to 10-week-old male CL57/B6 (wild-type) mice and IL-10 knockout mice were divided into a 12-week HFD group and a 12-week normal-fat diet (NFD) group, respectively. In addition, the effect of IL-10 administration was also investigated.

RESULTS:
HFD-induced obesity for 12 weeks significantly depressed serum levels of IL-10 but were found to increase several proinflammatory cytokines in wild-type mice. Adverse atrial remodeling, including atrial inflammation, lipidosis, and fibrosis, was induced in both wild-type and IL-10 knockout mice by HFD. Vulnerability to atrial fibrillation was also significantly enhanced by HFD. With regard to epicardial and pericardial adipose tissue, the total amount of epicardial adipose tissue+pericardial adipose tissue volume was increased by HFD. Besides, proinflammatory and profibrotic cytokines of epicardial adipose tissue+pericardial adipose tissue were also upregulated. In contrast, the protein level of adiponectin was downregulated by HFD. These HFD-induced obesity-caused adverse effects were further exaggerated in IL-10 knockout mice in comparison to wild-type mice. Systemic IL-10 administration markedly ameliorated HFD-induced obesity-caused left atrial remodeling and vulnerability to atrial fibrillation, in addition to improving the quality of epicardial adipose tissue+pericardial adipose tissue.

Conclusions:
Our results highlight IL-10 treatment as a potential therapeutic approach to limit the progression of HFD-induced obesity-caused atrial fibrillation.
Patient perspectives of being detained under section 136 of the Mental Health Act: Findings from a qualitative study in London
Authors: Sondhi Arun , Luger Lisa , Toleikyte Lina , Williams Emma 
Published: May 2018

Introduction Detention under section 136(1) of the Mental Health Act 1983 allows for the police to arrest a person from a public place and remove them to a ‘place of safety’, typically an emergency department or mental-health unit if it is ‘in the interests of that person or for the protection of other persons in immediate need of care or control’. Aims/objective: The aim of this study was to describe the views and perceptions of the process for people with lived experience of mental distress who have been detained under section 136 of the Mental Health Act 1983. Method Semi-structured interviews were conducted with a non-probability sample of people with lived experience of mental distress who have been detained under section 136 across Greater London. Interviews were transcribed and thematically analysed using grounded theory. Fifty-eight people with lived experience of mental distress detained under section 136, including four carers, participated in this study. Results Three interwoven themes were identified: (a) process or procedural issues; (b) the professional–patient relationship; and (c) the importance of a supportive therapeutic environment. Conclusion The length of time, multiple assessment points and processes juxtapose against the need for a humane physical environment and supportive therapeutic interactions from all professional agencies. It is unclear how changes proposed in the Policing and Crime Act 2017 will address these patient needs.
Factors associated with the size of the adhesio interthalamica based on 3.0-T magnetic resonance images
Authors: Yasaka Koichiro , Akai Hiroyuki , Kunimatsu Akira , Kiryu Shigeru , Abe Osamu 
Published: May 2018

Background Adhesio interthalamica (AI) is a small structure connecting bilateral thalami. Purpose To evaluate the effects of patient age, sex, and lateral diameter of the third ventricle on the long diameter of the AI using multivariate analyses based on magnetic resonance (MR) images obtained with 3.0-T scanners. Material and Methods This clinical retrospective study included images of 153 patients who underwent MR examination using 3.0-T scanners. The long diameter of the AI and lateral diameter of the third ventricle were measured on images in the mid-sagittal plane and axial plane at the anterior commissure, respectively. Univariate and multivariate analyses were performed. Results AI was observed in 138 patients (70 men, 68 women; mean age = 63.7 ± 13.7 years; mean AI size =5.34 ± 1.63 mm). By univariate analyses, patient age (r = −0.262, P = 0.002), sex ( P = 0.010), and lateral diameter of the third ventricle (r = −0.642, P < 0.001) were significantly associated with the long diameter of the AI. With multiple linear regression analyses with a stepwise selection of parameters, only the lateral diameter of the third ventricle (estimate = −0.432, P < 0.001) was significantly associated with the long diameter of the AI. The lateral diameter of the third ventricle was longer in patients without AI (15 patients) than in those with AI ( P = 0.006). Conclusion The lateral diameter of the third ventricle was a major factor negatively associated with the long diameter of the AI.
Diagnostic value of MRI signs in differentiating Ewing sarcoma from osteomyelitis
Authors: Kasalak Ömer , Overbosch Jelle , Adams Hugo JA , Dammann Amelie , Dierckx Rudi AJO , Jutte Paul C , Kwee Thomas C 
Published: May 2018

Background The value of magnetic resonance imaging (MRI) signs in differentiating Ewing sarcoma from osteomyelitis has not be thoroughly investigated. Purpose To investigate the value of various MRI signs in differentiating Ewing sarcoma from osteomyelitis. Material and Methods Forty-one patients who underwent MRI because of a bone lesion of unknown nature with a differential diagnosis that included both Ewing sarcoma and osteomyelitis were included. Two observers assessed several MRI signs, including the transition zone of the bone lesion, the presence of a soft-tissue mass, intramedullary and extramedullary fat globules, and the penumbra sign. Results Diagnostic accuracies for discriminating Ewing sarcoma from osteomyelitis were 82.4% and 79.4% for the presence of a soft-tissue mass, and 64.7% and 58.8% for a sharp transition zone of the bone lesion, for readers 1 and 2 respectively. Inter-observer agreement with regard to the presence of a soft-tissue mass and the transition zone of the bone lesion were moderate (κ = 0.470) and fair (κ = 0.307), respectively. Areas under the receiver operating characteristic curve of the diameter of the soft-tissue mass (if present) were 0.829 and 0.833, for readers 1 and 2 respectively. Mean inter-observer difference in soft-tissue mass diameter measurement ± limits of agreement was 35.0 ± 75.0 mm. Diagnostic accuracies of all other MRI signs were all < 50%. Conclusion Presence and size of a soft-tissue mass, and sharpness of the transition zone, are useful MRI signs to differentiate Ewing sarcoma from osteomyelitis, but inter-observer agreement is relatively low. Other MRI signs are of no value in this setting.
Rapid Muscle Loss Negatively Impacts Survival in Critically Ill Patients With Cirrhosis
Authors: Ju Sunmi , Choi Sun Mi , Park Young Sik , Lee Chang-Hoon , Lee Sang-Min , Yoo Chul-Gyu , Kim Young Whan , Han Sung Koo , Lee Jinwoo 
Published: May 2018

Purpose: To assess the impact of rapid muscle loss before admission to intensive care unit (ICU) in critically ill patients with cirrhosis. Materials and Methods: Patients with cirrhosis who had undergone 2 or more recent computed tomography scans before admission to the medical ICU were included. Muscle cross-sectional area at the level of the third lumbar vertebra was quantified using OsiriX software. The rate of muscle mass change and skeletal muscle index (SMI) were also calculated. Multivariable Cox proportional hazards regression was used to evaluate the association between muscle loss and mortality. Results: Among 125 patients, 113 (90.4%) patients were classified as having sarcopenia. The mean body mass index was 22.6 (3.9) kg/m2. Thirty-nine (31.2%) patients were within the normal range for muscle mass change, while 86 (68.8%) patients demonstrated rapid decline in muscle mass before admission to the ICU. Patients with rapid muscle loss showed high ICU mortality (59.3%) and in-hospital mortality (77.9%). Multivariate Cox analysis showed that ICU mortality and in-hospital mortality were independently associated with malignancy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, SMI, and rapid muscle loss. Conclusion: Rapid muscle decline is correlated with increased ICU mortality and in-hospital mortality in critically ill patients with cirrhosis.
Emergency physicians’ attitudes to implementing ultrasound in Dutch emergency departments after a 2-day training: A qualitative study
Authors: Ketelaars Rein , Van Heumen Esther , Baken Lambert P , Witten Marja , Scheffer Gert Jan , Engels Yvonne , Hoogerwerf Nico 
Published: May 2018

Background:Diagnostic ultrasound is increasingly used by nonradiologists in trauma victims and critically ill patients. In the emergency department, the extended focused assessment with sonography for trauma and Polytrauma Rapid Echo-evaluation Program protocol are often used to assess these patients. Dutch Polytrauma Rapid Echo-evaluation Program-trained Emergency physicians are implementing the use of ultrasound in the emergency department but might encounter barriers to overcome.Objectives:This study aims to explore individual experiences of Dutch emergency physicians.Methods:We performed a qualitative study by conducting semi-structured interviews in Dutch emergency physicians working in a Level 2 emergency department that completed the 2-day Polytrauma Rapid Echo-evaluation Program course at least 1 year before the interviews. Data were analyzed using directed content analysis.Results:Eight emergency physicians employed by eight different hospitals were interviewed. Thirteen categories were identified in the transcribed interviews and these were combined into four general themes: (1) the desire to develop the Emergency Medicine specialty, both nationally and local; (2) incentives to start using ultrasound; (3) exploring practical applications of ultrasound; and (4) barriers faced while implementing emergency physician-performed ultrasound on the emergency department. The interviewees regard the course to be a solid base and are eager to independently perform ultrasound examinations, although challenges are faced.Conclusion:This exploratory study provides essential insight in Dutch emergency physicians implementing ultrasound in their emergency department. It shows that there is a need to develop a quality assurance system and it identified barriers that have to be dealt with.