bluuebunny/crossref_metadata_2025_split huggingface dataset:
Birth weight in pregnancies complicated by maternal heart disease
Authors: Cauldwell Matthew , Steer Philip , Sterrenburg Monique , Wallace Suzanne , Malin Gemma , Ulivi Gemma , Everett Thomas , Jakes Adam Daniel , Head Catherine E G , Mohan Aarthi R , Haynes Sophie , Simpson Margaret , Brennand Janet , Johnson Mark R 
Published: September 2018

ObjectiveTo assess median and percentile birthweight distribution in women with various groups of heart disease relative to a contemporaneous comparison group.MethodsData on birth weight and gestational age were collected from 1321 pregnancies ≥24 weeks’ gestation in 1053 women with heart disease from seven UK maternity units. Women were assigned to one of 16 groups according to their cardiac lesion. In units where it was possible, data on two births, one delivering before and one after index cases, were collected, giving 2307 comparators. Birthweight percentiles (corrected for gestational age, sex and parity) were calculated using Aberdeen norms. We assessed the association of birth weight with cardiac lesion, maternal hypoxaemia (saturations <90%), systemic ventricular function and beta-blockers.Results1321 pregnancies in women with heart disease and 2307 comparators were studied. Almost all groups with heart disease had lower median and percentile birth weights than comparators, significantly in 10 groups, the biggest effect seen in women with Fontan circulation, pulmonary hypertension, prosthetic heart valves, systemic right ventricle, Marfan syndrome, repaired tetralogy of Fallot and cardiomyopathy (in that order). In 307 pregnancies, women took beta-blockers; median birth weight adjusted for maternal age, parity and the effect of the cardiac lesion was 3116.7 g (IQR 790.4) when beta-blockers were used and 3354.3 g (IQR 634.1) when they were not (p<0.001). 17 women had saturations <90%, and median birth weight was significantly lower, 3105.4 g (IQR 1288.9) versus 3387.7 g (IQR 729.8) (p=0.006).ConclusionOur findings identify specific groups of women with heart disease at risk of having a small baby.
Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology
Authors: Inoue Takanobu , Yagasaki Hideaki , Nishioka Junko , Nakamura Akie , Matsubara Keiko , Narumi Satoshi , Nakabayashi Kazuhiko , Yamazawa Kazuki , Fuke Tomoko , Oka Akira , Ogata Tsutomu , Fukami Maki , Kagami Masayo 
Published: September 2018

BackgroundRecently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.ObjectiveTo clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.MethodsWe studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for theZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylatedZNF597:TSS-DMR.ResultsWe identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.ConclusionWe suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.
A study of methods to prevent piping and erosion in buffer materials intended for a vertical deposition hole at the Horonobe Underground Research Laboratory
Authors: Jo Mayumi , Ono Makoto , Nakayama Masashi , Asano Hidekazu , Ishii Tomoko 
Published: September 2018

Abstract
Piping and erosion phenomena are serious problems affecting the integrity of buffer materials, which are an element of engineered barrier systems in the geological disposal of high-level radioactive waste. In this study, the outflow behaviour and the condition of buffer materials are investigated using a test pit drilled into host rock at the Horonobe Underground Research Laboratory to consider countermeasures to contain the outflow of the buffer material. The results are as follows: (1) Piping and erosion phenomena occur irrespective of the injection flow rate. However, when the rate is small, the buffer material is considered to be self-repairing and the outflow of the buffer material can be suppressed. (2) When the injection water contains large amounts of electrolytes, the surface of the buffer material peels off and precipitates, probably decreasing the waterproof performance. (3) Bentonite pellets are likely to be an effective countermeasure against piping and erosion.
Implications for understanding ischemic stroke as a sexually dimorphic disease: the role of pial collateral circulations
Authors: Li Zhaojin , Tremble Sarah M. , Cipolla Marilyn J. 
Published: September 2018

We investigated structural and functional differences in primary and pial collateral circulations in adult normotensive male and female Wistar rats. Male ( n = 10) and female ( n = 7) rats were subjected to middle cerebral artery (MCA) occlusion and changes in relative cerebral blood flow in MCA and pial collateral territories were measured by multisite laser-Doppler flowmetry. Rats were then transcardially perfused with a mixture of carbon black and latex, perfusion fixed, and imaged to compare primary and pial collateral structure between male ( n = 4) and female ( n = 3) rats, including lumen diameters and number. To study pial collateral function, leptomeningeal anastomoses (LMAs) were isolated and pressurized from male ( n = 7) and female ( n = 6) rats. Myogenic tone and reactivity to pressure, vascular function to pharmacological activator, or inhibitor of ion channels was measured and compared. There was no difference between relative cerebral blood flow in both MCA and pial collateral territories during occlusion and reperfusion between groups. Compared with male LMAs, female LMAs had similar myogenic tone (24.0 ± 7.3% vs. 16.0 ± 3.7%, P > 0.05) and reactivity to increased pressure and similar vascular responses to vasoconstrictive and vasodilatory stimuli. Additionally, compared with female LMAs, male LMAs had similar numbers (21 ± 1 vs. 20 ± 2, P > 0.05) and diameters (30.5 ± 2.0 vs. 26.2 ± 0.6 μm, P > 0.05), and no sex difference was detected in the diameter of arterial segments of circle of Willis. Together, our data establish no sex difference of cerebral collateral structure or function, suggesting that the reduced severity of stroke outcome in female rats is not likely due to differences in the cerebral collateral circulation. NEW & NOTEWORTHY Our work compared the function of leptomeningeal anastomoses between male and female adult normotensive rats with no sex difference found. We also confirmed no sex difference in primary and pial collateral structure in Wistar rats. Our findings suggest that the reduced severity of stroke in premenopausal women and reproductively intact female rodents is not likely due to improved primary and pial collateral circulations.
Chronic intermittent nicotine delivery via lung alveolar region-targeted aerosol technology produces circadian pharmacokinetics in rats resembling human smokers
Authors: Shao Xuesi M. , Liu Siyu , Lee Eon S. , Fung David , Pei Hua , Liang Jing , Mudgway Ross , Zhang Jingxi , Feldman Jack L. , Zhu Yifang , Louie Stan , Xie Xinmin S. 
Published: September 2018

Cigarette smoke is an aerosol containing microparticles that carry nicotine into the lung alveolar region where nicotine is rapidly absorbed into circulation. Nicotine exposure in smokers is a chronic intermittent process, with episodic intake during wakefulness and abstinence during sleep resulting in circadian fluctuation of blood nicotine levels. We developed an integrated platform where freely moving rodents can be exposed to episodic nicotine aerosol on an investigator-designed schedule. Plasma nicotine and its metabolite cotinine levels were determined with a LC-MS/MS method. We characterized the aerosol in the breathing zone of the rodent exposure chamber. The droplet-size distribution was within the respirable diameter range. The system can generate a wide range of nicotine concentrations in air that meet a variety of experimental needs. Rats were exposed to nicotine aerosol once every half hour in the dark phase of 12:12-h light-dark cycles for 10 days. We optimized the parameters of aerosol generation and exposure: plasma nicotine and cotinine concentrations reached 30–35 and 190–240 ng/ml, respectively. The nicotine levels and circadian patterns resembled the pharmacokinetic pattern of human smokers. In summary, we developed an aerosol system that can produce clinically relevant chronic intermittent nicotine exposure in unanesthetized, unrestrained rodents with route of administration and circadian blood pharmacokinetics resembling human smokers. This methodology is a novel tool for understanding the health effects of chronic intermittent nicotine exposure such as with tobacco cigarettes and electronic cigarettes for studies of behavior, pharmacology and toxicology, nicotine addiction, tobacco-related diseases, and teratogenicity, and for the discovery of therapeutics.NEW & NOTEWORTHY We developed a lung alveolar region-targeted aerosol method and a system that provides chronic intermittent nicotine exposure in freely moving rodents. The method produces in rodents clinically relevant nicotine exposure with the route and circadian pharmacokinetics resembling human smokers. This method is a novel tool for understanding the health impacts of chronic nicotine exposures such as with tobacco cigarettes and electronic cigarettes, for studying nicotine pharmacology, toxicology, addiction, and tobacco-related diseases, and for the discovery of therapeutics.
Passive stretch regulates skeletal muscle glucose uptake independent of nitric oxide synthase
Authors: Kerris Jarrod P. , Betik Andrew C. , Li Jinhua , McConell Glenn K. 
Published: September 2018

Skeletal muscle contraction increases glucose uptake via an insulin-independent mechanism. Signaling pathways arising from mechanical strain are activated during muscle contractions, and mechanical strain in the form of passive stretching stimulates glucose uptake. However, the exact mechanisms regulating stretch-stimulated glucose uptake are not known. Since nitric oxide synthase (NOS) has been implicated in the regulation of glucose uptake during ex vivo and in situ muscle contractions and during exercise, and NO is increased with stretch, we examined whether the increase in muscle glucose uptake during stretching involves NOS. We passively stretched isolated extensor digitorum longus muscles (15 min at ~100–130 mN) from control mice and mice lacking either neuronal NOSµ (nNOSµ) or endothelial NOS (eNOS) isoforms, as well as used pharmacological inhibitors of NOS. Stretch significantly increased muscle glucose uptake appoximately twofold ( P < 0.05), and this was unaffected by the presence of the NOS inhibitors NG-monomethyl-l-arginine (100 µM) or NG-nitro-l-arginine methyl ester (100 µM). Similarly, stretch-stimulated glucose uptake was not attenuated by deletion of either eNOS or nNOSµ isoforms. Furthermore, stretching failed to increase skeletal muscle NOS enzymatic activity above resting levels. These data clearly demonstrate that stretch-stimulated skeletal muscle glucose uptake is not dependent on NOS. NEW & NOTEWORTHY Passive stretching is known to activate muscle glucose uptake through mechanisms that partially overlap with contraction. We report that genetic knockout of endothelial nitric oxide synthase (NOS) or neuronal NOS or pharmacological NOS inhibition does not affect stretch-stimulated glucose uptake. Passive stretch failed to increase NOS activity above resting levels. This information is important for the study of signaling pathways that regulate stretch-stimulated glucose uptake and indicate that NOS should be excluded as a potential signaling factor in this regard.
CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status
Authors: Rubio Carolina , Martínez-Fernández Mónica , Segovia Cristina , Lodewijk Iris , Suarez-Cabrera Cristian , Segrelles Carmen , López-Calderón Fernando , Munera-Maravilla Ester , Santos Mirentxu , Bernardini Alejandra , García-Escudero Ramón , Lorz Corina , Gómez-Rodriguez Maria José , de Velasco Guillermo , Otero Irene , Villacampa Felipe , Guerrero-Ramos Felix , Ruiz Sergio , de la Rosa Federico , Domínguez-Rodríguez Sara , Real Francisco X. , Malats Núria , Castellano Daniel , Dueñas Marta , Paramio Jesus M. 
Published: September 2018

Abstract

Purpose:
Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).

Experimental Design:
Bladder cancer cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity.

Results:
Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.

Conclusions:
CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer
Authors: Tanaka Hiroshi , Sase Hitoshi , Tsukaguchi Toshiyuki , Hasegawa Masami , Tanimura Hiromi , Yoshida Miyuki , Sakata Kiyoaki , Fujii Toshihiko , Tachibana Yukako , Takanashi Kenji , Higashida Atsuko , Hasegawa Kiyoshi , Ono Yoshiyuki , Oikawa Nobuhiro , Mio Toshiyuki 
Published: September 2018

Abstract
Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion–positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion–positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion–positive cancer.
Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer
Authors: Nerlakanti Niveditha , Yao Jiqiang , Nguyen Duy T. , Patel Ami K. , Eroshkin Alexey M. , Lawrence Harshani R. , Ayaz Muhammad , Kuenzi Brent M. , Agarwal Neha , Chen Yunyun , Gunawan Steven , Karim Rezaul M. , Berndt Norbert , Puskas John , Magliocco Anthony M. , Coppola Domenico , Dhillon Jasreman , Zhang Jingsong , Shymalagovindarajan Subramaniam , Rix Uwe , Kim Youngchul , Perera Ranjan , Lawrence Nicholas J. , Schonbrunn Ernst , Mahajan Kiran 
Published: September 2018

Abstract
Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
Epigenetic Silencing of THY1 Tracks the Acquisition of the Notch1–EGFR Signaling in a Xenograft Model of CD44+/CD24low/CD90+ Myoepithelial Cells
Authors: Montanari Micaela , Carbone Maria Rita , Coppola Luigi , Giuliano Mario , Arpino Grazia , Lauria Rossella , Nardone Agostina , Leccia Felicia , Trivedi Meghana V. , Garbi Corrado , Bianco Roberto , Avvedimento Enrico V. , De Placido Sabino , Veneziani Bianca Maria 
Published: September 2018

Abstract

The surface glycoprotein THY is a marker of myoepithelial precursor cells, which are basal cells with epithelial–mesenchymal intermediate phenotype originating from the ectoderm. Myoepithelial precursor cells are lost during progression from in situ to invasive carcinoma. To define the functional role of Thy1-positive cells within the myoepithelial population, we tracked Thy1 expression in human breast cancer samples, isolated THY1-positive myoepithelial progenitor cells (CD44+/CD24low/CD90+), and established long-term cultures (parental cells). Parental cells were used to generate a xenograft model to examine Thy1 expression during tumor formation. Post-transplantation cell cultures lost THY1 expression through methylation at the THY1 locus and this is associated with an increase in EGFR and NOTCH1 transcript levels. Thy1-low cells are sensitive to the EGFR/HER2 dual inhibitor lapatinib. High THY1 expression is associated with poorer relapse-free survival in patients with breast cancer. THY1 methylation may track the shift of bipotent progenitors into differentiated cells. Thy1 is a good candidate biomarker in basal-like breast cancer.

Implications:
Our findings provide evidence that THY1 expression is lost in xenografts due to promoter methylation. Thy1-low cells with increased EGFR and Notch1 expression are responsive to target therapy. Because DNA methylation is often altered in early cancer development, candidate methylation markers may be exploited as biomarkers for basal-like breast cancer.
Subgroup Analysis Comparing Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin, Durable Polymer Everolimus-Eluting Stents in Acute Coronary Syndrome Patients
Authors: Roguin Ariel , Kandzari David E. , Marcusohn Erez , Koolen Jacques J. , Doros Gheorghe , Massaro Joseph M. , Garcia-Garcia Hector M. , Bennett Johan , Gharib Elie G. , Cutlip Donald E. , Waksman Ron 
Published: September 2018

Background:
Presentation with acute coronary syndromes (ACS) constitutes a high-risk subset of patients with worse outcome after percutaneous coronary intervention. We report clinical outcomes in subjects with ACS from the BIOFLOW V trial (BIOTRONIK – A Prospective Randomized Multicenter Study to Assess the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions) comparing an ultrathin strut (60 μm) bioresorbable polymer sirolimus-eluting stent (BP-SES) with a thin strut (81 μm) durable polymer everolimus-eluting stent (DP-EES).

Methods and Results:

Among 1334 patients randomized to 2:1 treatment with either BP-SES or DP-EES, 677 (50.7%) ACS patients without ST-segment–elevation myocardial infarction (MI; 454 BP-SES and 223 DP-EES) were identified in the retrospective post hoc analysis. The primary end point of 12-month target lesion failure, individual component end points, and stent thrombosis were evaluated. Recurrent MI was defined as a ≥50% increase of creatine kinase-myocardial band or in the absence of creatine kinase-myocardial band, troponin >50% increase over previous level and >3× the upper limit of normal). All events were adjudicated by a blinded independent clinical events committee. Overall, baseline clinical, angiographic, and procedural characteristics of the ACS population were similar between the 2 treatment groups. At 12 months, target lesion failure occurred in 5.6% (24/426) of BP-SES patients versus 11.0% (23/209) in DP-EES patients (
P
=0.02); target lesion failure composite components were cardiac death, 0% versus 1.0% (
P
=0.11); target vessel–related MI, 3.5% versus 9.7% (
P
=0.003); and clinically driven target lesion revascularization, 2.8% versus 3.4% (
P
=0.80). Spontaneous target vessel MI was 0.5% (2/425) for BP-SES versus 2.4% (5/206) for DP-EES (
P
=0.041). Stent thrombosis rates at 1 year were similar (0.5% versus 1.0%;
P
=0.601).

Conclusions:
In the ACS subgroup population of the BIOFLOW V study, treatment with BP-SES compared with DP-EES was associated with a significantly lower rate of 12-month target lesion failure, a difference driven by significantly lower periprocedural MI and spontaneous MI. These findings support treatment with an ultrathin strut BP-SES in ACS patients undergoing percutaneous coronary intervention.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02389946.