bluuebunny/crossref_metadata_2025_split huggingface dataset:
A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews
Authors: De Boer Martin , Gavrieli Ronit , van Leeuwen Karin , Wolf Haike Reznik , Dushnitzki Maya , Bar-Yosef Yifaat , Bar-Ziv Anat , Behar Doron , Lipitz Shlomo , Miller Tal Elkan , Tool Anton T J , Kuijpers Taco W , van den Berg Timo K , Wolach Baruch , Roos Dirk , Pras Elon 
Published: January 2018

BackgroundMutations in the NCF1 gene that encodes p47phox, a subunit of the NADPH oxidase complex, cause chronic granulomatous disease (CGD). In Kavkazi Jews, a c.579G>A (p.Trp193Ter) mutation in NCF1 is frequently found, leading to CGD. The same mutation is found in about 1% of Ashkenazi Jews, although Ashkenazi CGD patients with this mutation have never been described.MethodsWe used Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), gene scan analysis and Ion Torrent Next Generation Sequencing for genetic analysis, and measured NADPH oxidase activity and p47phox expression.ResultsIn an Ashkenazi couple expecting a baby, both parents were found to be heterozygotes for this mutation, as was the fetus. However, segregation analysis in the extended family was consistent with the fetus inheriting both carrier alleles from the parents. MLPA indicated four complete NCF1 genes in the fetus and three in each parent. Gene sequencing confirmed these results. Analysis of fetal leucocytes obtained by cordocentesis revealed substantial oxidase activity with three different assays, which was confirmed after birth. In six additional Ashkenazi carriers of the NCF1 c.579G>A mutation, we found five individuals with three complete NCF1 genes of which one was mutated (like the parents), and one individual with in addition a fusion gene of NCF1 with a pseudogene.ConclusionThese results point to the existence of a ‘false-carrier’ state in Ashkenazi Jews and have wide implications regarding pre-pregnancy screening in this and other population groups.
Airflow limitation in people living with HIV and matched uninfected controls
Authors: Ronit Andreas , Lundgren Jens , Afzal Shoaib , Benfield Thomas , Roen Ashley , Mocroft Amanda , Gerstoft Jan , Nordestgaard Børge G , Vestbo Jørgen , Nielsen Susanne D 
Published: January 2018

IntroductionWhether HIV influences pulmonary function remains controversial. We assessed dynamic pulmonary function in people living with HIV (PLWHIV) and uninfected controls.MethodsA total of 1098 PLWHIV from the Copenhagen Co-morbidity in HIV infection study and 12 161 age-matched and sex-matched controls from the Copenhagen General Population Study were included. Lung function was assessed using FEV1and FVC, while airflow limitation was defined by the lower limit of normal (LLN) of FEV1/FVC and by FEV1/FVC<0.7 with FEV1predicted <80% (fixed). Logistic and linear regression models were used to determine the association between HIV and pulmonary function adjusting for potential confounders (including smoking and socioeconomic status).ResultsIn predominantly white men with mean (SD) age of 50.6 (11.1) the prevalence of airflow limitation (LLN) was 10.6% (95% CI 8.9% to 12.6%) in PLWHIV and 10.6% (95% CI 10.0 to 11.1) in uninfected controls. The multivariable adjusted OR for airflow limitation defined by LLN for HIV was 0.97 (0.77–1.21, P<0.78) and 1.71 (1.34–2.16, P<0.0001) when defined by the fixed criteria. We found no evidence of interaction between HIV and cumulative smoking in these models (P interaction: 0.25 and 0.17 for LLN and fixed criteria, respectively). HIV was independently associated with 197 mL (152–242, P<0.0001) lower FEV1and 395 mL (344–447, P<0.0001) lower FVC, and 100 cells/mm3lower CD4 nadir was associated with 30 mL (7–52, P<0.01) lower FEV1and 51 mL (24–78, P<0.001) lower FVC.ConclusionHIV is a risk factor for concurrently decreased FEV1and FVC. This excess risk is not explained by smoking or socioeconomic status and may be mediated by prior immunodeficiency.Trial registration numberNCT02382822.
Impacts of Canada’s minimum age for tobacco sales (MATS) laws on youth smoking behaviour, 2000–2014
Authors: Callaghan Russell Clarence , Sanches Marcos , Gatley Jodi , Cunningham James K , Chaiton Michael Oliver , Schwartz Robert , Bondy Susan , Benny Claire 
Published: January 2018

BackgroundRecently, the US Institute of Medicine has proposed that raising the minimum age for tobacco purchasing/sales to 21 years would likely lead to reductions in smoking behavior among young people. Surprisingly few studies, however, have assessed the potential impacts of minimum-age tobacco restrictions on youth smoking.ObjectiveTo estimate the impacts of Canadian minimum age for tobacco sales (MATS) laws on youth smoking behaviour.DesignA regression-discontinuity design, using seven merged cycles of the Canadian Community Health Survey, 2000–2014.ParticipantsSurvey respondents aged 14–22 years (n=98 320).ExposureCurrent Canadian MATS laws are 18 years in Alberta, Saskatchewan, Manitoba, Quebec, the Yukon and Northwest Territories, and 19 years of age in the rest of the country.Main outcomesCurrent, occasional and daily smoking status; smoking frequency and intensity; and average monthly cigarette consumption.ResultsIn comparison to age groups slightly younger than the MATS, those just older had significant and abrupt increases immediately after the MATS in the prevalence of current smokers (absolute increase: 2.71%; 95% CI 0.70% to 4.80%; P=0.009) and daily smokers (absolute increase: 2.43%; 95% CI 0.74% to 4.12%; P=0.005). Average past-month cigarette consumption within age groups increased immediately following the MATS by 18% (95% CI 3% to 39%; P=0.02). There was no evidence of significant increases in smoking intensity for daily or occasional smokers after release from MATS restrictions.ConclusionThe study provides relevant evidence supporting the effectiveness of Canadian MATS laws for limiting smoking among tobacco-restricted youth.
Impact of a negative emotional antitobacco mass media campaign on French smokers: a longitudinal study
Authors: Guignard Romain , Gallopel-Morvan Karine , Mons Ute , Hummel Karin , Nguyen-Thanh Viêt 
Published: January 2018

BackgroundMass media campaigns to encourage smoking cessation have been shown to be effective in a context of comprehensive tobacco control programme. The effectiveness of antismoking ads that evoke negative emotions remains unclear, in particular in countries with high smoking prevalence and among smokers with low perceived susceptibility, low self-efficacy or who are not users of smoking cessation services.ObjectiveTo evaluate short-term and long-term effects of a 1-month French national highly emotional media campaign, with a focus on these specific targets.DesignA 6-month longitudinal survey by Internet. A sample of 3000 smokers were interviewed before the media campaign (T0). They were contacted again just after (T1) and 6 months after the campaign (T2).OutcomesPerceived susceptibility to the risks of smoking, self-efficacy to quit smoking, use of smoking cessation services (quitline and website) and 7-day quitting.MethodsThe analysis was carried out on 2241 individuals who answered at T1 and T2. Multiple logistic regressions were computed to test the association between the change in each outcome at T1 and T2 and the level of exposure based on self-reported recall.ResultsSelf-reported recall was associated with an increase in perceived susceptibility and with use of cessation services. Campaign recall was also associated with higher 7-day quitting immediately after the campaign (OR=1.8 (1.0 to 3.2), P<0.05).ConclusionsFear-appeal mass media campaigns can be effective in encouraging cessation among smokers in a country with high smoking prevalence (France), but should be accompanied by convincing self-efficacy messages.
In vitro propagation and reintroduction of golden paintbrush (Castilleja levisecta), a critically imperilled plant species
Authors: Salama Ahmed , Shukla Mukund R. , Popova Elena , Fisk Nathan S. , Jones Maxwell P. , Saxena Praveen K. 
Published: January 2018

Golden paintbrush (Castilleja levisecta Greenm.) is a hemiparasitic herbaceous perennial native to the Pacific Northwest of North America and is considered critically imperilled with only 11 populations remaining in the wild. The main objective of this study was to develop ex situ and in situ conservation through micropropagation and field plantings. In vitro cultures were initiated using nodal explants from two plants raised from seeds collected from a natural population. Shoots were then multiplied on Murashige and Skoog basal medium with 2.0 μmol L−1 6-benzylaminopurine (BA), 3.0 μmol L−1 kinetin (Kn), 2.2 g L−1 phytagel, and 3% sucrose. Explant position on source plants, culture vessel design, and application of different plant growth regulator levels for BA, Kn, and thiadiazuron (TDZ) were tested to optimize micropropagation protocols. Clones from the plants showed differences in plant height and number of nodes in response to various BA and TDZ concentrations. In vitro shoots were successfully rooted under ex vitro conditions using commercial rooting powder (0.8% indole-3-butyric acid) with an average of ∼17 roots per shoot and acclimatized in the greenhouse with 100% survival rate. Two-month-old plants were transferred to a Parks Canada restoration site at Fort Rodd Hill, Victoria, BC, with 7.5% survival. The use of micropropagation in combination with reintroduction efforts offers an excellent opportunity for conserving endangered plant biodiversity in vitro and facilitating in situ conservation efforts by providing plants for reintroduction.
Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model
Authors: Benten Daniel , Behrang Yasmin , Unrau Ludmilla , Weissmann Victoria , Wolters-Eisfeld Gerrit , Burdak-Rothkamm Susanne , Stahl Felix R. , Anlauf Martin , Grabowski Patricia , Möbs Markus , Dieckhoff Jan , Sipos Bence , Fahl Martina , Eggers Corinna , Perez Daniel , Bockhorn Maximillian , Izbicki Jakob R. , Lohse Ansgar W. , Schrader Jörg 
Published: January 2018

Abstract
Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired preclinical research in NET. Herein, we establish and characterize a lymph node–derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared with existing NET cell lines BON and QGP-1. In vivo growth was assessed in a xenograft mouse model. The neuroendocrine identity of NT-3 was verified by expression of multiple NET-specific markers, which were highly expressed in NT-3 compared with BON and QGP-1. In addition, NT-3 expressed and secreted insulin. Until now, this well-differentiated phenotype is stable since 58 passages. The proliferative labeling index, measured by Ki-67, of 14.6% ± 1.0% in NT-3 is akin to the original tumor (15%–20%), and was lower than in BON (80.6% ± 3.3%) and QGP-1 (82.6% ± 1.0%). NT-3 highly expressed somatostatin receptors (SSTRs: 1, 2, 3, and 5). Upon subcutaneous transplantation of NT-3 cells, recipient mice developed tumors with an efficient tumor take rate (94%) and growth rate (139% ± 13%) by 4 weeks. Importantly, morphology and neuroendocrine marker expression of xenograft tumors resembled the original human tumor.
Implications: High expression of somatostatin receptors and a well-differentiated phenotype as well as a slow growth rate qualify the new cell line as a relevant model to study neuroendocrine tumor biology and to develop new tumor treatments. Mol Cancer Res; 16(3); 496–507. ©2018 AACR.
Population-dependent Intron Retention and DNA Methylation in Breast Cancer
Authors: Kim Dongwook , Shivakumar Manu , Han Seonggyun , Sinclair Michael S. , Lee Young-Ji , Zheng Yonglan , Olopade Olufunmilayo I. , Kim Dokyoon , Lee Younghee 
Published: January 2018

Abstract
Regulation of gene expression by DNA methylation in gene promoter regions is well studied; however, the effects of methylation in the gene body (exons and introns) on gene expression are comparatively understudied. Recently, hypermethylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hypermethylated sites. This study examines whether the methylation status of an intron is correlated with how frequently the intron is retained during splicing using DNA methylation and RNA sequencing data from breast cancer tissue specimens in The Cancer Genome Atlas. Interestingly, hypomethylation of introns is correlated with higher levels of intron expression in mRNA and the methylation level of an intron is inversely correlated with its retention in mRNA from the gene in which it is located. Furthermore, significant population differences were observed in the methylation level of retained introns. In African-American donors, retained introns were not only less methylated compared to European-American donors, but also were more highly expressed. This underscores the need for understanding epigenetic differences in populations and their correlation with breast cancer is an important step toward achieving personalized cancer care.
Implications: This research contributes to the understanding of how epigenetic markers in the gene body communicate with the transcriptional machinery to control transcript diversity and differential biological response to changes in methylation status could underlie some of the known, yet unexplained, disparities in certain breast cancer patient populations. Mol Cancer Res; 16(3); 461–9. ©2018 AACR.
Epigenetically Regulated Chromosome 14q32 miRNA Cluster Induces Metastasis and Predicts Poor Prognosis in Lung Adenocarcinoma Patients
Authors: González-Vallinas Margarita , Rodríguez-Paredes Manuel , Albrecht Marco , Sticht Carsten , Stichel Damian , Gutekunst Julian , Pitea Adriana , Sass Steffen , Sánchez-Rivera Francisco J. , Lorenzo-Bermejo Justo , Schmitt Jennifer , De La Torre Carolina , Warth Arne , Theis Fabian J. , Müller Nikola S. , Gretz Norbert , Muley Thomas , Meister Michael , Tschaharganeh Darjus F. , Schirmacher Peter , Matthäus Franziska , Breuhahn Kai 
Published: January 2018

Abstract
Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify miRNAs involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis–associated miRNAs were identified in The Cancer Genome Atlas lung adenocarcinoma patient cohort (sequencing data; n = 449) and subsequently validated by qRT-PCR in an independent clinical cohort (n = 108). Overexpression of miRNAs located on chromosome 14q32 was associated with metastasis in lung adenocarcinoma patients. Importantly, Kaplan–Meier analysis and log-rank test revealed that higher expression levels of individual 14q32 miRNAs (mir-539, mir-323b, and mir-487a) associated with worse disease-free survival of never-smoker patients. Epigenetic analysis including DNA methylation microarray data and bisulfite sequencing validation demonstrated that the induction of 14q32 cluster correlated with genomic hypomethylation of the 14q32 locus. CRISPR activation technology, applied for the first time to functionally study the increase of clustered miRNA levels in a coordinated manner, showed that simultaneous overexpression of 14q32 miRNAs promoted tumor cell migratory and invasive properties. Analysis of individual miRNAs by mimic transfection further illustrated that miR-323b-3p, miR-487a-3p, and miR-539-5p significantly contributed to the invasive phenotype through the indirect regulation of different target genes. In conclusion, overexpression of 14q32 miRNAs, associated with the respective genomic hypomethylation, promotes metastasis and correlates with poor patient prognosis in lung adenocarcinoma.
Implications: This study points to chromosome 14q32 miRNAs as promising targets to inhibit tumor cell dissemination and to predict patient prognosis in lung adenocarcinoma. Mol Cancer Res; 16(3); 390–402. ©2018 AACR.
Targeted AKT Inhibition in Prostate Cancer Cells and Spheroids Reduces Aerobic Glycolysis and Generation of Hyperpolarized [1-13C] Lactate
Authors: Tee Sui Seng , Suster Izabela , Truong Steven , Jeong Sangmoo , Eskandari Roozbeh , DiGialleonardo Valentina , Alvarez Julio A. , Aldeborgh Hannah N. , Keshari Kayvan R. 
Published: January 2018

Abstract
The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials, and this study investigates the effect of MK2206, a non–ATP-competitive inhibitor, on the cellular metabolism of prostate cancer cells. We observed a reduction in cell motility and aerobic glycolysis in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes and transporters involved in glycolysis. However, a decreased ratio of NAD+/NADH was observed, motivating the use of hyperpolarized magnetic resonance spectroscopy (HP-MRS) to detect treatment response. Spectroscopic experiments were performed on tumor spheroids, 3D structures that self-organize in the presence of an extracellular matrix. Treated spheroids showed decreased lactate production with on-target inhibition confirmed using IHC, demonstrating that HP-MRS can be used to probe treatment response in prostate cancer spheroids and can provide a biomarker for treatment response. Mol Cancer Res; 16(3); 453–60. ©2018 AACR.
Tumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis
Authors: Morita Tsuyoshi , Hayashi Ken'ichiro 
Published: January 2018

Abstract
Although enhanced thymosin β4 (TMSB4X/Tβ4) expression is associated with tumor progression and metastasis, its tumor-promoting functions remain largely unknown. Here, it is demonstrated that TGFβ facilitates Tβ4 expression and leads to the activation of myocardin-related transcription factors (MRTF), which are coactivators of serum response factor (SRF) and regulate the expression of genes critical for the epithelial–mesenchymal transition (EMT) and tumor metastasis. In murine mammary gland cells (NMuMG), Tβ4 upregulation is required for full induction of a MRTF-regulated EMT gene expression program after TGFβ stimulation. Tβ4 levels are transcriptionally regulated via the novel cis-acting element AGACAAAG, which interacts with Smad and T-cell factor/lymphoid enhancer factor (TCF/LEF) to synergistically activate the Tβ4 promoter downstream of TGFβ. Murine skin melanoma cells (B16F0 and B16F1) also show the expression regulation of Tβ4 by Smad and TCF/LEF. Tβ4-knockout B16F1 (Tβ4 KO) clones show significantly diminished expression level of tumor-associated genes, which is regulated by the TGFβ/MRTFs pathway. In multiple human cancers, Tβ4 levels correlate positively with TGFβ1 and the tumor-associated gene expression levels through processes that respectively depend on TGFβ receptor 1 (TGFBR1) and MRTF expression. Kaplan–Meier survival analyses demonstrate that high Tβ4 expression associates with poor prognosis in an SRF expression–dependent manner in several cancers. In mice, Tβ4 KO clones show significantly decreased experimental metastatic potential; furthermore, ectopic expression of constitutively active MRTF-A fully restores the diminished metastatic activity. In conclusion, the TGFβ/Tβ4/MRTF/SRF pathway is critical for metastasis and tumor progression.
Implications: These findings define a molecular mechanism underlying a tumor-promoting function of thymosin β4 through activation of MRTF/SRF signaling. Mol Cancer Res; 16(5); 880–93. ©2018 AACR.
Novel Wearable Seismocardiography and Machine Learning Algorithms Can Assess Clinical Status of Heart Failure Patients
Authors: Inan Omer T. , Baran Pouyan Maziyar , Javaid Abdul Q. , Dowling Sean , Etemadi Mozziyar , Dorier Alexis , Heller J. Alex , Bicen A. Ozan , Roy Shuvo , De Marco Teresa , Klein Liviu 
Published: January 2018

Background
Remote monitoring of patients with heart failure (HF) using wearable devices can allow patient-specific adjustments to treatments and thereby potentially reduce hospitalizations. We aimed to assess HF state using wearable measurements of electrical and mechanical aspects of cardiac function in the context of exercise.

Methods and Results

Patients with compensated (outpatient) and decompensated (hospitalized) HF were fitted with a wearable ECG and seismocardiogram sensing patch. Patients stood at rest for an initial recording, performed a 6-minute walk test, and then stood at rest for 5 minutes of recovery. The protocol was performed at the time of outpatient visit or at 2 time points (admission and discharge) during an HF hospitalization. To assess patient state, we devised a method based on comparing the similarity of the structure of seismocardiogram signals after exercise compared with rest using graph mining (graph similarity score). We found that graph similarity score can assess HF patient state and correlates to clinical improvement in 45 patients (13 decompensated, 32 compensated). A significant difference was found between the groups in the graph similarity score metric (44.4±4.9 [decompensated HF] versus 35.2±10.5 [compensated HF];
P
<0.001). In the 6 decompensated patients with longitudinal data, we found a significant change in graph similarity score from admission (decompensated) to discharge (compensated; 44±4.1 [admitted] versus 35±3.9 [discharged];
P
<0.05).

Conclusions
Wearable technologies recording cardiac function and machine learning algorithms can assess compensated and decompensated HF states by analyzing cardiac response to submaximal exercise. These techniques can be tested in the future to track the clinical status of outpatients with HF and their response to pharmacological interventions.