bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2FISHresults in breast cancers with increasedCEN17 signals using alternative chromosome 17 probes – reclassifying cases in the equivocal category
Authors: Holzschuh Maria‐Anna , Czyz Zbigniew , Hauke Sven , Inwald Elisabeth C , Polzer Bernhard , Brockhoff Gero 
Published: May 2017

AimsHER2testing of invasive breast cancer byin‐situhybridization guides therapy decisions. ProbingHER2and centromere of chromosome 17 (cen17) simultaneously is supposed to reveal both a potentialHER2gene amplification and polysomy 17. However, a considerable number of breast cancer patients with quasi polysomy 17 are considered ‘equivocal’, which is diagnostically meaningless. Moreover, patients with equivocal/false polysomic tumours are prevented from a potentially beneficial anti‐HER2treatment. Here we evaluated theRAI1,D17S122andTP53hybridization markers to indicate true polysomy reliably and to reclassify equivocal samples accurately asHER2‐positive.Methods and resultsSamples with (n= 82) and without (n= 52) increased cen17 copy numbers and 78 evidentlyHER2‐amplified specimens were analysed using dual and triple marker hybridization probes. Selected putative polysomic samples were subjected to array‐based comparative genomic hybridization (aCGH). We found that 37.8% samples with putative polysomy 17 did not show any gain inRAI1,D17S122orTP53. Accordingly, aCGH revealed evidence for the presence ofHER2/cen17 co‐amplification rather than for true polysomy in those cases. Reflex testing using alternate 17p markers reclassified up to 56.3% equivocal cases asHER2‐positive and the combined assessment of a 17p and 17q locus allows the differentiation of true versus false polysomy.ConclusionsAn increased cen17 copy number does not necessarily reflect polysomy, and reflex testing facilitates the reclassification of ‘equivocals’. Nevertheless, the prognostic and predictive value of aHER2/cen17 co‐amplification versusHER2gene amplification alone must still be evaluated prospectively.
PD‐L1 overexpression in ampulla of Vater carcinoma and its pre‐invasive lesions
Authors: Saraggi Deborah , Galuppini Francesca , Remo Andrea , Urso Emanuele D L , Bacchin Deborah , Salmaso Roberta , Lanza Cristiano , Bao Riccardo Q , Fanelli Giuseppe N , Guzzardo Vincenza , Luchini Claudio , Scarpa Marco , Farinati Fabio , Fassan Matteo , Rugge Massimo 
Published: May 2017

AimsPD‐1/PD‐L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD‐L1 expression in ampulla of Vater carcinoma and its pre‐invasive lesions.Methods and resultsWe assessed the immunohistochemical expression of PD‐L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD‐L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD‐L1‐positive tumours (seven of 10) were intestinal‐type and poorly differentiated (G3). The number of PD‐L1‐positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD‐L1 expression. Four of the carcinomas were mismatch repair‐deficient and two of these were PD‐L1‐positive. Furthermore, mismatch repair‐deficient lesions showed a significantly higher average of PD‐L1‐positive stromal lymphoid cells than those of neoplastic PD‐L1‐negative samples (62.8 versus 21.6; P < 0.001).ConclusionsThe present results suggest a role of the PD‐1/PD‐L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours.
The TLR4–TRIF pathway can protect against the development of experimental allergic asthma
Authors: Shalaby Karim H. , Al Heialy Saba , Tsuchiya Kimitake , Farahnak Soroor , McGovern Toby K. , Risse Paul‐Andre , Suh Woong‐Kyung , Qureshi Salman T. , Martin James G. 
Published: May 2017

SummaryThe Toll‐like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin‐1 receptor and resistance protein (TIR) domain‐containing adaptor inducing interferon‐β (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4‐dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild‐type (WT), Trif−/− or Myd88−/− mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF‐dependent and MyD88‐independent. TRIF deficiency diminished the CD4+ ICOS+ T‐cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3− cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin‐induced CD4+ ICOS+ cells in the TRIF‐dependent inhibition of airway hyper‐responsiveness. Hence, our data demonstrate that stimulation of the TLR4‐TRIF pathway can protect against the development of allergic airway disease and that a TRIF‐dependent adjuvant effect on CD4+ ICOS+ T‐cell responses may be a contributing mechanism.
Association between cytokine profile and transcription factors produced by T‐cell subsets in early‐ and late‐onset pre‐eclampsia
Authors: Ribeiro Vanessa R. , Romao‐Veiga Mariana , Romagnoli Graziela G. , Matias Mariana L. , Nunes Priscila R. , Borges Vera Therezinha M. , Peracoli Jose C. , Peracoli Maria Terezinha S. 
Published: May 2017

SummaryPre‐eclampsia (PE) is an obstetric pathology characterized by abnormal activation of the innate and adaptive immune systems dependent on the imbalance of T helper subsets. The present study aimed to evaluate the gene and protein expression of T helper type 1 (Th1)/Th2/Th17/regulatory T (Treg) cell transcription factors in peripheral blood lymphocytes from pregnant women with PE employing quantitative RT‐PCR and flow cytometry techniques, as well as the cytokine profile produced by these CD4+ T‐cell subsets in the plasma of pregnant women with PE, classified as early‐onset PE (n = 20), late‐onset PE (n = 20) and normotensive pregnant women (n = 20). Results showed a higher percentage of CD4+ T cells expressing the RORc transcription factor (Th17) and a lower percentage of cells expressing FoxP3 (Treg) in women with early‐onset PE compared with late‐onset PE and normotensive groups. A lower gene expression of GATA‐3 transcription factor was detected in cells of women with early‐onset PE compared with the late‐onset PE group. Endogenous plasma levels of interleukin‐6 (IL‐6), IL‐17 and tumour necrosis factor‐α were significantly higher in the early‐onset PE group than in the late‐onset PE and normotensive groups, whereas IL‐4 (Th2 profile) and IL‐22 (Th17 profile), were not significantly different between the studied groups. The endogenous levels of transforming growth factor‐β and IL‐10 were significantly lower in the pre‐eclamptic than in the normotensive groups of the same gestational age, with a significant difference between early‐ and late‐onset PE. The results show that in women with PE there is an imbalance between inflammatory and anti‐inflammatory profiles in CD4+ T‐cell subsets, with polarization to Th17 profiles in the early‐onset PE, considered as the severe form of PE.
Epigenetic modifications of the VH region after DJH recombination in Pro‐B cells
Authors: Dong Yanying , Wu Caijun , Zhao Xiaohui , Zhang Ping , Zhang Hua , Zheng Mingzhe , Li Shichang , Jiao Junna , Yu Xiaozhuo , Lv Zhuangwei , Ji Yanhong 
Published: May 2017

SummaryThe variable region of murine immunoglobulin heavy chain (Igh) is assembled by sequential DH–JH and VH–DJH recombination. The accessibility of the Igh locus determines the order of rearrangement. Because of the large number of VH genes and the lack of a suitable model, the epigenetic modifications of VH genes after DJH recombination have not previously been characterized. Here, we employed two v‐Abl pro‐B cell lines, in which the Igh locus is in germline and DJH‐recombined configurations, respectively. The DJH junction displays the characteristics of a recombination centre, such as high levels of activation‐associated histone modifications and recombination‐activating gene protein (RAG) binding in DJH‐rearranged pro‐B cells, which extend the recombination centre model proposed for the germline Igh locus. The different domains of the VH region have distinct epigenetic characteristics after DJH recombination. Distal VH genes have higher levels of active histone modifications, germline transcription and Pax5 binding, and good quality recombination signal sequences. Proximal VH genes are relatively close to the DJH recombination centre, which partially compensates for the low levels of the above active epigenetic modifications. DJH recombination centre might serve as a cis‐acting element to regulate the accessibility of the VH region. Furthermore, we demonstrate that RAG weakly binds to functional VH genes, which is the first detailed assessment of RAG dynamic binding to VH genes. We provide a way for VH–DJH recombination in which the VH gene is brought into close proximity with the DJH recombination centre for RAG binding by a Pax5‐dependent chromosomal compaction event, and held in this position for subsequent cleavage and VH–DJH joining.
Functional analysis by minigene assay of putative splicing variants found in Bardet–Biedl syndrome patients
Authors: Álvarez‐Satta María , Castro‐Sánchez Sheila , Pousada Guillermo , Valverde Diana 
Published: May 2017

AbstractBardet–Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare diseases belonging to the group of ciliopathies. Although mutational screening studies of BBS/ALMS cohorts have been extensively reported, little is known about the functional effect of those changes. Thus, splicing variants are estimated to represent 15% of disease‐causing mutations, and there is growing evidence that many exonic changes are really splicing variants misclassified. In this study, we aimed to analyse for the first time several variants in BBS2, ARL6/BBS3, BBS4 and ALMS1 genes predicted to produce aberrant splicing by minigene assay. We found discordance between bioinformatics analysis and experimental data when comparing wild‐type and mutant constructs. Remarkably, we identified nonsense variants presumably resistant to nonsense‐mediated decay, even when a premature termination codon would be introduced in the second amino acid (p.(G2*) mutation in ARL6/BBS3 gene). As a whole, we report one of the first functional studies of BBS/ALMS1 variants using minigene assay, trying to elucidate their role in disease. Functional studies of variants identified in BBS and ALMS patients are essential for their proper classification and subsequent genetic counselling and could also be the start point for new therapeutic approaches, currently based only on symptomatic treatment.
Sodium‐glucose cotransporter‐2 inhibitor luseogliflozin added to glucagon‐like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: A 52‐week, open‐label, single‐arm study
Authors: Seino Yutaka , Yabe Daisuke , Sasaki Takashi , Fukatsu Atsushi , Imazeki Hisae , Ochiai Hidekazu , Sakai Soichi 
Published: May 2017

AbstractAims/IntroductionThe aim of the present study was to evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes.Materials and MethodsThis 52‐week, multicenter, open‐label, single‐arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy. Major efficacy end‐points included the changes from baseline in glycated hemoglobin, fasting plasma glucose and bodyweight. Body composition was also assessed in individuals who had access to bioelectrical impedance analysis. Safety assessments included adverse events, clinical laboratory tests, vital signs and 12‐lead electrocardiograms.ResultsOf 76 patients who received luseogliflozin, 62 completed the study. The changes from baseline in glycated hemoglobin, fasting plasma glucose, and bodyweight (mean ± SE) were −0.68 ± 0.10%, −32.1 ± 3.6 mg/dL and −2.71 ± 0.24 kg at week 52, respectively (all, P < 0.001 vs baseline). Luseogliflozin was associated with greater reductions in fat mass than lean mass at all measuring points (n = 22): fat vs lean mass changes (mean ± SE) at week 52 were −2.49 ± 0.45 kg (P < 0.001 vs baseline) and −0.44 ± 0.26 kg (P = 0.107 vs baseline), respectively. Insulin secretion and Matsuda Index were also improved at weeks 12 and 52 compared with baseline. Adverse events and adverse drug reactions occurred in 65.8 and 27.6% of patients, respectively. The overall safety profile, including frequency of hypoglycemia, was found to be consistent with those of previous studies and there were no new safety concerns.ConclusionsLuseogliflozin added to liraglutide was well tolerated, and improved glycemic control with bodyweight and fat mass reductions in Japanese type 2 diabetes patients.
In vivo microvascular imaging of cutaneous actinic keratosis, Bowen's disease and squamous cell carcinoma using dynamic optical coherence tomography
Authors: Themstrup L. , Pellacani G. , Welzel J. , Holmes J. , Jemec G.B.E. , Ulrich M. 
Published: May 2017

AbstractBackgroundA clear distinction between actinic keratosis (AK), Bowen's disease (BD) and squamous cell carcinoma (SCC) cannot reliably be made by clinical and dermoscopic evaluation alone. Dynamic optical coherence tomography (D‐OCT) is a novel angiographic variant of OCT that allows for non‐invasive, in vivo evaluation of the cutaneous microvascular morphology.ObjectiveTo investigate the microvascular structures of AK, BD and invasive SCC using D‐OCT in order to gain insights into the microvascular morphology of lesions in the spectrum of keratinocyte skin cancers.MethodsForty‐seven patients with a total of 54 lesions (18 AK, 12 BD and 24 SCC) were included in the study. D‐OCT still images of AK, BD and SCC at three predefined skin depths were prepared and randomized, creating a study set of 162 D‐OCT images. Three observers performed blinded evaluations of the randomized study set assessing multiple parameters including the different types of vascular morphology. Non‐blinded quantitative measurements of vascular diameter were also performed.ResultsThe blinded observer analysis suggests that D‐OCT evaluation of the vascular morphology may aid in distinguishing AK, BD and SCC lesions. We identified two vascular shapes that presented significantly differently across the lesion types, namely ‘blobs’ and ‘curves’. A strong presence of blobs at 300 μm skin depth was characteristically seen in a third of BD cases, while not or only slightly present in AK and SCC lesions. Vascular curves were predominantly present in AK lesions.ConclusionWe identified various vascular D‐OCT features that may aid in non‐invasively differentiating subtypes within the keratinocyte skin cancer spectrum.
Limited impact of awareness‐raising campaigns on hepatitis C testing practices among general practitioners
Authors: McLeod A. , Cullen B. L. , Hutchinson S. J. , Roy K. M. , Dillon J. F. , Stewart E. A. , Goldberg D. J. 
Published: May 2017

SummaryThe global hepatitis strategy calls for increased effort to diagnose those infected, with a target of 90% diagnosed by 2030. Scotland's Action Plan on Hepatitis C included awareness‐raising campaigns, undertaken during 2008‐2011, to promote testing by general practitioners. We examined hepatitis C virus (HCV) testing practice among general practitioners before and following these campaigns. Scottish general practitioners were surveyed, using Dillman's method, in 2007 and 2013; response rates were 69% and 60%, respectively. Most respondents offer testing when presented with a risk history (86% in 2007, 88% in 2013) but only one‐fifth actively sought out risk factors (19% in 2007, 21% in 2013). Testing was reportedly always/almost always/usually offered to people who inject drugs (84% in 2007, 87% in 2013). Significant improvements in the offer of testing were reported in patients with abnormal LFTs (41% in 2007, 65% in 2013, P<.001) and who had received medical/dental treatment in high prevalence countries (14% in 2007, 24% in 2013, P=.001). In 2013, 25% of respondents had undertaken HCV‐related continued professional development. This group was significantly more likely to actively seek out risk factors (P=.009) but only significantly more likely to offer a test to patients who had received medical/dental treatment in high prevalence countries (P=.001). Our findings suggest that government‐led awareness raising campaigns have limited impact on general practitioners’ testing practices. If the majority of the HCV‐infected population are to be diagnosed, practitioner‐based or physician‐centred interventions should be considered alongside educational initiatives targeted at professionals.
HIV/HCV coinfection and the risk of cardiovascular disease: A meta‐analysis
Authors: Osibogun O. , Ogunmoroti O. , Michos E. D. , Spatz E. S. , Olubajo B. , Nasir K. , Madhivanan P. , Maziak W. 
Published: May 2017

SummaryThe emergence of improved antiretroviral therapy has increased the life expectancy of human immunodeficiency virus (HIV)‐infected individuals, although there is an increased susceptibility to developing cardiovascular diseases (CVD). The risk for CVD is purported to be even higher among people with HIV and hepatitis C virus (HCV) coinfection because of the increased inflammatory response, which may synergistically impact CVD risk. However, studies comparing CVD outcomes between HIV alone and HIV/HCV individuals have been discordant. Accordingly, we conducted a meta‐analysis to clarify and quantify the association between HIV/HCV coinfection and the risk for CVD. We searched EMBASE, CINAHL, Google Scholar, PubMed, and Web of Science from inception to December 2016 to identify studies that provided information on HIV/HCV coinfection and CVD, defined as coronary artery disease, congestive heart failure and stroke. We used a random‐effects model to abstract and pool data on the hazard ratios (HRs) for CVD. HRs were adjusted for traditional CVD risk factors including age, sex, smoking, hypertension, diabetes and LDL cholesterol. Among the 283 articles reviewed, four cohort studies met inclusion criteria with a total of 33 723 participants. The pooled adjusted HRs for the association between HIV/HCV coinfection and CVD were 1.24 (95% CI: 1.07‐1.40) compared to HIV monoinfection. The test for heterogeneity was not statistically significant (I2=0.0%, P=.397). In conclusion, individuals with HIV/HCV coinfection had an increased CVD risk compared to those with HIV monoinfection. More research is needed to further examine the nature of this association, and response to traditional risk‐reduction therapies.
“Fix Me Another Marguerite!”: Species delimitation in a group of intensively hybridizing lineages of ox‐eye daisies (Leucanthemum Mill., Compositae‐Anthemideae)
Authors: Wagner Florian , Härtl Sabine , Vogt Robert , Oberprieler Christoph 
Published: May 2017

AbstractDelineating species boundaries in the framework of the multi‐species coalescent (MSC) proves to be a reliable, objective, and reproducible method in an increasing number of studies. However, the underlying model assumes the lack of gene flow after speciation; an assumption which may be frequently violated in plant evolution. This study evaluates the robustness of currently available species delimitation methods implemented in beast (BFD, BFD*, and dissect) in the closely‐knit ox‐eye daisy group around Leucanthemum ageratifolium Pau. Comprising five taxa being allopatrically distributed between northern Spain and southern Italy this study group shows signs of hybridization with the widespread and codistributed species Leucanthemum vulgare (Vaill.) Lam. to various extent. As expected, our empirical analyses based on both AFLP fingerprinting and sequence data demonstrate that the robustness of species delimitation results is considerably influenced by the intensity of hybridization among species and the number of hybrid individuals included. Therefore, we set up a methodological pipeline with a first step of identification and subsequent removal of individuals showing admixed genetic patterns caused by actual interbreeding using AFLP‐fingerprint and morphometric data, followed by application of different Bayesian MSC species delimitation methods based on the remnant individuals using both AFLP‐fingerprint and sequence data (four nuclear markers, five concatenated intergenic spacer regions of the plastid genome). The results argue for acknowledgement of Leucanthemum laciniatum, L. legraeanum, and L. ligusticum as independent species, show the close relationship of L. ageratifolium, L. monspeliense, and L. vulgare, and give rise to the description of three nothospecies new to science.
Unravelling seed dispersal through fragmented landscapes: Frugivore species operate unevenly as mobile links
Authors: González‐Varo Juan P. , Carvalho Carolina S. , Arroyo Juan M. , Jordano Pedro 
Published: May 2017

AbstractSeed dispersal constitutes a pivotal process in an increasingly fragmented world, promoting population connectivity, colonization and range shifts in plants. Unveiling how multiple frugivore species disperse seeds through fragmented landscapes, operating as mobile links, has remained elusive owing to methodological constraints for monitoring seed dispersal events. We combine for the first time DNA barcoding and DNA microsatellites to identify, respectively, the frugivore species and the source trees of animal‐dispersed seeds in forest and matrix of a fragmented landscape. We found a high functional complementarity among frugivores in terms of seed deposition at different habitats (forest vs. matrix), perches (isolated trees vs. electricity pylons) and matrix sectors (close vs. far from the forest edge), cross‐habitat seed fluxes, dispersal distances and canopy‐cover dependency. Seed rain at the landscape‐scale, from forest to distant matrix sectors, was characterized by turnovers in the contribution of frugivores and source‐tree habitats: open‐habitat frugivores replaced forest‐dependent frugivores, whereas matrix trees replaced forest trees. As a result of such turnovers, the magnitude of seed rain was evenly distributed between habitats and landscape sectors. We thus uncover key mechanisms behind “biodiversity–ecosystem function” relationships, in this case, the relationship between frugivore diversity and landscape‐scale seed dispersal. Our results reveal the importance of open‐habitat frugivores, isolated fruiting trees and anthropogenic perching sites (infrastructures) in generating seed dispersal events far from the remnant forest, highlighting their potential to drive regeneration dynamics through the matrix. This study helps to broaden the “mobile‐link” concept in seed dispersal studies by providing a comprehensive and integrative view of the way in which multiple frugivore species disseminate seeds through real‐world landscapes.