bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer
Authors: Hamaguchi Tetsuya , Denda Tadamichi , Kudo Toshihiro , Sugimoto Naotoshi , Ura Takashi , Yamazaki Kentaro , Fujii Hirofumi , Kajiwara Takeshi , Nakajima Takako Eguchi , Takahashi Shin , Otsu Satoshi , Komatsu Yoshito , Nagashima Fumio , Moriwaki Toshikazu , Esaki Taito , Sato Takeo , Itabashi Michio , Oki Eiji , Sasaki Toru , Chiron Marielle , Yoshino Takayuki 
Published: September 2019

AbstractAflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end‐products binding protein, insulin‐like growth factor‐binding protein 1, interleukin‐8, kallikrein 5, pulmonary surfactant‐associated protein D, tissue inhibitor of metalloproteinases 1, tenascin‐C, and tumor necrosis factor receptor 2. None correlated with progression‐free survival or maximum tumor shrinkage. Pre‐dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.
Circulating microRNA‐590‐5p functions as a liquid biopsy marker in non‐small cell lung cancer
Authors: Khandelwal Akanksha , Seam Rajeev Kumar , Gupta Manish , Rana Manjit Kaur , Prakash Hridayesh , Vasquez Karen M. , Jain Aklank 
Published: September 2019

AbstractDespite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR‐590‐5p as a potential prognostic marker in the progression of non‐small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real‐time PCR. Our data showed an ~7.5‐fold downregulation of miR‐590‐5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR‐590‐5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial‐to‐mesenchymal transition negatively correlated with miR‐590‐5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual‐luciferase reporter assays identified STAT3 as a direct target of miR‐590‐5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c‐Myc, Vimentin, and β‐catenin) involved in tumorigenesis. Taken together, our study suggests that miR‐590‐5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.
Ara h 7 isoforms share many linear epitopes: Are 3D epitopes crucial to elucidate divergent abilities?
Authors: Ehlers Anna M. , Klinge Marco , Suer Waltraud , Weimann Yvonne , Knulst André C. , Besa Frithjof , Le Thuy‐My , Otten Henny G. 
Published: September 2019

AbstractBackgroundThe peanut allergens Ara h 2, h 6, and h 7 are potent allergens and can trigger severe reactions. Ara h 7 consists of three isoforms differing in their ability to induce basophil degranulation, whereas the ability of Ara h 7.0201 is comparable to Ara h 2 and 6 as shown in previous literature.ObjectiveTo identify linear epitopes of Ara h 7.0101, Ara h 7.0201 and Ara h 7.0301 recognized by IgE and IgG4 from patients sensitized to Ara h 7 and to investigate their potential to elucidate divergent abilities of the Ara h 7 isoforms in inducing basophil activation.MethodsLinear epitopes recognized by IgE and IgG4 were mapped by peptide microarray analysis containing 15‐mer peptides of Ara h 2.0201, 6, 7.0101, 7.0201 and 7.0301 and 39 peanut allergic patients sensitized to Ara h 7 (discovery). For validation, 20‐mer peptides containing the minimal epitope and surrounding amino acids were incubated with 25 sensitized patients and 10 controls (validation).ResultsThree out of 14 linear epitopes were unique for each isoform (Ara h 7.0101: aa 97‐109; Ara h 7.0201: aa 122‐133; Ara h 7.0301: aa 65‐74) but scarcely recognized by IgE. The main linear IgE epitope (aa 51‐57) located in the long flexible loop of all Ara h 7 isoforms was bound by antibodies from 31% of the patients (discovery and validation cohort). Regarding IgG4, 55% of the patients recognized an epitope present on all isoforms (aa 55‐65), whereas epitope aa 129‐137, only present on Ara h 7.0101/0.0301, was recognized by 38% of the patients. Recognition was highly individual, although 20% of the patients recognized any linear epitope neither by IgE nor by IgG4 despite a low mean z‐score of ≥ 1.7. Remarkably, only 50% of the patients recognized one or more epitopes by IgE.Conclusion & Clinical RelevanceAra h 7 isoforms share many linear epitopes being easily accessible for antibody binding. Unique epitopes, essential to elucidate divergent potencies, were scarcely recognized, suggesting a crucial involvement of conformational epitopes.
A preclinical model links osseo‐densification due to misfit and osseo‐destruction due to stress/strain
Authors: Coyac Benjamin R. , Leahy Brian , Salvi Giuseppe , Hoffmann Waldemar , Brunski John B. , Helms Jill A. 
Published: September 2019

AbstractObjectivePrimary stability is a prerequisite for implant osseointegration. Some degree of misfit between an implant and its osteotomy is required to ensure primary stability, and this is typically achieved by undersizing an implant osteotomy. In this preclinical study, we aimed at understanding the relationship between misfit, insertion torque, implant stability, and their cumulative short‐ and longer‐term effects on peri‐implant bone.Materials and methodsWe placed implants in maxillary extraction sites of a rat; in the control group, these implants had minimal misfit while those in the test group had a high degree of misfit and therefore osseo‐densified the peri‐implant bone.ResultsCompared to controls, the misfit‐induced stresses produced by osseo‐densification led to micro‐fractures in the peri‐implant bone and an extensive zone of dying osteocytes. High interfacial pressures produced a pro‐resorptive environment as shown by tartrate‐resistant acid phosphatase activity and cathepsin K immunostaining (IHC). The lack of alkaline phosphatase activity and collagen I IHC supported the absence of new bone formation. Collectively, micro‐computed tomography imaging, quantification of bone–implant contact (BIC), vimentin, and IL1‐β IHCs demonstrated that implant failure occurred soon afterward, which presented as a crater‐like lesion filled with fibrous, inflamed granulation tissue around the test implants.ConclusionBy controlling every other risk indicator, we confirmed how excessive osseo‐densification can lead directly to osseo‐destruction.
Development evaluation in authoritarian states: A case from Kazakhstan
Authors: Knox Colin 
Published: September 2019

AbstractMotivationAuthoritarian states receive development funding from international donors for programmes and interventions, some aimed at improving their governance systems. This article reports on the evaluation of an EU‐funded programme in Kazakhstan, seen as the most progressive reformer in Central Asia. The EU Programme was aimed at enhancing Kazakhstan’s business competitiveness through better regulation and civil service modernization.PurposeThis article addresses two research questions. What was the impact of the EU‐funded intervention? What role, if any, did the evaluation play in reflective policy learning for the future?Approach and MethodsThe research draws on quantitative and qualitative evidence. This involved analysing secondary data sources on the effectiveness of governance over time in Kazakhstan and interviews for 34 key stakeholders on the impact of the EU interventions.FindingsWe find no significant improvements in governance over time. While the donor responded in a flexible way to meet the changing strategic goals of the state (which were at the personal behest of the President), this did not help to embed evaluation as part of the policy cycle for future learning. The key beneficiary here was the Government of Kazakhstan.Policy implicationsWider systemic change from upward accountability to downward accountability to citizens is needed to make evaluation relevant for authoritarian states. Upward accountability to the President is a feature of authoritarian regimes, which precludes citizens from being able to hold the state to account. Without these systemic changes, autocracies simply engage in development evaluation as a perfunctory exercise to meet donor requirements.
Factors predictive of the presence of a CSF1R mutation in patients with leukoencephalopathy
Authors: Kondo Y. , Matsushima A. , Nagasaki S. , Nakamura K. , Sekijima Y. , Yoshida K. 
Published: September 2019

Background and purposeThe purpose was to identify statistically factors that correlate with the presence of a colony‐stimulating factor 1 receptor (CSF1R) mutation and to reevaluate the accuracy of the current diagnostic criteria for CSF1R‐related leukoencephalopathy.MethodsCSF1R testing was conducted on 145 consecutive leukoencephalopathy cases who were clinically suspected of having adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia. From these, 135 cases whose detailed clinical information was available were enrolled. Forward logistic stepwise regression was performed to generate a probability model to predict a positive CSF1R mutation result. The current diagnostic criteria were also applied to our cohort and their sensitivity and specificity were calculated.ResultsTwenty‐eight CSF1R‐mutation‐positive cases and 107 CSF1R‐mutation‐negative cases were identified. Our probability model suggested that factors raising the probability of a CSF1R‐mutation‐positive result were younger onset, parkinsonism, thinning of the corpus callosum and diffusion‐restricted lesions. It also showed that involuntary movements and brainstem or cerebellar atrophy were negative predictors of a CSF1R‐mutation‐positive result. In our cohort, the sensitivity and specificity for ‘probable’ or ‘possible’ CSF1R‐related leukoencephalopathy were 81% and 14%, respectively.ConclusionsClinical and brain imaging features predictive of the presence of a CSF1R mutation are proposed. Consideration of these factors will help prioritize patients for CSF1R testing.
Founder effects and species introductions: A host versus parasite perspective
Authors: Blakeslee April M. H. , Haram Linsey E. , Altman Irit , Kennedy Kristin , Ruiz Gregory M. , Miller A. Whitman 
Published: September 2019

AbstractSpecies colonizations (both natural and anthropogenic) can be associated with genetic founder effects, where founding populations demonstrate significant genetic bottlenecks compared to native populations. Yet, many successfully established free‐living species exhibit little reduction in genetic diversity—possibly due to multiple founding events and/or high propagule pressure during introductions. Less clear, however, is whether parasites may show differential signatures to their free‐living hosts. Parasites with indirect life cycles may particularly be more prone to founder effects (i.e., more genetically depauperate) because of inherently smaller founding populations and complex life cycles. We investigated this question in native (east coast) and introduced (west coast) North American populations of a host snail Tritia obsoleta (formerly Ilyanassa obsoleta, the eastern mudsnail) and four trematode parasite species that obligately infect it. We examined genetic diversity, gene flow, and population structure using two molecular markers (mitochondrial and nuclear) for the host and the parasites. In the host snail, we found little to no evidence of genetic founder effects, while the trematode parasites showed significantly lower genetic diversity in the introduced versus native ranges. Moreover, the parasite's final host influenced infection prevalence and genetic diversity: Trematode species that utilized fish as final hosts demonstrated lower parasite diversity and heightened founder effects in the introduced range than those trematodes using birds as final hosts. In addition, inter‐regional gene flow was strongest for comparisons that included the putative historical source region (mid‐Atlantic populations of the US east coast). Overall, our results broaden understanding of the role that colonization events (including recent anthropogenic introductions) have on genetic diversity in non‐native organisms by also evaluating less studied groups like parasites.
Berberine ameliorates non‐steroidal anti‐inflammatory drugs‐induced intestinal injury by the repair of enteric nervous system
Authors: Chao Guanqun , Ye Fangxu , Yuan Yuan , Zhang Shuo 
Published: September 2019

AbstractThe study was to detect the role of GDNF, PGP9.5 (a neuronal marker), and GFAP (EGCs’ marker) in the mechanism of non‐steroidal anti‐inflammatory drugs (NSAIDs) related to intestinal injury and to clarify the protective effect of berberine in the treatment of NSAID‐induced small intestinal disease. Forty male SD rats were divided randomly into five groups (A–E): Group A: control group; Group B: model group received diclofenac sodium 7.5 mg/(kg*day) for 5 days; Group C–E: berberine low, medium and high dose groups were treated by 7.5 mg/(kg*day) diclofenac sodium for 5 days then received berberine 25 mg/(kg*day), 50 mg/(kg*day), and 75 mg/(kg*day), respectively, between the sixth and eighth day. Intestinal mucosa was taken on the ninth day to observe the general, histological injuries, and to measure the intestinal epithelial thickness. Then, immunohistochemistry was performed to detect the expression of PGP9.5 and GFAP, and Western blot was performed to detect GDNF expression. The histological score and the general score in the model group were, respectively, 5.75 ± 1.04 and 4.83 ± 0.92. Scores in berberine medium and high berberine group were lower compared with the model group (P < 0.05). The intestinal epithelial thickness in the model group was lower than in the control group and the berberine groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the model group and the three berberine groups were significantly lower than in the control groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the control group and the three berberine groups were higher compared with the model groups (P < 0.05). Berberine can protect the intestinal mucosa of NSAID users, and the mechanism is associated with the reparation of the enteric nervous system via upregulating the expression of PGP9.5, GFAP, and GDNF.
Multisite rate control analysis identifies ribosomal scanning as the sole high‐capacity/low‐flux‐control step in mRNA translation
Authors: Firczuk Helena , Teahan James , Mendes Pedro , McCarthy John E.G. 
Published: September 2019

Control of complex intracellular pathways such as protein synthesis is critical to organism survival, but is poorly understood. Translation of a reading frame in eukaryotic mRNA is preceded by a scanning process in which a subset of translation factors helps guide ribosomes to the start codon. Here, we perform comparative analysis of the control status of this scanning step that sits between recruitment of the small ribosomal subunit to the m7GpppG‐capped 5′end of mRNA and of the control exerted by downstream phases of polypeptide initiation, elongation and termination. We have utilized a detailed predictive model as guidance for designing quantitative experimental interrogation of control in the yeast translation initiation pathway. We have built a synthetic orthogonal copper‐responsive regulatory promoter (PCuR3) that is used here together with the tet07 regulatory system in a novel dual‐site in vivo rate control analysis strategy. Combining this two‐site strategy with calibrated mass spectrometry to determine translation factor abundance values, we have tested model‐based predictions of rate control properties of the in vivo system. We conclude from the results that the components of the translation machinery that promote scanning collectively function as a low‐flux‐control system with a capacity to transfer ribosomes into the core process of polypeptide production that exceeds the respective capacities of the steps of polypeptide initiation, elongation and termination. In contrast, the step immediately prior to scanning, that is, ribosome recruitment via the mRNA 5′ cap‐binding complex, is a high‐flux‐control step.
Animal models of leukodystrophy: a new perspective for the development of therapies
Authors: Rutherford Holly A. , Hamilton Noémie 
Published: September 2019

The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over 50 distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, accordingly, a range of animal models relating to each disorder. While both murine and zebrafish models continue to aid in the development of potential therapies, many of these models fail to truly recapitulate the human condition – thus leaving substantial weaknesses in our understanding of leukodystrophy pathogenesis. Additionally, the heterogeneity in leukodystrophy presentation – both in patients and in vivo models – often results in a narrow focus on single disorders in isolation across much of the literature. Thus, this review aims to synthesise prominent research regarding the most common leukodystrophies in order to provide an overview of key animal models and their utility in developing novel treatments. We begin by discussing the ongoing revolution across the leukodystrophy field following the rise of next generation sequencing, before focusing more extensively on existing animal models from the mouse and zebrafish fields. Finally, we explore how these preclinical models have shaped the development of therapeutic strategies currently in development. We propose future directions for the field and suggest a more critical view of the dogma which has underpinned leukodystrophy research for decades.
Economic Impact of Headache and Psychiatric Comorbidities on Healthcare Expenditures Among Children in the United States: A Retrospective Cross‐Sectional Study
Authors: Law Emily F. , Palermo Tonya M. , Zhou Chuan , Groenewald Cornelius B. 
Published: September 2019

ObjectiveTo examine the annual healthcare expenditures associated with childhood headache in the United States, and to evaluate whether psychiatric comorbidities increase the impact of headache on expenditures.BackgroundHeadache is prevalent in childhood and co‐occurs with anxiety disorders, depressive disorders, and attention deficit/hyperactivity disorder (ADHD), which may increase cost of illness.MethodsWe conducted a secondary data analysis using a nationally representative sample of 34,633 children ages 2‐17 from the 2012‐2015 Medical Expenditure Panel Surveys (MEPS), of which 779 (weighted 2.6%) were identified as having headache based on health service use associated with headache. Using a comprehensive cost‐of‐illness approach, we assessed the incremental expenditures associated with headache and determined excess expenditures associated with psychiatric comorbidities using standard adjusted 2‐part expenditure models.ResultsAnnual total healthcare expenditures were estimated to be 24.3% higher, 95% CI [1,55], in our headache group ($3036, 95% CI [2374,3699] vs $2350, 95% CI [2140,2559]). Total national expenditures associated with pediatric headache in the United States were estimated at $1.1 billion annually, 95% CI [.04, 2.2 billion]. Depression and ADHD were associated with higher incremental expenditures for the headache group (depression: $1815, 95% CI[676,2953] vs $1409, 95% CI[697,2112]; ADHD: $4742, 95% CI[1659,7825] vs $2935, 95% CI[1977,3894]); however, interactions between psychiatric comorbidities and headache did not reach statistical significance.ConclusionYouth with headache exert a considerable economic burden on families, healthcare systems, and society. Due to the limitations in methods used to classify youth with headache in MEPS, our findings may underestimate the true prevalence and cost of pediatric headache in the United States. Further research with larger sample sizes is needed to understand the impact of psychiatric comorbidities on healthcare expenditures in this population.
Clinical applications, accuracy and limitations of guided endodontics: a systematic review
Authors: Moreno‐Rabié C. , Torres A. , Lambrechts P. , Jacobs R. 
Published: September 2019

AbstractBackgroundThe novel concept of guided endodontics has been reported as an effective method to obtain safe and reliable results in root canal treatment.AimTo evaluate by means of a systematic review the clinical applications, accuracy and limitations of guided endodontic treatment.Data sourcesA search of the literature was performed on PubMed, Embase, Web of Science and Cochrane Library databases, until 25 April 2019. No language or year restrictions were applied.Study eligibility criteriaArticles that answered the research question, including case reports, in vitro and ex vivo studies were included. Data extraction was performed independently by two reviewers.Study appraisalQuality assessment was done using STROBE, CARE and Modified CONSORT guidelines for observational, case reports and pre‐clinical studies, respectively.ResultsA total of 22 articles, including fifteen case reports, six pre‐clinical studies (in vitro and ex vivo studies) and one observational study, were included.Limitations and ConclusionsEven though the level of evidence is low, and the methodology described among studies heterogeneous, all articles describe guided access cavity preparation and guided surgery as being highly accurate and successful techniques when comparing the drilled path to the planned treatment. More studies with a larger number of patients are necessary to obtain significant conclusions.