bluuebunny/crossref_metadata_2025_split huggingface dataset:
Process analytical technology implementation for protein refolding: GCSF as a case study
Authors: Hebbi Vishwanath , Thakur Garima , Rathore Anurag S. 
Published: December 2018

AbstractProcess analytical technology is gaining interest in the biopharmaceutical industry as a means to enable consistency in processing and thereby in product quality via process control. Protein refolding is known to be significantly impacted by critical process parameters and feed material attributes including composition and pH of the solubilisation and refolding buffers. Hence, to achieve robust process control and product quality, these attributes and parameters need to be monitored. This paper presents an approach towards statistical process control and monitoring of protein refolding, from buffer preparation to refold quenching, during manufacturing of therapeutic proteins from Escherichia coli based systems. The proposed approach utilises measurements of online redox potential, temperature, and pH for development of a statistical model. The model has then been integrated with LabView to permit real‐time monitoring of the refolding process. The proposed system has been demonstrated to successfully identify process deviations and thereby enable process control for manufacturing product of consistent quality.
A three‐dimensional microfluidized liver system to assess hepatic drug metabolism and hepatotoxicity
Authors: Corrado Brunella , De Gregorio Vincenza , Imparato Giorgia , Attanasio Chiara , Urciuolo Francesco , Netti Paolo A. 
Published: December 2018

AbstractIn this study, we propose the design and fabrication of a liver system on a chip. We first chose the most suitable three‐dimensional liver‐like model between cell spheroids and microtissue precursors, both based on the use of hepatocellular carcinoma cells (HepG2) to provide proof‐of‐concept data. Spheroids displayed high cell density but low expression of the typical hepatic biomarkers, whereas microtissue precursors showed stable viability and function over the entire culture time. The two liver‐like models were compared in terms of cell viability, function, metabolism, and the P‐glycoprotein 1 (P‐gp) transport‐protein expression with the microtissue precursors showing the best performance. Thus, we cultured them into a microfluidic biochip featured with three parallel channels shaped to mimic the hepatic sinusoids. To assess the detoxification potential of the microtissue‐loaded biochip we challenged it with a model molecule (ethanol) at different concentrations and time points. Ethanol cytotoxicity was detected by a noninvasive measurement of cell viability based on cell autofluorescence. As expected, a dose‐dependent decrease of albumin and urea secretion was observed in the ethanol‐treated samples. We believe that the described totally human‐derived platform, suitable for integration into a multiorgan microfluidic system, can provide a consistent innovative platform for drug development and toxicity studies.
A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer
Authors: Lin Alexander J. , Samson Pamela , DeWees Todd , Henke Lauren , Baranski Thomas , Schwarz Julie , Pfeifer John , Grigsby Perry , Markovina Stephanie 
Published: December 2018

AbstractBackgroundPrognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.MethodsIn patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho‐MEK, MAPK(dpERK), PPARγ, and phospho‐AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes.ResultsA total of 231 patients had archived formalin‐fixed, paraffin‐embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6‐82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPARγ (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22‐0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET‐negative and either MAPK(dpERK)‐positive or pAKT‐positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5‐11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3‐6.0).ConclusionCharacterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.
Periventricular microglial cells interact with dividing precursor cells in the nonhuman primate and rodent prenatal cerebral cortex
Authors: Noctor Stephen C. , Penna Elisa , Shepherd Hunter , Chelson Christian , Barger Nicole , Martínez‐Cerdeño Verónica , Tarantal Alice F. 
Published: December 2018

AbstractCortical proliferative zones have been studied for over 100 years, yet recent data have revealed that microglial cells constitute a sizeable proportion of ventricular zone cells during late stages of cortical neurogenesis. Microglia begin colonizing the forebrain after neural tube closure and during later stages of neurogenesis populate regions of the developing cortex that include the proliferative zones. We previously showed that microglia regulate the production of cortical cells by phagocytosing neural precursor cells (NPCs), but how microglia interact with NPCs remains poorly understood. Here we report on a distinct subset of microglial cells, which we term periventricular microglia, that are located near the lateral ventricle in the prenatal neocortex. Periventricular microglia exhibit a set of similar characteristics in embryonic rat and fetal rhesus monkey cortex. In both species, these cells occupy ~60 μm of the ventricular zone in the tangential axis and make contact with the soma and processes of NPCs dividing at the ventricle for over 50 μm along the radial axis. Periventricular microglia exhibit notable differences across species, including distinct morphological features such as terminal bouton‐like structures that contact mitotic NPCs in the fetal rhesus monkey but not in rat. These morphological distinctions suggest differential functions of periventricular microglia in rat and rhesus monkey, yet are consistent with the concept that microglia regulate NPC function in the developing cerebral cortex of mammalian species.
Primate neocortex development and evolution: Conserved versus evolved folding
Authors: Namba Takashi , Vaid Samir , Huttner Wieland B. 
Published: December 2018

AbstractThe neocortex, the seat of higher cognitive functions, exhibits a key feature across mammalian species—a highly variable degree of folding. Within the neocortex, two distinct subtypes of cortical areas can be distinguished, the isocortex and the proisocortex. Here, we have compared specific spatiotemporal aspects of folding between the proisocortex and the isocortex in 13 primates, including human, chimpanzee, and various Old World and New World monkeys. We find that folding at the boundaries of the dorsal isocortex and the proisocortex, which gives rise to the cingulate sulcus (CiS) and the lateral fissure (LF), is conserved across the primates studied and is therefore referred to asconserved folding. In contrast, the degree of folding within the dorsal isocortex exhibits huge variation across these primates, indicating that this folding, which gives rise to gyri and sulci, is subject to major changes during primate evolution. We therefore refer to the folding within the dorsal isocortex asevolved folding. Comparison of fetal neocortex development in long‐tailed macaque and human reveals that the onset ofconserved foldingprecedes the onset ofevolved folding. Moreover, the analysis of infant human neocortex exhibiting lissencephaly, a developmental malformation thought to be mainly due to abnormal neuronal migration, shows that theevolved foldingis perturbed more than theconserved folding. Taken together, our study presents a two‐step model of folding that pertains to primate neocortex development and evolution. Specifically, our data imply that theconserved foldingand theevolved foldingconstitute two distinct, sequential events.
DNA Aptamers in the Detection of Leukemia Cells by the Thickness Shear Mode Acoustics Method
Authors: Poturnayová Alexandra , Buríková Monika , Bízik Jozef , Hianik Tibor 
Published: December 2018

AbstractBy using the thickness shear mode acoustics method (TSM) and single‐molecule force spectroscopy (SMFS) we studied the interactions between DNA aptamers (sgc8c) specific to the protein tyrosine kinase 7 (PTK7), which is localized in the membranes of leukemia lymphoblastics (MOLT‐4), and lymphocyte (Jurkat) cell lines, as well with PTK7‐negative U266 myeloid leukemia cells. The TSM method allowed the development of a highly sensitive, label‐free biosensor for the detection leukemia cells with a limit of detection of (195±20) cells/mL. SMFS approved the high selectivity of the sgc8c aptamers to the PTK7 receptors at the cell surface and allowed determining the binding probability of the aptamers to the PTK7 receptors at different cell lines.
Centrifugation affects the purity of liquid biopsy‐based tumor biomarkers
Authors: Rikkert Linda G. , van der Pol Edwin , van Leeuwen Ton G. , Nieuwland Rienk , Coumans Frank A.W. 
Published: December 2018

AbstractBiomarkers in the blood of cancer patients include circulating tumor cells (CTCs), tumor‐educated platelets (TEPs), tumor‐derived extracellular vesicles (tdEVs), EV‐associated miRNA (EV‐miRNA), and circulating cell‐free DNA (ccfDNA). Because the size and density of biomarkers differ, blood is centrifuged to isolate or concentrate the biomarker of interest. Here, we applied a model to estimate the effect of centrifugation on the purity of a biomarker according to published protocols. The model is based on the Stokes equation and was validated using polystyrene beads in buffer and plasma. Next, the model was applied to predict the biomarker behavior during centrifugation. The result was expressed as the recovery of CTCs, TEPs, tdEVs in three size ranges (1–8, 0.2–1, and 0.05–0.2 μm), EV‐miRNA, and ccfDNA. Bead recovery was predicted with errors <18%. Most notable cofounders are the 22% contamination of 1–8 μm tdEVs for TEPs and the 8–82% contamination of <1 μm tdEVs for ccfDNA. A Stokes model can predict biomarker behavior in blood. None of the evaluated protocols produces a pure biomarker. Thus, care should be taken in the interpretation of obtained results, as, for example, results from TEPs may originate from co‐isolated large tdEVs and ccfDNA may originate from DNA enclosed in <1 μm tdEVs. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
Partitioning drivers of spatial genetic variation for a continuously distributed population of boreal caribou: Implications for management unit delineation
Authors: Priadka Pauline , Manseau Micheline , Trottier Tim , Hervieux Dave , Galpern Paul , McLoughlin Philip D. , Wilson Paul J. 
Published: December 2018

AbstractIsolation by distance (IBD) is a natural pattern not readily incorporated into theoretical models nor traditional metrics for differentiating populations, although clinal genetic differentiation can be characteristic of many wildlife species. Landscape features can also drive population structure additive to baseline IBD resulting in differentiation through isolation‐by‐resistance (IBR). We assessed the population genetic structure of boreal caribou across western Canada using nonspatial (STRUCTURE) and spatial (MEMGENE) clustering methods and investigated the relative contribution of IBD and IBR on genetic variation of 1,221 boreal caribou multilocus genotypes across western Canada. We further introduced a novel approach to compare the partitioning of individuals into management units (MU) and assessed levels of genetic connectivity under different MU scenarios. STRUCTURE delineated five genetic clusters while MEMGENE identified finer‐scale differentiation across the study area. IBD was significant and did not differ for males and females both across and among detected genetic clusters. MEMGENE landscape analysis further quantified the proportion of genetic variation contributed by IBD and IBR patterns, allowing for the relative importance of spatial drivers, including roads, water bodies, and wildfires, to be assessed and incorporated into the characterization of population structure for the delineation of MUs. Local population units, as currently delineated in the boreal caribou recovery strategy, do not capture the genetic variation and connectivity of the ecotype across the study area. Here, we provide the tools to assess fine‐scale spatial patterns of genetic variation, partition drivers of genetic variation, and evaluate the best management options for maintaining genetic connectivity. Our approach is highly relevant to vagile wildlife species that are of management and conservation concern and demonstrate varying degrees of IBD and IBR with clinal spatial genetic structure that challenges the delineation of discrete population boundaries.
The DAHANCA 32 study: Electrochemotherapy for recurrent mucosal head and neck cancer
Authors: Plaschke Christina Caroline , Johannesen Helle Hjorth , Hansen Rasmus Hvass , Hendel Helle Westergren , Kiss Katalin , Gehl Julie , Wessel Irene 
Published: December 2018

AbstractBackgroundElectrochemotherapy is an established treatment for cutaneous tumors. This study aimed at determining efficacy of electrochemotherapy in recurrent head and neck cancer.MethodsPhase II clinical trial in patients with recurrent head and neck carcinomas with no curative treatment options. Electrochemotherapy was performed under general anesthesia. Primary endpoint was tumor response (CT scanning) evaluated at week 8. Secondary endpoints included biopsy results, MRI and fluorodeoxyglucose‐positron emission tomography scanning, safety, toxicity, pain score, and quality‐of‐life questionnaires.ResultsOf 26 patients treated, 5 (19%) achieved complete response, 10 (39%) partial response, resulting in an objective response of 58%. Two responders remain without recurrence. No serious adverse events occurred during treatment. Four events occurred posttreatment: one bleeding episode, two episodes with mucosal swelling, and one patient died due to disease progression.ConclusionElectrochemotherapy is efficient against local recurrence of head and neck cancer with an overall response rate of 58%.
Salivary gland tumors: Molecular characterization and therapeutic advances for metastatic disease
Authors: Schvartsman Gustavo , Pinto Nathalia Almeida , Bell Diana , Ferrarotto Renata 
Published: December 2018

AbstractSalivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
Effect of radiotherapy on the chemical composition of root dentin
Authors: Campi Lívia Bueno , Lopes Fabiane Carneiro , Soares Luís Eduardo Silva , de Queiroz Alexandra Mussolino , de Oliveira Harley Francisco , Saquy Paulo César , de Sousa‐Neto Manoel Damião 
Published: December 2018

AbstractBackgroundThe radiotherapy can directly affect the bond strength of the adhesive materials, interfering in the prognosis of restorative treatments, which may be caused by chemical changes in dentin structure.MethodsTwenty inferior homologues premolars were distributed in 2 groups (in vitro study) (n = 10): nonirradiated and irradiated. The specimens were submitted to the analysis of phosphate (ν1PO43−;ν2PO43−;ν4PO43−), carbonate (ν3CO32−), amide I, CH2, amide III, and amide I/III ratio by confocal Raman spectroscopy. Data were submitted to statistical analysis (T test, P < .05).ResultsIn intracanal dentin, the irradiated group had lower ν4PO43− values (1.23 ± 0.06) compared to nonirradiated group (1.40 ± 0.18) (P < .05), with no difference for ν1PO43− and ν2PO43 peaks (P > .05). The irradiated (1.56 ± 0.06) had lower carbonate, amide III (1.05 ± 0.19), and amide I/III ratio values (0.19 ± 0.06) compared to nonirradiated group (1.42 ± 0.10, 1.28 ± 0.24, and 0.31 ± 0.10, respectively) (P < .05). For medium dentin irradiated group (1.30 ± 0.12) had lower phosphate values compared to nonirradiated group (1.48 ± 0.22) (P < .05). In cementum, there was no statistical difference between the groups.ConclusionThe radiotherapy was able to cause changes in ν4PO43−, carbonate, and amide III peaks of root dentin.
Heterozygosity of p16 expression in an oral squamous cell carcinoma with associated loss of heterozygosity and copy number alterations
Authors: Ambele Melvin A. , Pepper Michael S. , van Heerden Marlene B. , van Heerden Willie F. P. 
Published: December 2018

AbstractBackgroundOral field cancerization describes a multifocal development process involving many cells at once in response to prolong exposure to carcinogens. This case demonstrated differential p16 expression in different sections of the same HPV negative tumor on the floor of mouth in a patient with history of prolonged smoking.MethodsHistological examination, presence of HPV infection and OncoScan analysis of DNA extracted from two well‐defined areas with different p16 expression profiles were performed.ResultsHistological and immunochemical analysis revealed the presence of a dual architectural pattern squamous cell carcinoma with a p16 negative and a p16 positive component. OncoScan analysis showed genetic changes that define field cancerization of the p16 negative tumor as revealed by mosaicism in both loss of heterozygosity and copy number alterations in cancer‐associated genes located on 3p, 7p, 9p 11q, and 17p.ConclusionThese changes were indicative of field cancerization in response to tobacco exposure.
MIP‐1α induces inflammatory responses by upregulating chemokine receptor 1/chemokine receptor 5 and activating c‐Jun N‐terminal kinase and mitogen‐activated protein kinase signaling pathways in acute pancreatitis
Authors: Wu Xingmao , Ji Kaiqiang , Wang Haiyuan , Zhao Yang , Jia Jia , Gao Xiaopeng , Zang Bin 
Published: December 2018

AbstractObjectiveWe aimed to investigate the association of macrophage inflammatory protein (MIP)‐1α (CCL3) expression with the severity of acute pancreatitis (AP).MethodsThe patients with AP were selected and divided into mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP) groups according to the severity of AP. The pancreatic acinar cell line Ar42 j was treated with cerulein to induce in vitro cell AP model. The expression of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) and the activation of the c‐Jun N‐terminal kinase (JNK)/p38 mitogen‐activated protein kinase (MAPK) signaling pathway in stimulated or transfected Ar42 j cells were detected.ResultsWe detected that the upregulation of MIP‐1α was associated with the severity of AP. Patients with SAP showed the highest MIP‐1α contents, followed by MSAP, and, lastly, MAP. In cerulein‐stimulated Ar42 j cells, the upregulation of MIP‐1α, CCR5, TNF‐α, and IL‐6 was time dependent. In addition, in human recombinant MIP‐1α treated Ar42 j cells, the upregulation of TNF‐α and IL‐6 was MIP‐1α‐dose‐dependent. In contrast, we detected the inhibition of TNF‐α and IL‐6 in MIP‐1α small interfering RNA (siRNA)‐treated cells. Also, the activation of the JNK/p38 MAPK signaling pathway was induced and inhibited by human recombinant MIP‐1α and MIP‐1α siRNA, respectively.ConclusionThese results suggested that MIP‐1α might be used as a biomarker for the prognosis of AP severity. The MIP‐1α‐induced inflammatory responses in AP were mediated by TNF‐α and IL‐6, which were associated with the activation of the JNK/p38 MAPK signaling pathway.
Association between α‐adducin rs4961 polymorphism and hypertension: A meta‐analysis based on 40 432 subjects
Authors: Jin Hongyan , Huang Yupeng , Yang Guokang 
Published: December 2018

AbstractBackground: Recently, the role of α‐adducin rs4961 polymorphism in hypertension (HTN) was intensively analyzed, but the results of these studies were inconsistent. Therefore, we performed this study to better assess the relationship between α‐adducin rs4961 polymorphism and the likelihood of HTN.Methods: Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios with 95% confidence intervals were used to assess the relationship between α‐adducin rs4961 polymorphism and HTN.Results: A total of 33 studies with 40 432 participants were analyzed. Significant associations with the likelihood of HTN were detected for the α‐adducin rs4961 polymorphism with fixed effect models (FEM) (dominant model: P = 0.003; allele model: P = 0.003), but not with random effect models (REM). Further subgroup analysis according to ethnicity of participants revealed that the α‐adducin rs4961 polymorphism was significantly associated with the likelihood of HTN in Asians (7721 cases and 8299 controls) with both FEMs (dominant model: P < 0.0001; additive model: P = 0.01; allele model: P < 0.0001) and REMs (dominant model: P = 0.0005; additive model: P = 0.03; allele model: P = 0.0006).Conclusions: Our findings indicate that the α‐adducin rs4961 polymorphism may serve as a genetic biomarker of HTN in Asians.
Fastigial nucleus stimulation ameliorates cognitive impairment via modulating autophagy and inflammasomes activation in a rat model of vascular dementia
Authors: Xia Dongjian , Sui Rubo , Min Lianqiu , Zhang Ling , Zhang Zhuang 
Published: December 2018

AbstractBackgroundIt has been reported that the fastigial nucleus (FSN) plays an important role in the development of vascular dementia (VD). Both autophagy and inflammation are functionally involved in the pathogenesis of VD. In this study, we aimed to evaluate the therapeutic effect of electrical cerebellar fastigial nucleus stimulation (FNS) in VD treatment, as well as the effect of FNS on autophagy and inflammation.MethodsA Morris water maze was used to evaluate the effect of FNS on the learning and memory ability of VD rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to study the apoptosis status of neuron cells in different groups of rats. In addition, immunohistochemistry (IHC) assay, real‐time polymerase chain reaction, and Western blot analysis were carried out to measure the expression of various factors involved in autophagy and inflammation.ResultsRats with artery occlusion or FSN damages showed longer escape latency and spent less time in the target quadrant. In addition, FNS treatment could help to partly recover the lost learning and memory ability in VD rats. Meanwhile, FNS treatment could alleviate neuron cell apoptosis by downregulating light chain 3‐II expression and NLRP3 expression. In addition, the expression of caspase‐1, interleukin 1β (IL‐1β), and IL‐18 was markedly reduced in VD rats treated by FNS.ConclusionFNS treatment exerted a therapeutic effect during VD treatment by suppressing the autophagy process and by inhibiting inflammatory responses, thus alleviating neuron cell apoptosis and reducing the severity of VD.