bluuebunny/crossref_metadata_2025_split huggingface dataset:
The meaning of gross tumor type in the aspects of cytokeratin 19 expression and resection margin in patients with hepatocellular carcinoma
Authors: Gong Sung Chan , Cho Mee‐Yon , Lee Sang Woo , Kim Sung Hoon , Kim Moon Young , Baik Soon Koo 
Published: July 2015

AbstractBackground:There is no consensus on the safe resection margin in patients with hepatocellular carcinoma. Surgeons decide the extent of resection according to residual liver function and tumor location. We investigated the influence of resection margin on early recurrence with respect to gross tumor type and expression of cytokeratin 19 (CK19).Methods:We divided the patients into two groups based on the classification of The Korean Liver Cancer Study group as follows: group 1 included expanding and vaguely nodular types whereas group 2 included nodular with perinodular extension, multinodular confluent, and infiltrative types. We classified the resection margin as narrow (0.1–0.9 cm) or wide (greater than 1 cm). We compared clinicopathological features and CK19 positivity between the groups.Results:Group 2 had a higher prevalence of gross portal vein invasion, microscopic portal vein invasion, microvessel invasion, satellite nodules, intrahepatic metastasis, multicentric occurrence, and positivity for CK19. Group 1 showed no difference in recurrence according to the resection margin; however, group 2 showed a higher recurrence rate in patients with a narrow resection margin compared with those with a wide resection margin (P = 0.047). Patients in group 2 with CK19 positivity showed a higher prevalence of microvessel invasion than those without CK19 (P = 0.026).Conclusions:Although our study has the limitation of a small number of cases, the data suggest that patients with hepatocellular carcinoma of expanding and vaguely nodular gross types may safely undergo surgical resection with a narrow resection margin and a low risk of early recurrence.
Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α‐synuclein in oligodendroglial cells
Authors: Pukaß Katharina , Goldbaum Olaf , Richter‐Landsberg Christiane 
Published: July 2015

Abstractα‐Synuclein (α‐syn)‐containing glial cytoplasmic inclusions originating in oligodendrocytes are characteristically observed in multiple system atrophy. The mechanisms of glial cytoplasmic inclusion formation remain rather elusive. α‐Syn over‐expression, uptake from the environment, oxidative stress or impairment of the proteolytic degradation systems have been discussed. Here, we investigated whether in oligodendrocytes autophagy plays a major role in the degradation and aggregation of endogenously expressed α‐syn and of α‐syn taken up from the extracellular environment. Furthermore, we studied whether in cells with impaired mitochondria the accumulation and aggregation of exogenously added α‐syn is promoted. Using primary cultures of rat brain oligodendrocytes and an oligodendroglial cell line, genetically engineered to express green fluorescent protein–microtubule‐associated light chain 3 with or without α‐syn to monitor the autophagic flux, we demonstrate that both exogenously applied α‐syn and α‐syn stably expressed endogenously are effectively degraded by autophagy and do not affect the autophagic flux per se. Mitochondrial impairment with the protonophore carbonyl cyanide 3‐chlorophenylhydrazone or 3‐nitropropionic acid disturbs the autophagic pathway and leads to the accumulation of exogenously applied α‐syn and enhances its propensity to form aggregates intracellularly. Thus, mitochondrial dysfunction and oxidative stress, which occur over time and are significant pathological features in synucleinopathies, have an impact on the autophagic pathway and participate in pathogenesis.
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Glial cytoplasmic inclusions are characteristically observed in multiple system atrophy, their occurrence might be related to failure in protein degradation systems. Here, we show that in oligodendrocytes autophagy is the major route of α‐synuclein degradation which is either endogenously expressed or added exogenously (1, 2). Mitochondrial impairment (3) disturbs the autophagic flux and leads to the accumulation of exogenously applied α‐synuclein, and enhances its propensity to form aggregates intracellulary (4).
DISC1 regulates expression of the neurotrophin VGF through the PI3K/AKT/CREB pathway
Authors: Rodríguez‐Seoane Carmen , Ramos Adriana , Korth Carsten , Requena Jesús R. 
Published: July 2015

AbstractDisrupted in schizophrenia (DISC1) is a risk factor for chronic mental disease. In a previous proteomic study, we reported that knocking down DISC1 results in a sharp decrease in the levels of the neuropeptide precursor VGF (non‐acronymic) and leads to reduced activation of cAMP response element‐binding protein (CREB) and protein kinase B (AKT) in neurons. The main objective of this study is to complete the characterization of the route, or routes, involving AKT and CREB through which DISC1 modulates the expression of VGF. For that we explored known players upstream of AKT and the DISC1 binding partners glycogen synthase kinase‐3 beta and Phosphodiesterase‐4, which might in turn reach out to CREB in murine neuron primary culture. We found that DISC1 modulates the activation of Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K). Furthermore, pharmacological inhibition of PI3K resulted in decreased expression of VGF. All this suggests that the PI3K/AKT pathway plays a role in mediating the effects of DISC1 silencing on VGF expression. Given the important roles of VGF in mental disease, and its drugability, the DISC1‐VGF connection might prove to be important for efforts to develop new therapies for these diseases.
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Our data show that DISC1 regulates the activation state of the PI3K/AKT/CREB signaling route and in turn, contributes to regulate the expression of the neuropeptide precursor VGF in neurons. DISC1 might modulate this molecular pathway by regulating the localization of Grb2 in the cell that promotes the activation of PI3K. Given the important roles of VGF in mental disease, the DISC1‐VGF connection might prove to be important for efforts to develop new therapies for these devastating diseases.
GABAB receptors couple to Gαq to mediate increases in voltage‐dependent calcium current during development
Authors: Karls Andrew , Mynlieff Michelle 
Published: July 2015

AbstractMetabotropic GABAB receptors are known to modulate the activity of voltage‐dependent calcium channels. Previously, we have shown that GABAB receptors couple to a non‐Gi/o G‐protein to enhance calcium influx through L‐type calcium channels by activating protein kinase C in neonatal rat hippocampal neurons. In this study, the components of this signaling pathway were investigated further. Gαq was knocked down using morpholino oligonucleotides prior to examining GABAB‐mediated enhancement of calcium influx. When Gαq G‐proteins were eliminated using morpholino‐mediated knockdown, the enhancing effects of the GABAB receptor agonist baclofen (10 μM) on calcium current or entry were eliminated. These data suggest that GABAB receptors couple to Gαq to regulate calcium influx. Confocal imaging analysis illustrating colocalization of GABAB receptors with Gαq supports this hypothesis. Furthermore, baclofen treatment caused translocation of PKCα (protein kinase C α) but not PKCβ or PKCε, suggesting that it is the α isoform of PKC that mediates calcium current enhancement. Inhibition of calcium/calmodulin‐dependent kinase II did not affect the baclofen‐mediated enhancement of calcium levels. In summary, activation of GABAB receptors during development leads to increased calcium in a subset of neurons through Gαq signaling and PKCα activation without the involvement of calcium/calmodulin‐dependent kinase II.
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Activation of GABAB receptors in the neonatal rat hippocampus enhances voltage‐dependent calcium currents independently of Gi/o. In this study, knockdown of Gαq with morpholino oligonucleotides abolished enhancement of calcium influx and protein kinase Cα was activated by GABAB receptors. Therefore, we hypothesize that GABAB receptors couple to Gq to activate PKCα leading to enhancement of L‐type calcium current.
Live imaging of endogenous Ca2+/calmodulin‐dependent protein kinase II in neurons reveals that ischemia‐related aggregation does not require kinase activity
Authors: Barcomb Kelsey , Goodell Dayton J. , Arnold Don B. , Bayer K. Ulrich 
Published: July 2015

AbstractThe Ca2+/calmodulin‐dependent protein kinase II (CaMKII) forms 12meric holoenzymes. These holoenzymes cluster into larger aggregates within neurons under ischemic conditions and in vitro when ischemic conditions are mimicked. This aggregation is thought to be mediated by interaction between the regulatory domain of one kinase subunit with the T‐site of another kinase subunit in a different holoenzyme, an interaction that requires stimulation by Ca2+/CaM and nucleotide for its induction. This model makes several predictions that were verified here: Aggregation in vitro was reduced by the CaMKII inhibitors tatCN21 and tatCN19o (which block the T‐site) as well as by KN93 (which is CaM‐competitive). Notably, these and previously tested manipulations that block CaMKII activation all reduced aggregation, suggesting an alternative mechanism that instead requires kinase activity. However, experiments with the nucleotide‐competitive broad‐spectrum kinase inhibitors staurosporin and H7 showed that this is not the case. In vitro, staurosporine and H7 enabled CaMKII aggregation even in the absence of nucleotide. Within rat hippocampal neurons, an intra‐body enabled live monitoring of endogenous CaMKII aggregation. This aggregation was blocked by tatCN21, but not by staurosporine, even though both effectively inhibit CaMKII activity. These results support the mechanistic model for CaMKII aggregation and show that kinase activity is not required.
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CaMKII aggregation is prevented by inhibiting kinase activity with mutations (red italics; shown previously) or inhibitors (red bold; shown here), indicating requirement of kinase activity. However, we show here that nucleotide‐competitive inhibitors (green) allow CaMKII aggregation (including endogenous CaMKII within neurons), demonstrating that kinase activity is not required and supporting the current mechanistic model for CaMKII aggregation.
Elevated dopamine concentration in light‐adapted zebrafish retinas is correlated with increased dopamine synthesis and metabolism
Authors: Connaughton Victoria P. , Wetzell Bradley , Arneson Lynne S. , DeLucia Vittoria , L. Riley Anthony 
Published: July 2015

AbstractProbing zebrafish (Danio rerio) retinal cryostat sections, collected either 8 h into the light or dark cycle, with an antibody against tyrosine hydroxylase (TH) identified a single population of immunopositive cells in the inner retina. However, the observed labeling patterns were not identical in both sets of tissues – label intensity was brighter in light‐adapted tissue. This difference was quantified by probing western blots of retinal homogenates with the same TH antibody, which showed that TH expression increased by 42% in light‐adapted tissue. High‐performance liquid chromatography with electrochemical detection revealed that the concentrations of both dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) are also elevated in light‐adapted zebrafish retinal tissue. Dopamine levels increased by 14% and DOPAC levels increased by 25% when measured in retinal homogenates harvested during the light cycle. These results indicate that dopamine levels in zebrafish retina are significantly increased in light‐adapted tissue. The increase in dopamine content is correlated with an increase in both TH and DOPAC, suggesting that changes in dopamine concentration are due to light‐adaptive changes in the synthesis, release and metabolism of dopamine.
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Dopamine concentration is elevated in lighted‐adapted zebrafish retinas. This increase is correlated with an increase in both tyrosine hydroxylase (TH) and DOPAC (3,4‐dihydroxyphenylacetic acid), suggesting that changes in dopamine concentration are due to light‐adaptive changes in the synthesis, release and metabolism of dopamine. This is applicable to studies examining retinal mutants, the role of dopamine in disease or visual system development.
Corticotropin releasing factor up‐regulates the expression and function of norepinephrine transporter in SK‐N‐BE (2) M17 cells
Authors: Huang Jingjing , Tufan Turan , Deng Maoxian , Wright Gary , Zhu Meng‐Yang 
Published: July 2015

AbstractCorticotropin releasing factor (CRF) has been implicated to act as a neurotransmitter or modulator in central nervous activation during stress. In this study, we examined the regulatory effect of CRF on the expression and function of the norepinephrine transporter (NET) in vitro. SK‐N‐BE (2) M17 cells were exposed to different concentrations of CRF for different periods. Results showed that exposure of cells to CRF significantly increased mRNA and protein levels of NET in a concentration‐ and time‐dependent manner. The CRF‐induced increase in NET expression was mimicked by agonists of either CRF receptor 1 or 2. Furthermore, similar CRF treatments induced a parallel increase in the uptake of [3H] norepinephrine. Both increased expression and function of NET caused by CRF were abolished by simultaneous administration of CRF receptor antagonists, indicating a mediation by CRF receptors. However, there was no additive effect for the combination of both receptor antagonists. Chromatin immunoprecipitation assays confirm an increased acetylation of histone H3 on the NET promoter following treatment with CRF. Taken together, this study demonstrates that CRF up‐regulates the expression and function of NET in vitro. This regulation is mediated through CRF receptors and an epigenetic mechanism related to histone acetylation may be involved. This CRF‐induced regulation on NET expression and function may play a role in development of stress‐related depression and anxiety.
imageThis study demonstrated that corticotropin release factor (CRF) up‐regulated the expression and function of norepinephrine transporter (NET) in a concentration‐ and time‐dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress‐related physiological and pathological status.
Granulomatous reaction to red tattoo pigment treated with allopurinol
Authors: Godinho Mariana Marteleto , Aguinaga Felipe , Grynszpan Rachel , Lima Victor Maselli , Azulay David Rubem , Cuzzi Tullia , Ramos‐e‐Silva Marcia , Manela‐Azulay Mônica 
Published: July 2015

SummaryGranulomatous reactions to tattoo ink are most commonly associated with mercury sulfide, a component of red pigments. Treatment options show limited results. Allopurinol, an inhibitor of xanthine oxidase, has been reported as a successful alternative treatment to granulomatous disorders, such as sarcoidosis and granulomatous reactions to fillers and tattoos. We report a case of granulomatous reaction to red tattoo pigment treated with allopurinol for 6 months. Good clinical improvement could be noticed during this time. Two months after we stopped the treatment, the lesion recurred. Allopurinol emerges as an important drug for the management of granulomatous reactions caused by tattoo pigments. Based on the significant clinical improvement noticed during its use, we recommend new studies to elucidate all the potential benefits of the use of allopurinol for the treatment of granulomatous reactions to tattoo ink.
Human autoimmune diseases: a comprehensive update
Authors: Wang Lifeng , Wang Fu‐Sheng , Gershwin M. Eric 
Published: July 2015

AbstractThere have been significant advances in our understanding of human autoimmunity that have led to improvements in classification and diagnosis and, most importantly, research advances in new therapies. The importance of autoimmunity and the mechanisms that lead to clinical disease were first recognized about 50 years ago following the pioneering studies of Macfarlane Burnett and his Nobel Prize‐winning hypothesis of the ‘forbidden clone’. Such pioneering efforts led to a better understanding not only of autoimmunity, but also of lymphoid cell development, thymic education, apoptosis and deletion of autoreactive cells. Contemporary theories suggest that the development of an autoimmune disease requires a genetic predisposition and environmental factors that trigger the immune pathways that lead, ultimately, to tissue destruction. Despite extensive research, there are no genetic tools that can be used clinically to predict the risk of autoimmune disease. Indeed, the concordance of autoimmune disease in identical twins is 12–67%, highlighting not only a role for environmental factors, but also the potential importance of stochastic or epigenetic phenomena. On the other hand, the identification of cytokines and chemokines, and their cognate receptors, has led to novel therapies that block pathological inflammatory responses within the target organ and have greatly improved the therapeutic effect in patients with autoimmune disease, particularly rheumatoid arthritis. Further advances involving the use of multiplex platforms for diagnosis and identification of new therapeutic agents should lead to major breakthroughs within the next decade.
An evidence‐based approach to improving the quality of resource‐oriented well‐being interventions at work
Authors: Briner Rob B. , Walshe Neil D. 
Published: July 2015

Although there is much research on the links between work and well‐being, there is relatively little good‐quality research on resource‐based or other interventions such as more traditional stress management and job redesign. This paper provides guidance about how to improve the quality of intervention research. First, drawing on the logic of interventions and principles of evidence‐based practice, we take the example of a relatively simple resource‐oriented intervention to identify 11 key characteristics that we would expect to see in an evidence‐based intervention of this type. These characteristics and their underlying principles can be used to evaluate the quality of existing intervention studies and guide the design of future interventions. Second, we discuss an evidence‐based approach to reporting the process and the outcomes of interventions. Providing only limited information about an intervention means that it is difficult to replicate or use that method in practice. We describe a checklist developed in a more mature evidence‐based field (medicine) that can be used to ensure that sufficient intervention details are reported. Next, we discuss the importance of reporting all the outcomes of all interventions. Last, we consider the ways in which this approach to improving interventions is not only important scientifically and practically but also ethically.Practitioner points

Although many resource‐oriented well‐being interventions are available, their effectiveness is not always known, and they may be implemented without initial diagnosis.

An evidence‐based practice approach to intervention involves using local organizational evidence as well as evidence from scientific research.

Before implementing an intervention, it is important to gather information from the target population to ensure, for example, that there is a significant well‐being problem and that it is amenable to change, as well as seeking out research evidence for the efficacy of the intervention.

This approach is useful in terms of practice but also helps to ensure that we are working in an ethical way.
Perspectives on next steps in classification of oro‐facial pain – part 1: role of ontology
Authors: Ceusters W. , Michelotti A. , Raphael K. G. , Durham J. , Ohrbach R. 
Published: July 2015

SummaryThe purpose of this study was to review existing principles of oro‐facial pain classifications and to specify design recommendations for a new system that would reflect recent insights in biomedical classification systems, terminologies and ontologies. The study was initiated by a symposium organised by the International RDC/TMD Consortium Network in March 2013, to which the present authors contributed. The following areas are addressed: problems with current classification approaches, status of the ontological basis of pain disorders, insufficient diagnostic aids and biomarkers for pain disorders, exploratory nature of current pain terminology and classification systems, and problems with prevailing classification methods from an ontological perspective. Four recommendations for addressing these problems are as follows: (i) develop a hypothesis‐driven classification structure built on principles that ensure to our best understanding an accurate description of the relations among all entities involved in oro‐facial pain disorders; (ii) take into account the physiology and phenomenology of oro‐facial pain disorders to adequately represent both domains including psychosocial entities in a classification system; (iii) plan at the beginning for field‐testing at strategic development stages; and (iv) consider how the classification system will be implemented. Implications in relation to the specific domains of psychosocial factors and biomarkers for inclusion into an oro‐facial pain classification system are described in two separate papers.
Association of OCT4, SOX2, and NANOG expression with oral squamous cell carcinoma progression
Authors: Fu Ting‐Ying , Hsieh I‐Chien , Cheng Jiin‐Tsuey , Tsai Meng‐Han , Hou Yu‐Yi , Lee Jang‐Hwa , Liou Huei‐Han , Huang Sheng‐Feng , Chen Hung‐Chih , Yen Leing‐Ming , Tseng Hui‐Hwa , Ger Luo‐Ping 
Published: July 2015

BackgroundOCT4, SOX2, and NANOG are major transcription factors related to stem cell self‐renewal and differentiation. The aim of this study was to examine the association of OCT4, SOX2, and NANOG expression levels with the development and prognosis of patients with oral squamous cell carcinoma (OSCC).Materials and MethodsExpression levels of OCT4, SOX2, and NANOG were evaluated by immunohistochemistry with tissue microarray slides of 436 OSCC, 362 corresponding tumor‐adjacent normal (CTAN) tissues, and 71 normal uvula epithelium tissues. The clinicopathologic and follow‐up data of the OSCC patients were recorded.ResultsOCT4 expression was significantly higher in normal and CTAN tissues than in tumor tissue (both P < 0.001). SOX2 expression in CTAN tissue was significantly higher than that in normal (P = 0.021) and tumor tissues (P < 0.001). However, NANOG expression was significantly higher in CTAN (P = 0.014) and tumor tissues (P = 0.009) than in normal tissue. Higher OCT4 and SOX2 expressions were associated with earlier AJCC stage (P = 0.002 and P < 0.001), small tumor size (P = 0.017 and P = 0.001), and the absence of lymph node metastasis (P = 0.015 and P = 0.025). Higher levels of SOX2 expression were associated with better disease‐specific survival (P = 0.002) even after adjustment for clinicopathologic factors.DiscussionOCT4 and SOX2 are biomarkers of tumorigenesis and early stage OSCC. SOX2 is an independent prognostic factor for OSCC.