bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal distribution of glia in and around the developing mouse optic tract
Authors: Lee Melissa A. , Sitko Austen A. , Khalid Sania , Shirasu‐Hiza Mimi , Mason Carol A.
Published: May 2018

In the developing mouse optic tract, retinal ganglion cell (RGC) axon position is organized by topography and laterality (i.e., eye‐specific or ipsi‐ and contralateral segregation). Our lab previously showed that ipsilaterally projecting RGCs are segregated to the lateral aspect of the developing optic tract and found that ipsilateral axons self‐fasciculate to a greater extent than contralaterally projecting RGC axons in vitro. However, the full complement of axon‐intrinsic and ‐extrinsic factors mediating eye‐specific segregation in the tract remain poorly understood. Glia, which are known to express several guidance cues in the visual system and regulate the navigation of ipsilateral and contralateral RGC axons at the optic chiasm, are natural candidates for contributing to eye‐specific pre‐target axon organization. Here, we investigate the spatiotemporal expression patterns of both putative astrocytes (Aldh1l1+ cells) and microglia (Iba1+ cells) in the embryonic and neonatal optic tract. We quantified the localization of ipsilateral RGC axons to the lateral two‐thirds of the optic tract and analyzed glia position and distribution relative to eye‐specific axon organization. While our results indicate that glial segregation patterns do not strictly align with eye‐specific RGC axon segregation in the tract, we identify distinct spatiotemporal organization of both Aldh1l1+ cells and microglia in and around the developing optic tract. These findings inform future research into molecular mechanisms of glial involvement in RGC axon growth and organization in the developing retinogeniculate pathway.
Formulation and In Vitro, In Vivo Correlation Between Two Candesartan Cilexetil Tablets
Authors: Zaid Abdel Naser , Radwan Asma , Jaradat Nidal , Mousa Ayman , Ghazal Nadia , Bustami Rana
Published: May 2018

In this study, the in vitro and in vivo interchangeability between generic candesartan 16 mg and the branded formulation was assessed. The in vitro release of these products was conducted in 3 pH media (1.2, 5.0, and 6.8), and similarity factors (f2) were calculated. This bioequivalence study was a randomized, 2‐period crossover study that included 42 healthy adult male subjects under fasting conditions with a 9‐day washout. The pharmacokinetic (PK) parameters AUC0‐last, AUC0‐∞, and Cmax, tmax, and the elimination half‐life time were assessed based on the plasma concentrations of candesartan, using a newly developed and validated liquid chromatography‐tandem mass spectrometry bioanalytical method with acceptable degrees of linearity, sensitivity, precision, and accuracy. The geometric mean (ng·h/mL) of the AUC0‐∞ for the test and brand was 1595.49 and 1620.54, respectively, and the Cmax (ng/mL) was 160.91 and 160.88, respectively. The 90%CIs of geometric mean ratios (test‐to‐reference ratios) were 98.26%, 98.45%, and 99.86% for AUC0‐last, AUC0‐∞, and Cmax respectively. These PK parameters lie within the US Food and Drug Administration– and European Medicines Agency–specified bioequivalence limit (80%‐125%). Both products were well tolerated by all the subjects. The tested drug product was bioequivalent to the reference drug and had the same safety profile.
The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways
Authors: Zhou Hong , Sun Yonghong , Zhang Lihui , Kang Wenyuan , Li Na , Li Yongjun
Published: May 2018

Aims

To understand the roles of the RhoA/ROCK and mitogen‐activated protein kinase (MAPK) pathways in high glucose (HG)‐induced apoptosis and oxidative stress in cardiomyocytes.

Materials and methods

Neonatal rat cardiomyocytes were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 30 mmol/L D‐glucose, in the presence or absence of fasudil (50 or 100 μM), SB203580, SP600125, or PD98059 (10 μM, respectively). The percentage of early apoptotic cardiomyocytes was evaluated using flow cytometry. The superoxide dismutase activity and malondialdehyde contents in the cellular supernatants were measured. The Bax and Bcl‐2 mRNA levels were determined by quantitative real‐time PCR. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1), p38MAPK, JNK, and ERK as well as the protein levels of Bax, Bcl‐2, and cleaved caspase‐3 was analysed by Western blot.

Results

Fasudil, SB203580, and SP600125 effectively inhibited the HG‐induced early apoptosis increase and decreased Bax mRNA expression, the Bax/Bcl‐2 protein expression ratio, and cleaved caspase‐3 protein levels in the cardiomyocytes; this was accompanied by upregulation of the Bcl‐2 mRNA. Moreover, fasudil markedly increased the superoxide dismutase activity level and suppressed the elevation in HG‐induced malondialdehyde content and the phosphorylation of MYPT1, p38MAPK and JNK.

Conclusions

The RhoA/ROCK pathway mediates HG‐induced cardiomyocyte apoptosis via oxidative stress and activation of p38MAPK and JNK in neonatal rats in vitro. Fasudil effectively ameliorates HG‐induced cardiomyocyte apoptosis by suppressing oxidative stress and the p38MAPK and JNK pathways.
Synthesis of Polycyclic Spironaphthofuran Derivatives by Acid‐Catalyzed Domino Reaction of 2‐Naphthols with Tetraarylbut‐2‐yne‐1,4‐diols
Authors: Sousa Céu M. , Berthet Jerome , Delbaere Stephanie , Coelho Paulo J.
Published: May 2018

The acid‐catalyzed condensation of 2‐naphthols with tetraphenylbut‐2‐yne‐1,4‐diols affords a mixture of spiro[indene‐1,1′‐naphthofurans] and dinaphthofurans through a cascade of intramolecular reactions, whereas using the more reactive thienyltriphenylbut‐2‐yne‐1,4‐diol leads to the formation of a single spiranic compound joining a cyclopenta[b]thiophene to a naphtho[2,1‐b]furan.
Are socio‐emotional and neurocognitive functioning predictors of therapeutic outcomes for adults with anorexia nervosa?
Authors: Oldershaw Anna , Lavender Tony , Schmidt Ulrike
Published: May 2018

Background

Emotional, social, and neurocognitive factors are theorised to maintain anorexia nervosa (AN). Yet whether they predict outcomes or relate to clinical change remains unclear.

Methods

Seventy‐one consecutive adult outpatient eating disorder service referrals presenting with AN, who participated in a randomised controlled trial comparing 2 psychotherapies, were assessed for emotional processing, social cognition, and neurocognition pretherapy and posttherapy. Intention‐to‐treat analysis employed maximum‐likelihood methods to model missing data. Baseline self‐reported emotional processing, social cognitive, or neurocognitive task performance was entered into forward stepwise regression models with posttreatment clinical outcomes (weight, eating disorder psychopathology, psychosocial functioning) as dependent variables. Correlation analyses examined relationships between clinical and self‐report/task score change.

Results

Self‐reported emotional avoidance (behavioural/cognitive avoidance, low acceptance) and submissive behaviour predicted clinical outcomes. Social cognitive (emotion recognition, emotional theory of mind) and neurocognitive performance (set‐shifting, detail focus) had limited predictive ability.

Conclusions

Emotional avoidance and submissiveness may represent maintenance factors for AN.
Special Issue: Gravel Bed Rivers 8
Authors: Laronne Jonathan B. , Tsutsumi Daizo
Published: May 2018

Theoretical, modeling, experimental and monitoring of sediment transport in gravel bed rivers are introduced. The key findings of 27 papers on this theme were published in Earth Surface Processes and Landforms during the past year. Among these, 18 papers were published by attendants of the 8th Gravel Bed River Workshop held in Japan in 2015. This Commentary introduces the main themes associated with these papers including innovations in sediment transport conceptualization and modeling and monitoring, and also three wider themes: the importance of sediment supply; relationships between gravel bed river science and restoration; and the growing recognition of the critical role played by wood in gravel bed rivers. Copyright © 2018 John Wiley & Sons, Ltd.
Cooperative NOMA with full‐duplex amplify‐and‐forward relaying
Authors: Abbasi Omid , Ebrahimi Afshin
Published: May 2018

In this paper, we study the performance of a cooperative non‐orthogonal multiple access (NOMA) system with a dedicated relay. This relay is full duplex (FD) and works in an amplify‐and‐forward (AF) mode. Our NOMA system consists of two users where one of them is near to the base station and the other one is assumed to be far from the base station. We derive exact expressions for outage probability and ergodic achievable rate of two NOMA users. The simulations demonstrate that in the case of imperfect self‐interference cancelation, our proposed FD‐AF relaying scheme has better performance rather than FD decode‐and‐forward NOMA scheme. In addition, we calculate the outage probability of users in high signal‐to‐noise ratio (SNR) regime and derive diversity order of unity for each of NOMA users. We show that in high SNRs, the ergodic achievable rate of near user increases with transmit SNR, but the rate of far user tends to a fixed value. Ergodic sum rate expression in high SNR regime shows that it is independent of NOMA power allocation coefficient and increases log‐linearly with transmit SNR. Finally, we verify our analytical formulas for outage probability and ergodic achievable rate by Monte Carlo simulations.
Using Natural Disturbance and Portfolio Concepts to Guide Aquatic–Riparian Ecosystem Management
Authors: Penaluna Brooke E , Reeves Gordon H , Barnett Zanethia C , Bisson Peter A , Buffington John M , Dolloff C. Andrew , Flitcroft Rebecca L , Luce Charles H , Nislow Keith H , Rothlisberger John D , Warren Melvin L
Published: May 2018

The U.S. Forest Service and other federal land managers are responsible for maintaining the productivity of aquatic–riparian ecosystems, the associated native biota, and the ecosystem services they provide. These public lands are important sources of water, recreation opportunities, and habitat for a suite of animals and plants, including many that are protected under the Endangered Species Act. To meet these challenges and responsibilities, recent science suggests modifying practices to provide a broader array of habitat, biological conditions, and ecosystem functions than are associated with traditional management approaches. We suggest that by linking approaches based on natural disturbance and portfolio concepts, managers can achieve a robust strategy and desired outcomes more reliably and cost effectively. Locally complex habitat conditions created by natural disturbances provide the template for biological diversity to play out if provided enough time. Accordingly, natural disturbance regimes play an important role in creating and sustaining habitat and biological complexities on the landscape, suggesting that, to the extent possible, management actions should emulate natural disturbance processes at appropriate spatial and temporal scales. In concert with this approach, the portfolio effect (i.e., diversity that mitigates risk) provides justification for promoting connected heterogeneous habitats that reduce the risk of synchronous large-scale population and ecosystem collapse. In this article, we describe how disturbance and portfolio concepts fit into a broader strategy of conserving ecosystem integrity and dynamism and provide examples of how these concepts can be used to address a wide range of management concerns. Ultimately, the outcome for populations, habitats, and landscapes depends on how well environmental change is understood, the degree to which change is appropriately addressed by natural resource managers, and solutions that allow populations and ecosystems to persist in the presence of and be resilient to a growing scope of human influences.
Historical Perspectives and a New U.S. Forest Service Strategy for Fish and Aquatic Stewardship
Authors: Shively Dan , Rothlisberger John D , Gillespie Nathaniel , Dombeck Mike , Moore Virgil , Roghair Craig , Demario Devin , McCormick Frank , Weldon Leslie
Published: May 2018

The U.S. Forest Service has a long, rich history of helping to steward the nation's fish and aquatic resources and contributing to the broader fish and aquatic conservation and scientific community in the United States and worldwide. The agency recently updated its national strategy for fish and aquatic resource stewardship. The new strategy builds on 30 years of lessons learned through implementing the agency's original Rise to the Future: National Fish and Aquatic Strategy, the first national freshwater fisheries strategy by a federal agency. It also addresses 21st century challenges, establishing a stronger foundation for integrated aquatic resource stewardship throughout the agency and renewing an emphasis on cooperation with local, state, federal, and tribal governments and partnering with nongovernmental organizations, private landowners and water users, private businesses, the sportfishing industry, and others. The new strategy outlines six goals that provide a robust framework to guide future efforts: (1) conserve fish and aquatic resources; (2) connect people to the outdoors through fishing, boating, and other aquatic activities; (3) strengthen partnerships and work across boundaries; (4) deliver and apply scientific research; (5) build capacity through mentoring and training; and (6) communicate the value of fish and aquatic resources.
The role of urban growth, climate change, and their interplay in altering runoff extremes
Authors: Arnone Elisa , Pumo Dario , Francipane Antonio , La Loggia Goffredo , Noto Leonardo V.
Published: May 2018

Changes in climate and urban growth are the most influential factors affecting hydrological characteristics in urban and extra‐urban contexts. The assessment of the impacts of these changes on the extreme rainfall–runoff events may have important implications on urban and extra‐urban management policies against severe events, such as floods, and on the design of hydraulic infrastructures.

Understanding the effects of the interaction between climate change and urban growth on the generation of runoff extremes is the main aim of this paper. We carried out a synthetic experiment on a river catchment of 64 km2 to generate hourly runoff time series under different hypothetical scenarios. We imposed a growth of the percentage of urban coverage within the basin (from 1.5% to 25%), a rise in mean temperature of 2.6 °C, and an alternatively increase/decrease in mean annual precipitation of 25%; changes in mean annual precipitation were imposed following different schemes, either changing rainstorm frequency or rainstorm intensity. The modelling framework consists of a physically based distributed hydrological model, which simulates fast and slow mechanisms of runoff generation directly connected with the impervious areas, a land‐use change model, and a weather generator. The results indicate that the peaks over threshold and the hourly annual peaks, used as hydrological indicators, are very sensitive to the rainstorm intensity. Moreover, the effects of climate changes dominate on those of urban growth determining an exacerbation of the fast runoff component in extreme events and a reduction of the slow and deep runoff component, thus limiting changes in the overall runoff.
Heterogeneity in risk of prostate cancer: ASwedish population‐based cohort study of competing risks and Type 2 diabetes mellitus
Authors: Häggström Christel , Van Hemelrijck Mieke , Garmo Hans , Robinson David , Stattin Pär , Rowley Mark , Coolen Anthony C.C. , Holmberg Lars
Published: May 2018

Most previous studies of prostate cancer have not taken into account that men in the studied populations are also at risk of competing event, and that these men may have different susceptibility to prostate cancer risk. The aim of our study was to investigate heterogeneity in risk of prostate cancer, using a recently developed latent class regression method for competing risks. We further aimed to elucidate the association between Type 2 diabetes mellitus (T2DM) and prostate cancer risk, and to compare the results with conventional methods for survival analysis. We analysed the risk of prostate cancer in 126,482 men from the comparison cohort of the Prostate Cancer Data base Sweden (PCBaSe) 3.0. During a mean follow‐up of 6 years 6,036 men were diagnosed with prostate cancer and 22,393 men died. We detected heterogeneity in risk of prostate cancer with two distinct latent classes in the study population. The smaller class included 9% of the study population in which men had a higher risk of prostate cancer and the risk was stronger associated with class membership than any of the covariates included in the study. Moreover, we found no association between T2DM and risk of prostate cancer after removal of the effect of informative censoring due to competing risks. The recently developed latent class for competing risks method could be used to provide new insights in precision medicine with the target to classify individuals regarding different susceptibility to a particular disease, reaction to a risk factor or response to treatment.
Low serum cholesterol levels predict inferior prognosis and improve NCCN‐IPI scoring in diffuse large B cell lymphoma
Authors: Gao Rui , Liang Jin‐Hua , Wang Li , Zhu Hua‐Yuan , Wu Wei , Cao Lei , Fan Lei , Li Jian‐Yong , Yang Tao , Xu Wei
Published: May 2018

Low circulating cholesterol concentration is associated with elevated cancer incidence and mortality. However, the association between cholesterol levels and diffuse large B cell lymphoma (DLBCL) remains unknown. The aim of our study was to evaluate the prognostic value of serum lipid profile in DLBCL. Five hundred and fifty enrolled subjects with detailed serum lipid levels at diagnosis of DLBCL were randomly divided into a training set (n = 367) and a validation set (n = 183) (ratio, 2:1). Multivariate Cox regression analyses screened the prognostic factors associated with progression‐free survival (PFS) and overall survival (OS). Performances of models were compared using C‐index and area under the curve in internal and external validation. The results showed that decreased levels of total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) were associated with unfavorable PFS and OS in the rituximab era, and concurrently low HDL‐C together with low LDL‐C was an independent prognostic indicator for both PFS and OS. Patients achieving complete remission or partial remission after 6–8 circles of chemotherapies had significantly increased cholesterol levels compared to the levels at DLBCL diagnosis, and HDL‐C or LDL‐C elevations were correlated with better survival. Furthermore, the predictive and discriminatory capacity of the National Comprehensive Cancer Network (NCCN)‐International Prognostic Index (IPI) together with low cholesterol levels was superior to NCCN‐IPI alone both in the training and validation set. In conclusion, serum cholesterol levels are simple and routinely tested parameters, which may be good candidates for predicting prognosis in the future clinical practice of DLBCL.
Impact of Sea Level Rise and Tsunami on Coastal Areas of North‐West Peninsular Malaysia
Authors: Ghazali Nor Hisham M. , Awang Nor Aslinda , Mahmud Mahran , Mokhtar Arman
Published: May 2018

The states of Perlis, Kedah, Penang and Perak in the north‐west of Peninsular Malaysia have a total coastline of 550 km of which almost 40% are adjacent to agricultural lands. Parts of these lands were once intertidal and following their conversion into agricultural land, have been protected from the sea by coastal embankments since the 1950s. Extreme tides and wave erosion used to be the known hazards to these coastal lands, but over the past two decades sea level rise and the tsunami of 2004 have emerged as additional threats. A predicted sea level rise of 0.52 m by 2100 and a tsunami inundation distance exceeding 1000 m inshore have raised concerns as to the sustainability of existing coastal defences, hinterland communities and economic activities. The combined impacts of both sea level rise and tsunami have made the north‐west coastline the most vulnerable to coastal erosion and flooding. This paper compiles the findings of two key studies that assessed these coastal threats and determined the scientific basis for adaptive measures. The findings of the studies indicate that the north‐west coast is the most vulnerable coast in Peninsular Malaysia. The paper also presents the physical impacts of these threats and the proposed adaptive strategies to mitigate them. Copyright © 2018 John Wiley & Sons, Ltd.
A comparison of analysis methods to estimate contingency strength
Authors: Lloyd Blair P. , Staubitz Johanna L. , Tapp Jon T.
Published: May 2018

To date, several data analysis methods have been used to estimate contingency strength, yet few studies have compared these methods directly. To compare the relative precision and sensitivity of four analysis methods (i.e., exhaustive event‐based, nonexhaustive event‐based, concurrent interval, concurrent+lag interval), we applied all methods to a simulated data set in which several response‐dependent and response‐independent schedules of reinforcement were programmed. We evaluated the degree to which contingency strength estimates produced from each method (a) corresponded with expected values for response‐dependent schedules and (b) showed sensitivity to parametric manipulations of response‐independent reinforcement. Results indicated both event‐based methods produced contingency strength estimates that aligned with expected values for response‐dependent schedules, but differed in sensitivity to response‐independent reinforcement. The precision of interval‐based methods varied by analysis method (concurrent vs. concurrent+lag) and schedule type (continuous vs. partial), and showed similar sensitivities to response‐independent reinforcement. Recommendations and considerations for measuring contingencies are identified.
Spillovers among sovereign debt markets: Identification through absolute magnitude restrictions
Authors: De Santis Roberto A. , Zimic Srečko
Published: May 2018

This paper studies spillovers among US and European sovereign yields. We employ absolute magnitude restrictions on the impact matrix to identify the countries that were the main sources of spillovers. Despite the large size of shocks from euro area stressed countries, connectedness among sovereign yields declined between 2008 and 2012 due to financial fragmentation, particularly between countries with more divergent business and fiscal cycles. We show that none of the sovereign yields were insulated from foreign shocks and that shocks to the Greek bond market in 2010 explained 20–30% of the variance of sovereign yields in stressed countries, while in 2011–2012 Italy (not Spain) was the source of systemic risk.
Front Cover: Photoluminescence intensity ratio of Eu‐conjugated lactates—A simple optical imaging technique for biomarker analysis for critical diseases (J. Biophotonics 5/2018)
Authors: Kakkar Tarun , Thomas Nikita , Kumi‐Barimah Eric , Jose Gin , Saha Sikha
Published: May 2018

Eu3+integrated photoluminescence intensity ratio (PLIR) approach for optical detection of lactates in blood serum, plasma and confocal imaging of brain tissues has very high potential for exploitation of this technique in both in vitro monitoring and in vivo bioimaging applications for the detection of biomarkers in various diseases states. This image is diagrammatic representation of fact that the overall PLIR is higher with more lactates conjugated with Eu3+ ions.

Further details can be found in the article by Tarun Kakkar et al. (e201700199).

image
Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture
Authors: Sing Chor-Wing , Wong Angel YS , Kiel Douglas P , Cheung Elaine YN , Lam Joanne KY , Cheung Tommy T , Chan Esther W , Kung Annie WC , Wong Ian CK , Cheung Ching-Lung
Published: May 2018

The risk of cardiovascular events (CVEs) with alendronate use in real-world hip fracture patients is unknown. This study aimed to investigate the risk of CVE with and without use of alendronate in patients with hip fracture. We conducted a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with hip fracture from 2005 through 2013 were followed until November 6, 2016. Alendronate and other antiosteoporosis medications use during the study period were examined. We matched treated and nontreated patients based on time-dependent propensity score. The risks of cardiovascular mortality, myocardial infarction, and stroke between treatment groups were evaluated using conditional Cox regression stratified by match pairs. To examine the associations over time, outcomes were assessed at 1 year, 3 years, 5 years, and 10 years. Among 34,991 patients with newly diagnosed hip fracture, 4602 (13.2%) received antiosteoporosis treatment during follow-up. Physical functioning or survival prospect was not significantly different between treated and nontreated patients. A total of 4594 treated patients were matched with 13,568 nontreated patients. Results of Cox regression analysis revealed that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33; 95% CI, 0.17 to 0.65) and incident myocardial infarction (HR 0.55; 95% CI, 0.34 to 0.89), whereas marginally significant reduction in risk of stroke was observed at 5 years and 10 years (HR at 5 years: 0.82; 95% CI, 0.67 to 1.00; p = 0.049; HR at 10 years: 0.83; 95% CI, 0.69 to 1.01; p = 0.065). The strength of the association declined over time but remained significant. Similar results were observed when all nitrogen-containing bisphosphonates (N-BPs) were analyzed together. These findings were robust in multiple sensitivity analyses. Additional studies in other population samples and randomized clinical trials may be warranted to further understand the relationship between use of various antiosteoporosis medication and risk of CVE in patients with hip fracture. © 2018 American Society for Bone and Mineral Research.
Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9
Authors: Wang Jing‐Xian , Yang Yuan , Li Kun
Published: May 2018

Long non‐coding RNAs (lncRNAs) have been identified to play vital roles in cancers, including human retinoblastoma (RB). However, the deepgoing mechanism is still ambiguous. In present study, we investigate the biological role of lncRNA DANCR (differentiation antagonizing non‐protein coding RNA) in carcinogenesis of RB. Results revealed that DANCR was up‐regulated in RB tissue and cell lines. Moreover, the ectopic overexpression of DANCR indicated poor overall survivals and disease free survival (DFS) for RB patients. In vitro and in vivo experiments, DANCR knockdown suppress the proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) correlated protein (N‐cadherin, Vimentin) of RB cells. Bioinformatics analysis predicted that miR‐34c and miR‐613 targeted with 3′‐UTR of DANCR, besides, miR‐34c and miR‐613 also targeted with 3′‐UTR of MMP‐9, which was validated by luciferase reporter assay. Functional experiments demonstrated that miR‐34c and miR‐613 could reverse the oncogenic function of DANCR in RB tumorigenesis. In conclusion, our results reveal that DANCR function as competing endogenous RNA (ceRNA) for miR‐34c and miR‐613 to modulate progression and metastasis in RB oncogenesis via targeting MMP‐9, presenting the in‐depth regulation of DANCR in RB and providing a novel insight for ceRNA mechanism for RB.
Photobiomodulation therapy and vitamin C on longevity of cell sheets of human dental pulp stem cells
Authors: Pedroni Ana C.F. , Diniz Ivana M.A. , Abe Gabriela L. , Moreira Maria S. , Sipert Carla R. , Marques Márcia M.
Published: May 2018

Photobiomodulation therapy (PBMT) can improve processes relevant to tissue regeneration, such as survival, proliferation, migration, and differentiation of cells, including stem cells. Thus, PBMT could be applied as auxiliary therapy for tissue regeneration. Cell sheets (CSs) induced by vitamin C (VC) can generate large amount of cells, which would also be useful for tissue regeneration. VC and PBMT cause opposite effects on cell metabolism (e.g., VC is antioxidative, and PBMT generates reactive oxygen species); however, hDPSC CSs were formed when VC and PBMT+VC were applied. Thus, this study showed that PBMT does not interfere with the formation of cell sheets induced by VC. Additionally, PBMT improved the functional differentiation of the cells isolated from the CSs. Thus, due to the clinical benefits of PBMT, the association of this therapy with cell sheets seems promising for future applications in tissue regeneration.
Isolation and identification of chemotherapy‐enriched sphere‐forming cells from a patient with gastric cancer
Authors: Bagheri Vahid , Memar Bahram , Behzadi Ramezan , Aliakbarian Mohsen , Jangjoo Ali , Bahar Mostafa Mehrabi , Talebi Samaneh , Gholamin Mehran , Abbaszadegan Mohammad R.
Published: May 2018

Gastric cancer (GC) is the third and fifth cause of cancer‐associated mortality for men and women throughout the world, respectively. Despite the use of surgery and chemotherapy for GC therapy, there are no efficient therapeutic protocols for it to date. Cancer stem cells (CSCs) due to their pivotal role in tumor initiation, growth, progression, invasion, distant metastasis, recurrence and resistance to anticancer drugs are very appealing targets for cancer therapies. Here, we isolated and identified CSCs from a chemotherapy‐treated patient. Small subpopulation of dissociated cells after tissue digestion formed spheroid colonies in serum‐free media under the non‐adherent condition. These spheroid colonies differentiated into epithelial like cells in serum‐containing medium. Few sphere‐forming cells carried CD44 and CD54 markers overexpressed DLL4 that is responsible for tumor growth and angiogenesis. Subcutaneous injections of sphere‐forming cells in different passages conferred tumorigenicity in nude mice. Sphere‐forming cells upregulated CD44 polymorphisms CD44v3, ‐v6, and ‐v8 ‐10, stemness factors OCT4, SOX2, SALL4 and Cripto‐1, self‐renewal molecules IHh, Wnt, β‐catenin and BMI1, and epithelial mesenchymal transition (EMT) markers Twist1 and Snail1 in vitro and in vivo. Moreover, these cells similar to sphere‐forming cells isolated from a chemotherapy‐free patient expressed Oct‐4 and β‐catenin proteins. However, the Twist1 protein was only expressed by sphere‐forming cells derived from the chemotherapy‐treated patient. Thus, these cells have all the characteristics of stationary and migratory CSCs, including tumorigenicity, self‐renewal, pluripotency, invasion and metastasis. Taken together, targeting chemotherapy‐enriched CSCs as chemo‐resistance cells observed in GC patients can provide more effective therapeutic strategies compared to untreated patients.
Photochemical tissue bonding promotes the proliferation and migration of injured tenocytes through ROS/RhoA/NF‐κB/Dynamin 2 signaling pathway
Authors: Yao Zuochao , Wang Xi , Zhang Wen , Liu Yushu , Ni Tao
Published: May 2018

Photochemical tissue bonding (PTB) has been found to promote the healing of Achilles tendon tissue injury and to reduce postoperative complications. However, the underlying cellular and molecular mechanisms are not clear. In this study, the cell proliferation, ROS generation, migration and the protein expression of DNM2, NF‐κB p65, TGF‐β1 and VEGF in tenocytes after PTB treatment were measured by CCK‐8, flow cytometry, Transwell and western blot assay, respectively. And those in tenocytes after DNM2 silencing or overexpressing or treatment with inhibitors of NF‐κB, ROS and RhoA were also measured. Our results showed that 10 mW PTB treatment for 80 and 120 s significantly increased cell proliferation and increased ROS generation in tenocytes. 10 mW PTB treatment for 40 and 80 s significantly activated RhoA and increased the protein expression of DNM2, NF‐κB p65, TGF‐β1 and VEGF, but 10 mW PTB treatment for 120 s decreased the protein expression of those. DNM2 silencing significantly suppressed cell migration and the expression of DNM2, TGF‐β1, and VEGF in tenocytes after PTB treatment (10 mW, 80 s), which was inhibited by DNM2 overexpression. Individual treatment with inhibitor of NF‐κB, ROS, and RhoA in tenocytes showed decreased protein expression of DNM2, TGF‐β1, and VEGF. Moreover, in vivo experiment found that PTB treatment significantly inhibited cell apoptosis and the expression of DNM2, NF‐κB p65, RhoA, TGF‐β1, and VEGF in a time‐dependent manner. Taken together, our results suggest that PTB promotes the proliferation and migration of injured tenocytes through ROS/RhoA/NF‐κB/DNM2 signaling pathway.
Exogenous H2S exerts biphasic effects on porcine mammary epithelial cells proliferation through PI3K/Akt‐mTOR signaling pathway
Authors: Zhang Jing , Ye Jiayi , Yuan Cong , Fu Qin , Zhang Fenglin , Zhu Xiaotong , Wang Lina , Gao Ping , Shu Gang , Jiang Qingyan , Wang Songbo
Published: May 2018

This study aimed to investigate the effects of exogenous H2S on the proliferation of porcine mammary gland epithelial cells (PMECs) and explore the underlying mechanisms. We found that exposure of PMECs to NaHS, at concentrations ranging from 10 to 200 µM, stimulated cell proliferation. However, high concentration of NaHS (600 µM) inhibited PMECs proliferation. Accordingly, 10 µM NaHS significantly increased the percentage of cells undergoing DNA replication, elevated the mRNA and/or protein expression of Cyclin A2, Cyclin D1/3, Cyclin E2 and PCNA, and decreased p21 mRNA expression. In contrast, 600 µM NaHS elicited the opposite effects to that of 10 µM NaHS. In addition, PI3 K/Akt and mTOR signaling pathways were activated or inhibited in response to 10 or 600 µM NaHS, respectively. Furthermore, the promotion of PMECs proliferation, the change of proliferative genes expression, and the activation of mTOR signaling pathway induced by 10 µM NaHS were effectively blocked by PI3 K inhibitor Wortmannin. Similarly, inhibition of mTOR with Rapamycin totally abolished the 10 µM NaHS‐induced stimulation of PMECs proliferation and alteration of proliferative genes expression, with no influence on PI3 K/Akt signaling pathway. Moreover, constitutive activation of Akt pathway via transfection of Akt‐CA completely eliminated the inhibition of PMECs proliferation and mTOR signaling pathway, and the change of proliferative genes expression induced by 600 µM NaHS. In conclusion, our findings provided evidence that exogenous H2S supplied by NaHS exerted biphasic effects on PMECs proliferation, with stimulation at lower doses and suppression at high dose, through the intracellular PI3 K/Akt‐mTOR signaling pathway.
Genome–wide binding of transcription factor ZEB1 in triple‐negative breast cancer cells
Authors: Maturi Varun , Enroth Stefan , Heldin Carl‐Henrik , Moustakas Aristidis
Published: May 2018

Zinc finger E‐box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial‐mesenchymal transition (EMT). Triple–negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple–negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR‐Cas9‐mediated 30 bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage‐independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro‐tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple–negative mesenchymal breast cancer cells into more differentiated, epithelial‐like clones, but can reduce tumorigenic potential, suggesting that not all pro‐tumorigenic actions of ZEB1 are linked to the EMT.
Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S‐phase transition
Authors: Ghule Prachi N. , Seward David J. , Fritz Andrew J. , Boyd Joseph R. , van Wijnen Andre J. , Lian Jane B. , Stein Janet L. , Stein Gary S.
Published: May 2018

Fidelity of histone gene regulation, and ultimately of histone protein biosynthesis, is obligatory for packaging of newly replicated DNA into chromatin. Control of histone gene expression within the 3‐dimensional context of nuclear organization is reflected by two well documented observations. DNA replication‐dependent histone mRNAs are synthesized at specialized subnuclear domains designated histone locus bodies (HLBs), in response to activation of the growth factor dependent Cyclin E/CDK2/HINFP/NPAT pathway at the G1/S transition in mammalian cells. Complete loss of the histone gene regulatory factors HINFP or NPAT disrupts HLB integrity that is necessary for coordinate control of DNA replication and histone gene transcription. Here we review the molecular histone‐related requirements for G1/S‐phase progression during the cell cycle. Recently developed experimental strategies, now enable us to explore mechanisms involved in dynamic control of histone gene expression in the context of the temporal (cell cycle) and spatial (HLBs) remodeling of the histone gene loci.
Efficacy and Safety of Elbasvir‐Grazoprevir Fixed Dose in the Management of Polytreated HCV Patients: Evidence From Real‐Life Clinical Practice
Authors: Caroleo Benedetto , Colangelo Lidia , Perticone Maria , De Sarro Giovambattista , Gallelli Luca
Published: May 2018

Chronic hepatitis C virus (HCV) infection represents a global public health challenge, and new drugs have been authorized for its treatment. In this study, we evaluated both the clinical efficacy and safety of elbasvir‐grazoprevir fixed‐dose combination in HCV patients. We performed a prospective single‐blind study on patients admitted to the Regional Center for HCV Treatment of the University of Catanzaro from March 1, 2017, to December 31, 2017, in patients >30 years old with a history of chronic HCV infection. During the study period, we enrolled 29 HCV patients (18 women and 11 men; age, 62.5 ± 14 years, range 36‐82; HCV‐RNA: 2 384 859 ± 2 487 747 IU/mL, range, 60 400 − 8 930 000 IU/mL genotype 1b). In 28 of 29 patients (96.5%) we documented a rapid and complete remission of HCV infection 4 weeks after the beginning of the treatment, while in 1 patient it was reached in 8 weeks. During the study, we did not record any serious adverse drug reaction or drug interaction and no patients discontinued the treatment. However, 4 patients (13.8%) developed an asymptomatic plasma transaminase increase that appeared at 8 weeks after the beginning of the treatment and disappeared 4 weeks later in 3 patients and 8 weeks later in 1 patient. In conclusion, we documented that in real life the development of plasma transaminase increase in 4 elderly women >70 years old, suggesting that more attention must be focused on this age population.
Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials
Authors: Novakovic A.M. , Thorsted A. , Schindler E. , Jönsson S. , Munafo A. , Karlsson M.O.
Published: May 2018

The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting‐relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC‐related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit‐linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC‐derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism‐specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.
Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma
Authors: Takechi Tomoki , Kumokawa Tadao , Kato Rumiko , Higuchi Takeshi , Kaneko Tsuyoshi , Ieiri Ichiro
Published: May 2018

This study aimed to characterize the population pharmacokinetics and exposure‐response relationship of propranolol (Hemangiol® Syrup for Pediatric) in infants with infantile hemangioma. Using nonlinear mixed‐effects modeling with 63 pooled sets of plasma concentration‐time data from 32 Japanese patients aged 35‐150 days, we described the disposition of propranolol adequately by a 1‐compartment model with first‐order absorption. The estimated population mean apparent clearance and apparent central volume of distribution were 9.34 L/h and 146 L, respectively. Body weight and postnatal age influenced the population pharmacokinetic model. The clinical end points—success (complete or nearly complete resolution of the target hemangioma) and failure—at weeks 12 and 24 were characterized by logistic regression using the area under the concentration‐time curve (AUC), estimated from the final population pharmacokinetic model, as an exposure predictor. The logistic regression showed that a higher AUC was associated with a higher probability of successful treatment. At each exposure level, probability of successful treatment was correlated with gestational age and treatment duration. Model‐predicted probabilities of successful treatment were consistent with actual results in the clinical trial. Simulations using several dosing regimens indicated that oral propranolol at 3 mg/kg per day was effective and would be appropriate for treating Japanese infants. These simulation results can support optimization of dosing regimens, such as selecting amounts, treatment durations, and dosing intervals, for clinical use.
A Change in Posture Significantly Affects Plasma Concentrations of Large Molecules Such as IgG Antibodies
Authors: van Iersel Mattheus (Thijs) , Velinova Maria I.
Published: May 2018

In several studies with monoclonal antibodies, we observed spikes in plasma concentration profiles coinciding with a change of posture of study subjects. We hypothesized that these unexpected changes were due to fluid shifts from plasma to the interstitium. The objective of this study was to investigate size and time course of the change in total immunoglobulin G (IgG) concentration after a change in posture. Thirty‐two healthy subjects were enrolled. After entry in the clinic, subjects remained upright for at least 1 hour, followed by IgG sampling. Thereafter, subjects remained supine or seated (16 subjects each) for 60 minutes while IgG was sampled frequently. The within‐subject day‐to‐day variability of IgG measured in the same position was only 2.6%. After a change in posture from standing to supine, IgG dropped rapidly in all subjects during the first 10 minutes in the supine position (9.0% decrease) and more slowly thereafter, up to a 12.3% decrease after 60 minutes. After a change in posture from standing to sitting, the decrease in IgG was more variable and modest. After 10 minutes of sitting, IgG was 3.6% lower, and after 60 minutes IgG was 7.8% lower. Changing posture causes a bias of more than 10% in plasma concentrations of total IgG. Most of the change is reached after being 15 minutes in the same position. In clinical trials in which plasma concentrations of high‐molecular drugs, highly protein‐bound drugs, endogenous proteins, or blood cells are assessed, standardizing posture per time point is a useful approach for reducing variability.
Treatment of petroleum wastewater using an up‐flow anaerobic sludge blanket (UASB) reactor and turf soil as a support material
Authors: Wang Qinghong , Liang Jiahao , Zhan Yali , Yao Xianyang , Liu Zhiyuan , Li Qing X , Guo Shaohui , Chen Chunmao , Yoza Brandon A
Published: May 2018

BACKGROUND

Cost‐effective treatment of wastewater remains a challenge for the petroleum industry. In this study, turf soil (R1) was used as a support material in a mesophilic up‐flow anaerobic sludge blanket (UASB) reactor for the treatment of petroleum wastewater.

RESULTS

At a high organic loading rate (11 kg COD/m3 d), turf soil as a support material reduced COD (91.7%) more efficiently and produced more biogas (1.5 m3/m3 d) in comparison with the no support material control (R0) (89.4% and 0.4 m3/m3 d). Higher percentages of large granular sludge (≥0.6 mm) were formed in the turf soil‐supported UASB reactor (R1), which exhibited better settling, structural resilience and higher biological activity. The rough surface and porous structure of turf soil provided a favorable environment for microbial diversity and habitat. Filamentous bacterial communities putatively promoted anaerobic granular sludge formation and enhanced biodegradation of petroleum organics, particularly alkanes and organic compounds with fewer than 17 carbons. The high content of humic substances promoted the anaerobic degradation of organics, and both humic acid and fulvic acid improved alkaline pH tolerance.

CONCLUSION

Use of turf soil enhanced the performance of the UASB system, relative to the control, by shortening the time required to reach stable operation through faster biological community development and improved sludge granulation. © 2018 Society of Chemical Industry
Early ligation of the dorsal pancreatic artery with a mesenteric approach reduces intraoperative blood loss during pancreatoduodenectomy
Authors: Iede Kiyotsugu , Nakao Akimasa , Oshima Kenji , Suzuki Ryota , Yamada Hironori , Oshima Yukiko , Kobayashi Hironobu , Kimura Yasunori
Published: May 2018

Background

Early ligation of the inferior pancreatoduodenal artery has been advocated to reduce blood loss during pancreatoduodenectomy. However, the impact of early ligation of the dorsal pancreatic artery (DPA) remains unclear. This study was performed to investigate the clinical implications of early ligation of the DPA.

Methods

From October 2014 to April 2017, 34 consecutive patients underwent pancreatoduodenectomy using a mesenteric approach. The patients were divided into the early DPA ligation group (n = 15) and late DPA ligation group (n = 19). The clinical features were retrospectively compared between the two groups (H29‐044).

Results

Preoperative multidetector row computed tomography and intraoperative findings revealed that the right branch of the DPA supplied the pancreatic head region in all cases. Intraoperative blood loss was significantly lower in the early than late ligation group (median 609 ml [range 94–1,013 ml] vs. 764 ml [range 367–1,828 ml], respectively; P = 0.008). Multivariable analysis revealed that early DPA ligation was independently associated with blood loss (P = 0.023). The DPAs arising from the superior mesenteric artery underwent early ligation at a significantly higher rate.

Conclusions

Early ligation of the DPA during pancreaticoduodenectomy with a mesenteric approach could reduce intraoperative blood loss.