bluuebunny/crossref_metadata_2025 huggingface dataset:
The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar‐simulated ultraviolet radiation exposure
Authors: Qutob Sami S. , Chauhan Vinita , Kuo Byron , Williams Andrew , Yauk Carole L. , McNamee James P. , Gollapudi B.
Published: May 2018

Considerable data has been generated to elucidate the transcriptional response of cells to ultraviolet radiation (UVR) exposure providing a mechanistic understanding of UVR‐induced cellular responses. However, using these data to support standards development has been challenging. In this study, we apply benchmark dose (BMD) modeling of transcriptional data to derive thresholds of gene responsiveness following exposure to solar‐simulated UVR. Human epidermal keratinocytes were exposed to three doses (10, 20, 150 kJ/m2) of solar simulated UVR and assessed for gene expression changes 6 and 24 hr postexposure. The dose‐response curves for genes with p‐fit values (≥ 0.1) were used to derive BMD values for genes and pathways. Gene BMDs were bi‐modally distributed, with a peak at ∼16 kJ/m2 and ∼108 kJ/m2 UVR exposure. Genes/pathways within Mode 1 were involved in cell signaling and DNA damage response, while genes/pathways in the higher Mode 2 were associated with immune response and cancer development. The median value of each Mode coincides with the current human exposure limits for UVR and for the minimal erythemal dose, respectively. Such concordance implies that the use of transcriptional BMD data may represent a promising new approach for deriving thresholds of actinic effects. Environ. Mol. Mutagen. 59:502–515, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society
Method to estimate the approximate samples size that yield a certain number of significant GWAS signals in polygenic traits
Authors: Bacanu Silviu‐Alin , Kendler Kenneth S.
Published: May 2018

To argue for increased sample collection for disorders without significant findings, researchers resorted to plotting, for multiple traits, the number of significant findings as a function of the sample size. However, for polygenic traits, the prevalence of the disorder confounds the relationship between the number of significant findings and the sample size. To adjust the number of significant findings for prevalence, we develop a method that uses the expected noncentrality of the contrast between liabilities of cases and controls. We empirically find that, when compared to the sample size, this measure is a better predictor of number of significant findings. Even more, we show that the sample size effect on the number of signals is explained by the noncentrality measure. Finally, we provide an R script to estimate the required sample size (noncentrality) needed to yield a prespecified number of significant findings, along with the converse.
Interfacial tension and contact angle in CO2‐water/nanofluid‐quartz system
Authors: Zheng Xianglei , Barrios Ana C. , Perreault François , Yun Tae Sup , Jang Jaewon
Published: May 2018

Nanoparticles can modify the interface properties that are critical for fluid flow in porous media. The interfacial tension (IFT) between CO2 and water and the contact angle (CA) of a water droplet on a mineral surface under high CO2 pressure are critical parameters for CO2‐related applications such as CO2 geological sequestration and CO2‐enhanced resource recovery. This study investigated the IFT and CA in a water‐CO2‐quartz system and a nanofluid (water including either Al2O3 or TiO2 nanoparticles)‐CO2‐quartz system. The values of the IFT and CA were obtained by axisymmetric drop shape analysis (ADSA) for a droplet on a quartz surface in a chamber pressurized with CO2. The effect of nanoparticles on the IFT and CA was explored by comparing the values for the pure water‐CO2‐quartz system. In addition, the effect of CO2 adsorption onto the substrate on the wettability was investigated. The results show that the values of the IFT decrease with increasing CO2 pressure, and the addition of nanoparticles to pure water lowers the IFT further (∼up to a 40% reduction in the liquid CO2 pressure range). The de‐wetting phenomenon was observed for both gaseous and liquid CO2 conditions. © 2018 Society of Chemical Industry and John Wiley & Sons, Ltd.
Extracellular interleukin‐17F has a protective effect in oral tongue squamous cell carcinoma
Authors: Almahmoudi Rabeia , Salem Abdelhakim , Sieviläinen Meri , Sundquist Elias , Almangush Alhadi , Toppila‐Salmi Sanna , Paavonen Timo , Salo Tuula , Al‐Samadi Ahmed
Published: May 2018

Background

Oral tongue squamous cell carcinoma (SCC) is characterized by early metastasis and poor prognosis. Interleukin‐17F (IL‐17F) plays a protective role in many tumors. However, IL‐17F expression in oral tongue SCC tissue has not been investigated.

Methods

Immunostaining of 83 oral tongue SCC specimens and blinded‐scoring were used to map IL‐17F expression, location, and distribution. Survival curves were constructed according to Kaplan‐Meier method. The Cox proportional hazard model was applied for univariate and multivariate survival analyses.

Results

Mast cells are the major source of IL‐17F in oral tongue SCC. In multivariate analysis, only the extracellular mast cell‐derived IL‐17F at the tumor invasion front was associated with better disease‐specific survival in patients with all‐stages and early‐stages of oral tongue SCC.

Conclusion

Extracellular mast cell‐derived IL‐17F is antitumorigenic in oral tongue SCC. It separates patients with early‐stage disease who are at high risk from patients who are at low risk. Furthermore, when analyzing tentative prognostic molecules, we conclude that in addition to the staining intensity, attention must be paid to the cellular source, distribution, and location of the molecule.
Data assimilation in groundwater modelling: ensemble Kalman filter versus ensemble smoothers
Authors: Li Liangping , Puzel Ryan , Davis Arden
Published: May 2018

Groundwater modelling calls for an effective and robust data integrating method to fill the gap between the model and observation data. The ensemble Kalman filter (EnKF), a real‐time data assimilation method, has been increasingly applied in multiple disciplines such as petroleum engineering and hydrogeology. In this approach, a groundwater model is updated sequentially with measured data such as hydraulic head and concentration. As an alternative to the EnKF, the ensemble smoother (ES) has been proposed for updating groundwater models using all the data together, with much less computational cost. To further improve the performance of the ES, an iterative ES has been proposed for continuously updating the model by assimilating measurements together. In this work, we compare the performance of the EnKF, the ES, and the iterative ES using a synthetic example in groundwater modelling. Hydraulic head data modelled on the basis of the reference conductivity field are used to inversely estimate conductivities at unsampled locations. Results are evaluated in terms of the characterization of conductivity and groundwater flow predictions. It is concluded that (a) the iterative ES works better than the standard ES because of its continuous updating and (b) the iterative ES could achieve results comparable with those of the EnKF, with less computational cost. These findings show that the iterative ES should be paid much more attention for data assimilation in groundwater modelling.
The isotopic signature of monsoon conditions, cloud modes, and rainfall type
Authors: Zwart Costijn , Munksgaard Niels C. , Protat Alain , Kurita Naoyuki , Lambrinidis Dionisia , Bird Michael I.
Published: May 2018

This work provides a comprehensive physically based framework for the interpretation of the north Australian rainfall stable isotope record (δ18O and δ2H). Until now, interpretations mainly relied on statistical relationships between rainfall amount and isotopic values on monthly timescales. Here, we use multiseason daily rainfall stable isotope and high resolution (10 min) ground‐based C‐band polarimetric radar data and show that the five weather types (monsoon regimes) that constitute the Australian wet season each have a characteristic isotope ratio. The data suggest that this is not only due to changes in regional rainfall amount during these regimes but, more importantly, is due to different rain and cloud types that are associated with the large scale circulation regimes. Negative (positive) isotope anomalies occurred when stratiform rainfall fractions were large (small) and the horizontal extent of raining areas were largest (smallest). Intense, yet isolated, convective conditions were associated with enriched isotope values whereas more depleted isotope values were observed when convection was widespread but less intense. This means that isotopic proxy records may record the frequency of which these typical wet season regimes occur. Positive anomalies in paleoclimatic records are most likely associated with periods where continental convection dominates and convection is sea‐breeze forced. Negative anomalies may be interpreted as periods when the monsoon trough is active, convection is of the oceanic type, less electric, and stratiform areas are wide spread. This connection between variability of rainfall isotope anomalies and the intrinsic properties of convection and its large‐scale environment has important implications for all fields of research that use rainfall stable isotopes.
Soil moisture response to rainfall on the Chinese Loess Plateau after a long‐term vegetation rehabilitation
Authors: Jin Zhao , Guo Li , Lin Henry , Wang Yunqiang , Yu Yunlong , Chu Guangcheng , Zhang Jing
Published: May 2018

The Chinese Loess Plateau (CLP) is a unique Critical Zone with deep loess deposits, where soil moisture is primarily replenished by seasonal monsoon rainfall. However, the role of vegetation, coupled with complex topography, on rainwater infiltration on the CLP, especially after long‐term revegetation for controlling erosion, is inadequately quantified. Over the growing season of 2016, we monitored soil moisture at the 30‐min interval at 5 depths (10, 20, 40, 60, and 100 cm) in an afforested catchment and a nearby catchment with natural regrowth of grasses. Two monitoring sites were established in each catchment, one in the downhill gully and the other in the uphill slope. We found that vegetation, topography, and rainfall attributes together determined rainwater infiltration and soil moisture replenishment. An accumulated rainfall amount of 9 mm was required to trigger soil moisture response at 10‐cm depth at the 2 grassland sites and the forestland uphill‐slope site whereas 14 mm of rainfall was required for the forestland gully site covered by dense undergrowth and trees. Rainfall events with larger sums and higher peak intensities permitted rainwater infiltration to deeper soil depths. However, no rain recharged soil moisture to 100‐cm depth during the monitoring period. The forestland uphill‐slope site showed the deepest wetting depth (up to 60‐cm depth), fastest wetting‐front velocity (up to 4 cm/hr below 10‐cm depth), and the most significant soil moisture increase (up to 15% cm 3 cm−3 increase at 10‐cm depth) after rainfall in the growing season. The grassland gully site had the highest soil water storage, whereas soil moisture was depleted the most at the forestland gully site. Findings of this study reveal the transient dynamics of soil moisture after rainfall on the CLP, which signifies the role of revegetation on rainwater infiltration in the loess Critical Zone.
LncRNA NKILA suppresses TGF‐β‐induced epithelial–mesenchymal transition by blocking NF‐κB signaling in breast cancer
Authors: Wu Wei , Chen Fei , Cui Xiuying , Yang Limei , Chen Jianing , Zhao Jinghua , Huang Di , Liu Jiang , Yang Linbin , Zeng Jiayi , Zeng Zhiqing , Pan Yunbao , Su Fengxi , Cai Junchao , Ying Zhongfu , Zhao Qiyi , Song Erwei , Su Shicheng
Published: May 2018

TGF‐β plays a central role in mediating epithelial–mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF‐β‐induced EMT is NF‐κB‐dependent in various cancer types. However, it is largely unclear if NF‐κB mediates TGF‐β‐induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF‐β activates the NF‐κB pathway. Inhibition of NF‐κB signaling markedly abrogates TGF‐β‐induced EMT. By studying the regulatory mechanism of TGF‐β‐induced NF‐κB signaling, we found that lncRNA NKILA was upregulated by TGF‐β and was essential for the negative feedback regulation of the NF‐κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF‐β‐induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA‐mediated negative feedback affects TGF‐β‐induced NF‐κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.
Influence of collagen‐based integrin α1 and α2 mediated signaling on human mesenchymal stem cell osteogenesis in three dimensional contexts
Authors: Becerra‐Bayona Silvia M. , Guiza‐Arguello Viviana R. , Russell Brooke , Höök Magnus , Hahn Mariah S.
Published: May 2018

Collagen I interactions with integrins α1 and α2 are known to support human mesenchymal stem cell (hMSC) osteogenesis. Nonetheless, elucidating the relative impact of specific integrin interactions has proven challenging, in part due to the complexity of native collagen. In the present work, we employed two collagen‐mimetic proteins—Scl2‐2 and Scl2‐3— to compare the osteogenic effects of integrin α1 versus α2 signaling. Scl2‐2 and Scl2‐3 were both derived from Scl2‐1, a triple helical protein lacking known cell adhesion, cytokine binding, and matrix metalloproteinase sites. However, Scl2‐2 and Scl2‐3 were each engineered to display distinct collagen‐based cell adhesion motifs: GFPGER (binding integrins α1 and α2) or GFPGEN (binding only integrin α1), respectively. hMSCs were cultured within poly(ethylene glycol) (PEG) hydrogels containing either Scl2‐2 or Scl2‐3 for 2 weeks. PEG‐Scl2‐2 gels were associated with increased hMSC osterix expression, osteopontin production, and calcium deposition relative to PEG‐Scl2‐3 gels. These data indicate that integrin α2 signaling may have an increased osteogenic effect relative to integrin α1. Since p38 is activated by integrin α2 but not by integrin α1, hMSCs were further cultured in PEG‐Scl2‐2 hydrogels in the presence of a p38 inhibitor. Results suggest that p38 activity may play a key role in collagen‐supported hMSC osteogenesis. This knowledge can be used toward the rational design of scaffolds which intrinsically promote hMSC osteogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2594–2604, 2018.
microRNA‐665 promotes the proliferation and matrix degradation of nucleus pulposus through targeting GDF5 in intervertebral disc degeneration
Authors: Tan Hongyu , Zhao Liang , Song Ruipeng , Liu Yilin , Wang Limin
Published: May 2018

Growing evidences suggested that microRNAs (miRNAs) played important roles in the development of intervertebral disc degeneration (IDD). However, the expression level and function of miR‐665 in IDD remain unknown. In this study, we showed that the expression level of miR‐665 was upregulated in degenerative human NP samples. In addition, miR‐665 expression level gradually increased with the exacerbation of disc degeneration grade. Moreover, miR‐665 expression level was positively associated with the Pfirrmann grade. Ectopic expression of miR‐665 promoted NP cell growth. Furthermore, miR‐665 overexpression decreased aggrecan and Col II expression and ectopic expression of miR‐665 increased MMP‐3 and MMP‐13 expression in NP cell. We identified growth differentiation factor 5 (GDF5) was a direct target gene of miR‐665 in NP cell and enforced expression of miR‐665 decreased GDF5 expression. Elevated expression of miR‐665 enhanced NP cell proliferation and decreased aggrecan and Col II expression. In addition, ectopic expression of miR‐665 increased MMP‐3 and MMP‐13 expression through inhibiting GDF5 expression in NP cells. These results suggested that dysregulated miR‐665 expression might act an important role in the development of IDD.
Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A
Authors: Zhang Rui , Xu Jian , Zhao Jian , Bai Jing H.
Published: May 2018

Recent research has shown that TOP2A plays an important role in the tumorigenesis of many malignancies, such as breast cancer, ovarian cancer, and prostate cancer. However, few studies have been conducted on TOP2A expression and functions in colon cancer. In the present study, we found that TOP2A expression was obviously elevated in colon cancer tissues compared to adjacent non‐cancerous tissues. Depletion of TOP2A in HCT116 and SW480 colon cancer cells by transfection of specific small interfering RNA significantly suppressed proliferation and inhibited invasion of cells, even induced apoptosis as indicated by both MTT assay, Annexin V/propidium iodide staining, and Transwell assay. Furthermore, we explored the underlying mechanisms. Knockdown of TOP2A not only affects the expression of cell apoptosis‐related (Bcl‐2 and Bax) and invasion‐related proteins (MMP‐2 and MMP‐9), but also reduced the phosphorylation levels of ERK and AKT. In conclusion, we showed that TOP2A was upregulated in colon cancer tissue samples and that TOP2A may serve as an oncogene in colon cancer.
Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants
Authors: Jagadeb Manaswini , Rath Surya N. , Sonawane Avinash
Published: May 2018

Emergence of multi‐drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi‐drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first‐line anti‐tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild‐type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta‐butyl(2S,4S)‐4‐amino‐2‐cyclopropyl‐6‐(trifluoromethyl)‐3,4‐dihydro‐2H‐quinoline‐1‐carboxylate) to be more effective against PZA resistant Mtb strains in comparison to PZA. The lead molecule showed better drug‐like properties such as high affinity and atomic interactions with wild‐type and drug‐resistant mutations in Mtb PncA proteins. Further, molecular dynamic simulation studies showed that this lead molecule has better conformational stability and compatibility with drug‐resistant PncA proteins in comparison to PZA drug. We hypothesized that the predicted lead compound could be more effective, and thus may improve the treatment of PZA resistant tuberculosis.
The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation
Authors: Park Sunwoo , Bazer Fuller W. , Lim Whasun , Song Gwonhwa
Published: May 2018

Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti‐oxidant, anti‐proliferative, and anti‐tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case‐control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti‐cancer mechanism of formononetin in ovarian cancer are unknown. We investigated the toxicological mechanism of formononetin in ES2 and OV90 ovarian cancer cells. Formononetin suppressed cell proliferation through sub G0/G1 phase arrest and increased apoptosis in both cell lines. Furthermore, it induced loss of mitochondrial membrane potential and generation of reactive oxygen species in ES2 and OV90 cells. The formononetin‐mediated regulation of cell proliferation and apoptosis involved decreased phosphorylation of ERK1/2, P90RSK, AKT, P70S6K, and S6 proteins, and increased phosphorylation of P38 protein in ES2 and OV90 cells. Co‐treatment of formononetin with pharmacological inhibitors (LY294002 or U0126) revealed additional anti‐proliferative effects on the two human ovarian cancer cell types. Conclusively, the results indicate the potential value of formononetin as an anti‐cancer agent in human ovarian cancer.
Predicting lysine‐malonylation sites of proteins using sequence and predicted structural features
Authors: Taherzadeh Ghazaleh , Yang Yuedong , Xu Haodong , Xue Yu , Liew Alan Wee‐Chung , Zhou Yaoqi
Published: May 2018

Malonylation is a recently discovered post‐translational modification (PTM) in which a malonyl group attaches to a lysine (K) amino acid residue of a protein. In this work, a novel machine learning model, SPRINT‐Mal, is developed to predict malonylation sites by employing sequence and predicted structural features. Evolutionary information and physicochemical properties are found to be the two most discriminative features whereas a structural feature called half‐sphere exposure provides additional improvement to the prediction performance. SPRINT‐Mal trained on mouse data yields robust performance for 10‐fold cross validation and independent test set with Area Under the Curve (AUC) values of 0.74 and 0.76 and Matthews’ Correlation Coefficient (MCC) of 0.213 and 0.20, respectively. Moreover, SPRINT‐Mal achieved comparable performance when testing on H. sapiens proteins without species‐specific training but not in bacterium S. erythraea. This suggests similar underlying physicochemical mechanisms between mouse and human but not between mouse and bacterium. SPRINT‐Mal is freely available as an online server at: http://sparks-lab.org/server/SPRINT-Mal/. © 2018 Wiley Periodicals, Inc.
Spectroscopic, thermal analysis, and nematicidal evaluation of new mixed ligand complexes of bidentate Schiff base and 1,10 phenanthroline with some transition metals
Authors: El‐Attar Mohamed S.
Published: May 2018

Mononuclear Co(II), Cu(II), Y(III), Zr(IV), La(III), and U(VI) complexes of 2‐[(2‐hydroxybenzylidene)‐amino]‐benzoic acid (H2L) ligand in presence of 1,10‐phenanthroline (Phen) were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV–vis, and 1H‐NMR), X‐ray powder diffraction and magnetic measurements. The results prove that H2L acts with the mentioned metal salts as a bidentate ON donor ligand and Phen as an NN donor ligand. The calculated bond length and force constant F(UO) in the uranyl complex are 1.732 Å and 708.90 nM−1, respectively. The electronic spectra and the magnetic susceptibility data support the octahedral geometry for the mononuclear Co(II), Y(III), Zr(IV), La(III), and U(VI) complexes and square‐pyramidal geometry for the Cu(II) complex. Thermogravimetric analysis was performed to determine the thermal stability of the synthesized compounds. The kinetic parameters, that is, the activation energy (E*), pre‐exponential factor (A), entropy of activation (ΔS*), enthalpy of activation (ΔH*) and free energy of activation (ΔG*), of the thermal degradation process were evaluated using Coats–Redfern (C–R) and Horowitz–Metzger (H–M) methods for all the complexes, and the best fit results could be obtained. In the present work, all the synthesized complexes showed nematicidal activity against the root knot nematode (Meloidgyne javanica) by inhibiting egg hatching and causing larval mortality of second‐stage juveniles.
Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood‐derived megakaryocytes
Authors: Gertz Jacqueline M. , McLean Kelley C. , Bouchard Beth A.
Published: May 2018

Plasma‐ and platelet‐derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet‐derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41+ cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34+ cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b+ cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in α‐granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood.
Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus)
Authors: Wei Yanhong , Gong Lingchen , Fu Weiwei , Xu Shenhui , Wang Zhe , Zhang Jie , Ning Er , Chang Hui , Wang Huiping , Gao Yunfang
Published: May 2018

As a typical hibernator, the Daurian ground squirrel (Spermophilus dauricus) spends considerable time in a state of reduced activity with prolonged fasting. Despite this, they experience little muscle atrophy and have thus become an interesting anti‐disuse muscle atrophy model. The IKKβ/NF‐κB signaling pathway is significant to muscle atrophy due to the protein degradation resulting from the upregulation of the E3 ubiquitin ligase MuRF1. The current study showed that the IKKβ/NF‐κB signaling pathway and MuRF1 maintained relatively steady mRNA and protein expression levels, with little muscle atrophy observed in the soleus (slow‐twitch, SOL) or extensor digitorum longus (fast‐twitch, EDL) during hibernation (HIB); however, mRNA expression significantly increased in the SOL and EDL muscle during interbout arousal (IBA), as did the MuRF1 mRNA level in the SOL and MuRF1 protein level in the EDL. Interestingly, the expressions of p50 and MuRF1 significantly increased during HIB in the gastrocnemius (mixed muscle, GAS) and showed moderate atrophy, but dramatically decreased during IBA. Elevated IKKβ and p50 mRNA and protein expression in the cardiac muscle (CM) during HIB did not accompany increased MuRF1 expression or muscle wasting. Importantly, almost all increased or decreased indicators in the tested tissues recovered to pre‐hibernation levels after HIB. This is the first study to report on the unexpected regulation of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in Daurian ground squirrels during hibernation. Furthermore, we found that different types of muscles exhibited different strategies to cope with prolonged hibernation‐induced disuse muscle atrophy.
Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation
Authors: Zheng Xiaowei , Xu Gaoqi , Zhu Liqin , Fang Luo , Zhang Yiwen , Ding Haiying , Tong Yinghui , Sun Jiao , Huang Ping
Published: May 2018

The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD‐based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp.
In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
Authors: Li Yan , Liu Liangang , Wang Xiaomin , Zhang Chengyue , Reyes Josephine , Hoffmann Matthew , Palmisano Maria , Zhou Simon
Published: May 2018

Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1‐21 of repeated 28‐day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open‐label, single‐dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0‐inf) and the plasma peak exposure (Cmax), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0‐inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50‐mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.
Risk of Hypoglycemia After Concomitant Use of Antidiabetic, Antihypertensive, and Antihyperlipidemic Medications: A Database Study
Authors: Gosho Masahiko
Published: May 2018

Hypoglycemia is the most important complication of antidiabetic medications. Most patients with diabetes mellitus take multiple medications. In this study, we explored clinical drug‐drug interactions that result in hypoglycemia by analyzing the Japanese Adverse Drug Event Report (JADER) database. The primary outcome was the report of hypoglycemia. The Norén and Gosho methods, which quantitatively measure the discrepancy between the observed and expected number of adverse events under the combination of 2 drugs, were used as the criteria for detecting drug‐drug interactions. The JADER database contained patient characteristics with 468 292 records, drug information with 2 973 172 records, and adverse reactions with 741 016 records. We noted that hypoglycemia was reported in 6208 patients. Concomitant use of linagliptin/glibenclamide, sitagliptin/glibenclamide, sitagliptin/buformin, exenatide/voglibose, mitiglinide/perindopril, repaglinide/barnidipine, alogliptin/cilnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was noted using the 2 criteria for drug‐drug interactions. Concomitant use of teneligliptin and barnidipine produced the highest values for the 2 criteria. The second‐and third‐highest values were observed for teneligliptin/urapidil and exenatide/candesartan combinations, respectively. The same analysis was performed using the US Food and Drug Administration Adverse Event Reporting System database to assess the validity of the result from the JADER database. The concomitant use of sitagliptin/buformin, exenatide/voglibose, repaglinide/barnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was detected in both the JADER and Food and Drug Administration Adverse Event Reporting System databases. Combination therapy with the drugs listed above would show potential interactions that could result in hypoglycemia in patients with diabetes mellitus.
ROSCAs as Lenders of Last Resort after Financial Crises: Lessons from Indonesia
Authors: Acquah Joseph Kofi , Dahal Roshani
Published: May 2018

This study investigated the lending capabilities of Rotating Savings and Credit Association (ROSCA) institutions in the 2 years following the 1998 Indonesian financial crisis. We found that lending increased threefold and resulted in 2 percent of ROSCA members securing ROSCA loans. Loans were small (US$28.8) with 92 percent of loan recipients reporting that they knew no other place to borrow. Factors that positively influenced lending capacities of ROSCA loans were ROSCA size (30–43 members) and diversity in employment sectors of ROSCA members. Additionally, members that participated in multiple ROSCAs and experienced hardships in 1998 were more likely to receive ROSCA loans. Copyright © 2018 John Wiley & Sons, Ltd.
Synthesis and characterization of a deuterium labeled stercobilin: A potential biomarker for autism
Authors: Coffey Jordan M. , Vadas Andrew J. , Puleo Thomas R. , Lewis Katelyn P. , Pirrone Gregory F. , Rudolph Heather L. , Helms Eric D. , Wood Troy D. , Flynn‐Charlebois Amber
Published: May 2018

Stercobilin is an end‐stage metabolite of hemoglobin, a component of red blood cells. It has been found that there is a significantly lower concentration of stercobilin in the urine of people diagnosed with autism spectrum disorders, suggesting potential use as a biomarker. In vitro, we have synthesized stercobilin from its precursor bilirubin through a reduction reaction proceeded by an oxidation reaction. In addition, we have isotopically labeled the stercobilin product with deuterium using this protocol. Nuclear magnetic resonance investigations show the products of the unlabeled stercobilin (Rxn 1) and the deuterated stercobilin (Rxn 2) both had a loss of signals in the 5.0‐ to 7.0‐ppm range indicating proper conversion to stercobilin. Changes in the multiplicity of the sp3 region of the proton nuclear magnetic resonance suggest proper deuterium incorporation. Mass spectrometry studies of Rxn 1 show a difference in fragmentation patterns than that of Rxn 2 proposing potential locations for deuterium incorporation. This isotopologue of stercobilin is stable (>6 mo), and further analysis permits investigation for its use as a biomarker and potential quantitative diagnostic probe for autism spectrum disorders.
Radiomics analysis of apparent diffusion coefficient in cervical cancer: A preliminary study on histological grade evaluation
Authors: Liu Ying , Zhang Yuwei , Cheng Runfen , Liu Shichang , Qu Fangyuan , Yin Xiaoyu , Wang Qin , Xiao Bohan , Ye Zhaoxiang
Published: May 2018

Background

The role of apparent diffusion coefficient (ADC)‐based radiomics features in evaluating histopathological grade of cervical cancer is unresolved.

Purpose

To determine if there is a difference between radiomics features derived from center‐slice 2D versus whole‐tumor volumetric 3D for ADC measurements in patients with cervical cancer regarding tumor histopathological grade, and systematically assess the impact of the b value on radiomics analysis in ADC quantifications.

Study Type

Prospective.

Subjects

In all, 160 patients with histopathologically confirmed squamous cell carcinoma of uterine cervix.

Field Strength/Sequence

Conventional and diffusion‐weighted MR images (b values = 0, 800, 1000 s/mm2) were acquired on a 3.0T MR scanner.

Assessment

Regions of interest (ROIs) were drawn manually along the margin of tumor on each slice, and then the center slice of the tumor was selected with naked eyes in the course of whole‐tumor segmentation. A total of 624 radiomics features were derived from T2‐weighted images and ADC maps. We randomly selected 50 cases and did the reproducibility analysis.

Statistical Tests

Parameters were compared using Wilcoxon signed rank test, Bland–Altman analysis, t‐test, and least absolute shrinkage and selection operator (LASSO) regression with crossvalidation.

Results

In all, 95 radiomics features were insensitive to ROI variation among T2 images, ADC map of b800, and ADC map of b1000 (P > 0.0002). There was a significant statistical difference between the performances of 2D center‐slice and 3D whole‐tumor radiomics models in both ADC feature sets of b800 and b1000 (P < 0.0001, P < 0.0001). Compared with ADC features of b800 (0.3758 ± 0.0118), the model of b1000 ADC features appeared to be slightly lower in overall misclassification error (0.3642 ± 0.0162) (P = 0.0076).

Data Conclusion

Several radiomics features extracted from T2 images and ADC maps were highly reproducible. Whole‐tumor volumetric 3D radiomics analysis had a better performance than using the 2D center‐slice of tumor in stratifying the histological grade of cervical cancer. A b value of 1000 s/mm2 is suggested as the optimal parameter in pelvic DWI scans.

Level of Evidence: 1

Technical Efficacy: Stage 1

J. Magn. Reson. Imaging 2019;49:280–290.
Influence of plaque control on the relationship between rheumatoid arthritis and periodontal health status among Japanese rheumatoid arthritis patients
Authors: Hashimoto Hiroko , Hashimoto Shimpei , Muto Akinori , Dewake Nanae , Shimazaki Yoshihiro
Published: May 2018

Background

Functional disability of the finger joints in rheumatoid arthritis (RA) patients could affect their oral hygiene and periodontal status because of poor plaque control. We examined the influence of plaque control on the relationship between the severity of RA and periodontal status in RA patients.

Methods

This study recruited 89 Japanese RA patients who reported no difficulty in performing oral hygiene. We assessed RA severity using four indices: the Steinbrocker stage and class, the Health Assessment Questionnaire (HAQ) and the Disease Activity Score (DAS). Probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were taken as parameters of periodontal status. Oral hygiene status was assessed using the plaque index (PlI). We examined the association between the severity of RA and periodontal parameters using multivariable linear regression analyses.

Results

In multivariable linear regression analyses not including PlI, Steinbrocker stage III–IV patients had significantly higher PlI scores and greater PD compared with those of stage I. The class III–IV patients had significantly higher PlI scores and greater PD. Patients with an HAQ score ≥0.5 had a significantly higher PlI score than those with an HAQ score of 0. However, when PlI was added to each multivariable model as an independent variable, no significant relationship between RA severity and periodontal status was observed.

Conclusions

This study suggests that it is important to consider the influence of plaque control when assessing the relationship between RA severity and periodontal health status in RA patients.
The evaluation of salivary oxidative stress in patients with familial Mediterranean fever and chronic periodontitis
Authors: Dinç Gözde , Fentoğlu Özlem , Doğru Atalay , İlhan İlter , Kırzıoğlu F. Yeşim , Orhan Hikmet
Published: May 2018

Background

Familial Mediterranean fever (FMF) is an inherent autoinflammatory disease and have a high prevalence in Mediterranean countries. The aim of this study was to evaluate salivary levels of oxidative stress parameters in patients with FMF and chronic periodontitis.

Methods

The study population consists of 81 patients with FMF and 85 systemically healthy controls. The test and control groups were classified as chronic periodontitis and periodontally healthy [FMF‐periodontitis (n = 37); FMF‐periodontally healthy (n = 44); systemically healthy‐periodontitis (n = 37); systemically and periodontally healthy (n = 48]. Total salivary samples were collected. Clinical periodontal parameters including plaque index, gingival index (GI), probing depth (PD), the percentage of bleeding on probing (BOP%), and clinical attachment level (CAL), were measured. Salivary total antioxidant status (TAS), total oxidant status (TOS), 8‐hydroxydeoxyguanosine (8‐OHdG), malondialdehyde (MDA), and oxidative stress index (OSI) were evaluated.

Results

The FMF‐periodontitis group had significantly higher levels of 8‐OHdG, MDA, and OSI than that of the FMF‐periodontally healthy group. In the FMF‐periodontitis group, PD, 8‐OHdG, MDA, and OSI levels were significantly higher than in the systemically healthy‐periodontitis group (P = 0.035, P = 0.000, P = 0.000, and P = 0.000, respectively). 8‐OHdG values were significantly correlated with BOP% and GI, and TOS values were significantly correlated with PD and CAL in the FMF‐periodontitis group.

Conclusions

In the presence of FMF and chronic periodontitis, there were increased salivary levels of oxidative stress. Thus, oxidative stress could be an important inflammatory mechanism in the FMF and chronic periodontitis. Further studies need to clarify the oxidative mechanisms of FMF and chronic periodontitis.
The value of inflammation based prognostic scores in patients undergoing surgical resection for oesophageal and gastric carcinoma
Authors: Wen Jiaxin , Bedford Matthew , Begum Ruksana , Mitchell Harriet , Hodson James , Whiting John , Griffiths Ewen
Published: May 2018

Background and Objectives

Surgical interventions for oesophagogastric cancer carry a significant burden of morbidity and mortality. A range of inflammation based prognostic scores have been proposed in an attempt to predict outcome. This study evaluated five such prognostic scores in oesophageal and gastric carcinoma patients.

Methods

The modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), and Prognostic Nutrition Index (PNI) were calculated for 723 consecutive patients undergoing oesophagectomy or gastrectomy at a single center. The predictive accuracy of each score was assessed using ROC curves and survival analyses.

Results

Overall, only PLR and PNI were significantly predictive of patient survival (both P < 0.001), with no significant association detected for mGPS (P = 0.480), NLR (P = 0.210), or PI (P = 0.808). Subgroup analysis found the predictive accuracy of PNI to be significantly greater in oesophagectomy than gastrectomy patients (hazard ratio 2.75 vs 1.39, P = 0.016) and mGPS to be predictive of patient survival only in oesophagectomies (P < 0.001).

Conclusions

Inflammation based prognostic scores may have a role in patients undergoing resection for oesophageal and gastric cancer. These scores are easily calculable from routinely collected data and could be used as an adjunct to existing staging modalities.
Ultra high performance liquid chromatography with tandem mass spectrometry method for determining dinotefuran and its main metabolites in samples of plants, animal‐derived foods, soil, and water
Authors: Zhang Ying , Wu Xiaohu , Duan Tingting , Xu Jun , Dong Fengshou , Liu Xingang , Li Xiaogang , Du Pengqiang , Zheng Yongquan
Published: May 2018

An ultra high‐performance liquid chromatography with tandem triple quadrupole mass spectrometry residue method was developed and validated for the quantification and identification of dinotefuran and its main metabolites 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) urea and 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) guanidine in fruit (watermelon), vegetable (cucumber), cereal (rice), animal‐derived foods (milk, egg, and pork), soil, and water. The samples were extracted with acetonitrile containing 15% v/v acetic acid and purified with dispersive solid‐phase extraction with octadecylsilane, primary secondary amine, graphitized carbon black, or zirconia‐coated silica prior to analysis. The method had an excellent linearity (R2 ≥ 0.9942, 1–500 μg/L) and satisfactory recoveries (73–102%) at five spiked levels (0.001, 0.01, 0.05, 0.5, and 2 mg/kg) with intra‐ or interday precision in the range of 0.8–9.5% and 3.0–12.8% for the three compounds in the eight matrices. The limits of quantification were 10 μg/kg for 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) guanidine and 1 μg/kg for 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) urea and dinotefuran. The applicability of the developed method was demonstrated by determining the occurrence of dinotefuran, 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) guanidine, and 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) urea in various samples from plants, animal‐derived foods, and the environment. From 80 samples, 70 contained dinotefuran (0.8–11.7 μg/kg), among which six also contained 1‐methyl‐3‐(tetrahydro‐3‐furylmethyl) urea (water and rice, 0.5–0.9 μg/kg).