bluuebunny/crossref_metadata_2025 huggingface dataset:
Three cases of acute distal demyelinating neuropathy with recovery
Authors: Österlund‐Tauriala Emilia , Partanen Juhani V.
Published: April 2017

Key Clinical Message

Guillain–Barré syndrome (GBS) may present as distal acute inflammatory demyelinating polyradiculoneuropathy (AIDP), with severe distal demyelination of the peripheral nerves in the absence of radiculitis. Clinical course is benign, and prognosis seems favorable, but nerve conduction studies (NCS) findings at nadir may resemble some chronic forms of polyneuropathy, so close follow‐up during recovery is needed.
Endocardial and epicardial focal activation pattern due to microreentry ventricular tachycardia in a patient with cardiac sarcoidosis
Authors: Kawakami Hiroshi , Nakajima Ikutaro , Wada Mitsuru , Satomi Kazuhiro , Kusano Kengo
Published: April 2017

Key Clinical Message

Majority of ventricular tachycardias (VTs) are caused by scar‐related macroreentry in patients with cardiac sarcoidosis. These VTs usually exhibit the reentry circuit on electroanatomic maps. We here describe a rare case of VT that exhibits a focal activation pattern on the electroanatomic map despite reentrant VT.
A Randomized, Placebo‐ and Positive‐Controlled, Single‐Dose, Crossover Thorough QT/QTc Study Assessing the Effect of Daprodustat on Cardiac Repolarization in Healthy Subjects
Authors: Caltabiano Stephen , Collins Jon , Serbest Gul , Morgan Lisa , Smith Deborah A. , Ravindranath Ramiya , Cobitz Alexander R.
Published: April 2017

Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor in phase 3 clinical studies for the treatment of anemia associated with chronic kidney disease. This study was conducted to evaluate the effect of daprodustat on cardiac repolarization and enrolled 55 healthy adult male (29) and female (26) subjects who received single‐dose 75 and 500 mg daprodustat, 400 mg moxifloxacin, and placebo. Mean placebo‐corrected change from baseline QT interval for daprodustat showed no statistically significant increase. However, statistically significant decreases in the ΔΔQTcF were observed for both doses of daprodustat, reaching a lowest value of –2.74 milliseconds for 75 mg and –5.93 milliseconds for 500 mg daprodustat; this minor shortening effect is not considered clinically significant. The moxifloxacin group showed a statistically significant increase in the ΔΔQTcF value, reaching a maximal increase of 11.47 milliseconds at 4 hours. Forty subjects (73%) reported at least 1 adverse event, with the highest incidence with 500 mg daprodustat. This group had a higher incidence of gastrointestinal adverse events compared to the other treatment groups. These results suggest that 500 mg daprodustat was not well tolerated; however, daprodustat at 75 mg was generally well tolerated. No new safety concerns were identified in subjects who received 500 mg daprodustat.
A New Paradigm. “Learn – Learn More”; Dose‐Exposure‐Response at the Center of Drug Development and Regulatory Approval
Authors: Maloney Alan
Published: April 2017

In his seminal paper, Lewis Sheiner introduced the “Learning versus Confirming” paradigm. From that foundation, this work proposes why the precise estimation of the dose‐exposure‐response (D‐E‐R) for both efficacy and safety endpoints should be the ultimate goal for most drug development programs. The subsequent identification and approval of an optimal dose regimen range will provide a pragmatic framework for delivering personalized medicine based on dose titration for each and every patient.
Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials
Authors: Longo DM , Generaux GT , Howell BA , Siler SQ , Antoine DJ , Button D , Caggiano A , Eisen A , Iaci J , Stanulis R , Parry T , Mosedale M , Watkins PB
Published: April 2017

Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa‐treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., “Hy's Law”). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug‐induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.
Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients
Authors: Freise KJ , Jones AK , Verdugo ME , Menon RM , Maciag PC , Salem AH
Published: April 2017

Exposure–response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose‐ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1–3 prior lines of therapy and nonrefractory to bortezomib.
Hobnail variant of papillary thyroid carcinoma: A case with an unusual presentation
Authors: Lilo Mohammed T. , Bishop Justin A. , Ali Syed Z.
Published: April 2017

Variants of papillary thyroid carcinoma (PTC) account for up to 25% of the cases, some of which are proven to be associated with aggressive clinical behavior such as tall cell and columnar cell variants. Hobnail variant of PTC (HVPTC) is recently described as a rare and aggressive variant of PTC. Herein, we are reporting a case of HVPTC in a patient who presented with hemoptysis and an intratracheal blood clot that was aspirated and submitted for cytopathological examination. Cytomorphology displayed neoplastic cells with profound micropapillary architecture, elongated nuclei, and prominent hobnail configuration. Nuclear features of PTC such as pseudoinclusions, nuclear overlapping, crowding, and grooves were readily identified. Subsequent total thyroidectomy revealed a 1.4 cm PTC with columnar and hobnail components. HVPTC is a rare locally aggressive subtype, which may present with metastasis from an occult thyroid primary. HVPTC needs to be included in the differential diagnosis of metastatic carcinoma with micropapillary architecture on fine needle aspiration, particularly in head and neck area. Diagn. Cytopathol. 2017;45:754–756. © 2017 Wiley Periodicals, Inc.
Mixed oil formulations enriched in essential fatty acids and reduced ratio of n‐6/n‐3
Authors: Dillenburg Meinhart Adriana , Ferreira Ferreira da Silveira Tayse , Petrarca Mateus Henrique , Silva Leonardo Henrique , de Moraes Maria Rosa , Ballus Cristiano Augusto , de Souza Patrícia Oliveira , de Souza Thais Cristina Lima , Wagner Roger , Bolini Helena Maria André , Bruns Roy Edward , Godoy Helena Teixeira
Published: April 2017

In this work, a mixed oil formulation was developed to obtain a product rich in essential fatty acids and with reduced ratio of linoleic and linolenic fatty acids. The formulations were optimized using techniques of multivariate mixture designs. Three formulations of different compositions were chosen and they were assessed regarding oxidative stability, sensory acceptance, fatty acid composition, phytosterols, and tocopherols. The formulation with improved sensory acceptance was composed of 85% of extra‐virgin olive oil, 3% of linseed oil, and 12% of safflower oil. The new formulation showed the lowest ratio of linoleic and linolenic acids when compared to the extra‐virgin olive oil, higher oxidative stability, and higher levels of phytosterols and tocopherols.

Practical applications: The mixed oil formulation developed here possess practical application as a product nutritionally enriched for use as ingredient in several food products. It can also be largely used in industrial scale to enrich food products with high contents of essential fatty acids, phytosterols and tocopherols, helping to obtain final products with a more adequate n‐6/n‐3 fatty acids ratio and promoting health benefits through its consumption.

In this study, a mixed oil formulation which contains high levels of essential fatty acids and reduced ratio of n‐6/n‐3 to be used as ingredient in foods is developed. The main parameters related to oxidative stability, chemical composition, and sensory acceptance of the final product are evaluated.
Removal of lead (II) from synthetic solution and industry wastewater using almond shell activated carbon
Authors: Thitame Prasad V. , Shukla Sanjeev R.
Published: April 2017

Pb (II) is extensively used by various industries and the wastewater generated is hazardous to the environment. In the present study, efficiency of a cheap adsorbent in the form of activated carbon, developed from waste biomass for the Pb (II) adsorption is investigated. With BET surface area 1133.25 m2/g and the pore volume 1.41 cm3/g, its adsorption capacity for Pb (II) was found to be 823.1 mg/g, at an initial pH of 6.0. The adsorption was best described by the Langmuir isotherm, suggesting monolayer adsorption and was favorable. The adsorption followed second order kinetics, indicating chemisorption of Pb (II), mainly by ion exchange. The adsorption was controlled by the intraparticle diffusion with significant contribution of the film diffusion. With 0.5 g/L of adsorbent dosage, complete removal of Pb (II) ions was achieved from battery industry wastewater, making it safe discharge in water bodies. © 2017 American Institute of Chemical Engineers Environ Prog, 36: 1628–1633, 2017
BOLD neurovascular coupling does not change significantly with normal aging
Authors: Grinband Jack , Steffener Jason , Razlighi Qolamreza R , Stern Yaakov
Published: April 2017

Studies of cognitive function that compare the blood oxygenation level dependent (BOLD) signal across age groups often require the assumption that neurovascular coupling does not change with age. Tests of this assumption have produced mixed results regarding the strength of the coupling and its relative time course. Using deconvolution, we found that age does not have a significant effect on the time course of the hemodynamic impulse response function or on the slope of the BOLD versus stimulus duration relationship. These results suggest that in cognitive studies of healthy aging, group differences in BOLD activation are likely due to age‐related changes in cognitive–neural interactions and information processing rather than to impairments in neurovascular coupling. Hum Brain Mapp 38:3538–3551, 2017. © 2017 Wiley Periodicals, Inc.
The Network‐Performance Relationship in Knowledge‐Intensive Contexts—A Meta‐Analysis and Cross‐Level Comparison
Authors: Brennecke Julia , Stoemmer Natalie
Published: April 2017

This study examines the generalizability of the network‐performance relationship across individual and group levels, focusing on knowledge‐intensive contexts. Drawing on a meta‐analytical approach, we synthesize the results of 102 empirical studies to test whether network characteristics such as centrality, brokerage, and tie strength similarly influence the job performance of individuals and groups. Results show that while there are no differences in the direction of the network‐performance relationship across levels, there are substantial differences in magnitude. Individual performance profits more strongly from a high number of direct connections, whereas groups reap higher benefits from brokerage positions. Additional analyses reveal that the network measurement method, tie content, and performance criteria function as moderators of the network performance relationship, but their influence is consistent neither across network characteristics nor across levels. By meta‐analytically comparing and contrasting the network‐performance relationship for individuals and groups, we contribute to multilevel research on networks and organizations. Particularly, we move toward the development of a multilevel homology theory of networks. Implications for theory, practice, and future research are discussed. © 2017 Wiley Periodicals, Inc.
Spectroscopic evidences of toxic trans‐crotonaldehyde trapped and transformed by resveratrol to prevent the damage of mitochondrial DNA
Authors: Su Yanbin , Chen Lei , Su Yanwen , Li Zhengqiang , Zhang Chuang , Mu Tongxing
Published: April 2017

The purpose of this study is to probe the spectroscopic evidences of toxic trans‐crotonaldehyde (TCA) trapped and transformed by resveratrol (Res) to prevent the damage of mitochondrial DNA. In aldehyde dehydrogenase (ALDH) at the different pH or mitochondria, the spectroscopic characteristics of TCA trapped and transformed by Res were observed by means of both UV‐vis and Raman spectra. When Res interacted with TCA, TCA peak at 316 nm immediately disappeared while Res main peak at 305 nm and shoulder peak at 320 nm were dramatically changed, Raman peaks of TCA at 1,688 cm−1 assigned to CHO and 1,641 cm−1 affiliated to CC were strikingly shifted, Raman peaks of Res itself were significantly displaced or disappeared, especially in mitochondria and ALDH at different pH. The active groups of Res were the OH at C5 and C10. The results of theoretical calculations are in agreement on the whole with the experimental data. The Res plays undoubtedly an important role via the structural change in TCA. The toxic CHO of TCA was effectively trapped and transformed by Res by means of itself OH at C5 and C10. The mitochondrial alkaline microenvironment and ALDH promoted the elimination of toxic TCA. © 2017 IUBMB Life, 69(7):500–509, 2017
Bone marrow‐derived stem/stromal cells and adipose tissue‐derived stem/stromal cells: Their comparative efficacies and synergistic effects
Authors: Im Gun‐Il
Published: April 2017

Mesenchymal stem cells (MSCs) are heterogeneous cell populations that serve as reserves for tissue regeneration in the presence of disease or injury. Although MSCs are found in various tissues, bone marrow‐derived stem/stromal cells (BMSCs) and adipose tissue‐derived stem/stromal cells (ADSCs) have been most thoroughly investigated. Furthermore, ADSCs have recently emerged as an attractive source of MSCs due to their abundance and availability. BMSCs and ADSCs demonstrate similar morphological characteristics, but their in vitro characteristics and differentiation abilities appear to differ. In this review, the author summarizes and compares current knowledge on BMSCs and ADSCs with particular emphasis on in vitro expansion and osteogenic/angiogenic potential, and reviews knowledge of their synergistic effects when co‐applied. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2640–2648, 2017.
Ag‐loaded MgSrFe‐layered double hydroxide/chitosan composite scaffold with enhanced osteogenic and antibacterial property for bone engineering tissue
Authors: Cao Dandan , Xu Zhengliang , Chen Yixuan , Ke Qinfei , Zhang Changqing , Guo Yaping
Published: April 2017

Bone tissue engineering scaffolds for the reconstruction of large bone defects should simultaneously promote osteogenic differentiation and avoid postoperative infection. Herein, we develop, for the first time, Ag‐loaded MgSrFe‐layered double hydroxide/chitosan (Ag‐MgSrFe/CS) composite scaffold. This scaffold exhibits three‐dimensional interconnected macroporous structure with a pore size of 100–300 μm. The layered double hydroxide nanoplates in the Ag‐MgSrFe/CS show lateral sizes of 200–400 nm and thicknesses of ∼50 nm, and the Ag nanoparticles with particle sizes of ∼20 nm are uniformly dispersed on the scaffold surfaces. Human bone marrow‐derived mesenchymal stem cells (hBMSCs) present good adhesion, spreading, and proliferation on the Ag‐MgSrFe/CS composite scaffold, suggesting that the Ag and Sr elements in the composite scaffold have no toxicity to hBMSCs. When compared with MgFe/CS composite scaffold, the Ag‐MgSrFe/CS composite scaffold has better osteogenic property. The released Sr2+ ions from the composite scaffold enhance the alkaline phosphatase activity of hBMSCs, promote the extracellular matrix mineralization, and increase the expression levels of osteogenic‐related RUNX2 and BMP‐2. Moreover, the Ag‐MgSrFe/CS composite scaffold possesses good antibacterial property because the Ag nanoparticles in the composite scaffold effectively prevent biofilm formation against S. aureus. Hence, the Ag‐MgSrFe/CS composite scaffold with excellent osteoinductivity and antibacterial property has a great potential for bone tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 863–873, 2018.
Perinatal DNA Methylation at CDKN2A Is Associated With Offspring Bone Mass: Findings From the Southampton Women's Survey
Authors: Curtis Elizabeth M , Murray Robert , Titcombe Philip , Cook Eloïse , Clarke-Harris Rebecca , Costello Paula , Garratt Emma , Holbrook Joanna D , Barton Sheila , Inskip Hazel , Godfrey Keith M , Bell Christopher G , Cooper Cyrus , Lillycrop Karen A , Harvey Nicholas C
Published: April 2017

Poor intrauterine and childhood growth has been linked with the risk of osteoporosis in later life, a relationship that may in part be mediated through altered epigenetic regulation of genes. We previously identified a region within the promoter of the long non-coding RNA ANRIL encoded by the CDKN2A locus, at which differential DNA methylation at birth showed correlations with offspring adiposity. Given the common lineage of adipocytes and osteoblasts, we investigated the relationship between perinatal CDKN2A methylation and bone mass at ages 4 and 6 years. Using sodium bisulfite pyrosequencing, we measured the methylation status of the 9 CpGs within this region in umbilical cord samples from discovery (n = 332) and replication (n = 337) cohorts of children from the Southampton Women's Survey, whose bone mass was assessed by dual-energy X-ray absorptiomietry (DXA; Hologic Discovery). Inverse associations were found between perinatal CDKN2A methylation and whole-body minus head bone area (BA), bone mineral content (BMC), and areal bone mineral density (BMD). This was confirmed in replication and combined data sets (all p < 0.01), with each 10% increase in methylation being associated with a decrease in BMC of 4 to 9 g at age 4 years (p ≤ 0.001). Relationships were similar with 6-year bone mass. Functional investigation of the differentially methylated region in the SaOS-2 osteosarcoma cell line showed that transcription factors bound to the identified CpGs in a methylation-specific manner and that CpG mutagenesis modulated ANRIL expression. In conclusion, perinatal methylation at CDKN2A is associated with childhood bone development and has significance for cell function. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Fibronectin From Oviductal Cells Fluctuates During the Estrous Cycle and Contributes to Sperm–Oviduct Interaction in Cattle
Authors: Osycka‐Salut Claudia E. , Castellano Luciana , Fornes Daiana , Beltrame Jimena S. , Alonso Carlos A.I. , Jawerbaum Alicia , Franchi Ana , Díaz Emilce S. , Perez Martinez Silvina
Published: April 2017

During the passage of sperm through the oviduct, spermatozoa bind to the oviductal epithelium and form the oviductal reservoir. This interaction keeps the fertilizing capacity of sperm until ovulation‐associated signals induce sperm release from the oviductal epithelium, allowing the transit of spermatozoa to the fertilization site. Fibronectin is a glycoprotein from the extracellular matrix that binds to α5β1 receptors. Fibronectin has been found to be expressed in the oviduct, whereas α5β1 has been found to be expressed in the sperm of different species. Fibronectin is involved through α5β1 in sperm functions. The aim of this work was to study the participation of oviductal fibronectin in the regulation of the sperm–oviduct interaction in cattle. We found that oviductal epithelial cells differentially expressed all mRNA splice variants of fibronectin during the estrous cycle. Fibronectin was localized in the apical region of oviductal epithelial cells and fibronectin levels in the oviductal fluid fluctuated during the estrous cycle. Also, bovine spermatozoa expressed α5β1. Using in vitro sperm–oviduct co‐cultures, we found that spermatozoa were attached to the oviductal epithelium through α5β1. The incubation of co‐cultures with fibronectin induced sperm release from the oviductal cells through α5β1. The sperm population released from oviductal cells by fibronectin was enriched in motile and capacitated spermatozoa. Based on our in vitro culture system results, we propose that fibronectin and α5β1 are involved in the sperm–oviduct interaction. Also, an increase in fibronectin levels in the oviductal fluid during the pre‐ovulatory period may promote sperm release from the oviductal epithelium in cattle. J. Cell. Biochem. 118: 4095–4108, 2017. © 2017 Wiley Periodicals, Inc.
The endoplasmic reticulum‐associated protein, OS‐9, behaves as a lectin in targeting the immature calcium‐sensing receptor
Authors: Ward Bryan K. , Rea Sarah L. , Magno Aaron L. , Pedersen Bernadette , Brown Suzanne J. , Mullin Shelby , Arulpragasam Ajanthy , Ingley Evan , Conigrave Arthur D. , Ratajczak Thomas
Published: April 2017

The mechanisms responsible for the processing and quality control of the calcium‐sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two‐hybrid screen of the CaSR C‐terminal tail (residues 865–1078), we identified osteosarcoma‐9 (OS‐9) protein as a binding partner. OS‐9 is an ER‐resident lectin that targets misfolded glycoproteins to the ER‐associated degradation (ERAD) pathway through recognition of specific N‐glycans by its mannose‐6‐phosphate receptor homology (MRH) domain. We show by confocal microscopy that the CaSR and OS‐9 co‐localize in the ER in COS‐1 cells. In immunoprecipitation studies with co‐expressed OS‐9 and CaSR, OS‐9 specifically bound the immature form of wild‐type CaSR in the ER. OS‐9 also bound the immature forms of a CaSR C‐terminal deletion mutant and a C677A mutant that remains trapped in the ER, although binding to neither mutant was favored over wild‐type receptor. OS‐9 binding to immature CaSR required the MRH domain of OS‐9 indicating that OS‐9 acts as a lectin most likely to target misfolded CaSR to ERAD. Our results also identify two distinct binding interactions between OS‐9 and the CaSR, one involving both C‐terminal domains of the two proteins and the other involving both N‐terminal domains. This suggests the possibility of more than one functional interaction between OS‐9 and the CaSR. When we investigated the functional consequences of altered OS‐9 expression, neither knockdown nor overexpression of OS‐9 was found to have a significant effect on CaSR cell surface expression or CaSR‐mediated ERK1/2 phosphorylation.
Activation of ClC‐3 chloride channel by 17β‐estradiol relies on the estrogen receptor α expression in breast cancer
Authors: Yang Haifeng , Ma Lianshun , Wang Yawei , Zuo Wanhong , Li Bingxue , Yang Yaping , Chen Yehui , Chen Lixin , Wang Liwei , Zhu Linyan
Published: April 2017

Although extensively studied, the mechanisms by which estrogen promotes breast cancer growth remain to be fully elucidated. Tamoxifen, an antiestrogen agent to treat ERα+ breast cancer, is also a high‐affinity blocker of the chloride channels. In this study, we explored the involvement of the chloride channels in the action of estrogen in breast cancer. We found that 17β‐estradiol (17β‐E2) concentration‐dependently activated the chloride currents in ERα+ breast cancer MCF‐7 cells. Extracellular hypertonic challenge and chloride channel blockers, NPPB and DIDS inhibited the 17β‐E2‐activated chloride currents. Decreased the ClC‐3 protein expression caused the depletion of the 17β‐E2‐activated chloride currents. 17β‐E2‐activated chloride currents which relied on the ERα expression were demonstrated by the following evidences. Firstly, 17β‐E2‐activated chloride currents could not be observed in ERα‐ breast cancer MDA‐MB‐231 cells. Secondly, ER antagonists, tamoxifen and ICI 182,780, and downregulation of ERα expression inhibited or abolished the 17β‐E2‐activated chloride currents. Thirdly, ERα expression was induced in MDA‐MB‐231 cells by ESR1 gene transfection, and then 17β‐E2‐activated chloride currents could be observed. In MCF‐7 cells, ERα and ClC‐3 mainly located in nucleus and translocated to cell plasma and membrane with respect to co‐localization following treatment of 17β‐E2. Downregulation of ERα expression could decrease the expression of ClC‐3 protein. Conversely, downregulation of ClC‐3 expression did not influence the ERα expression. Taken together, our findings demonstrated that ClC‐3 is a potential target of 17β‐E2 and is modulated by the ERα in breast cancer cell. Pharmacological modulation of ClC‐3 may provide a deep understanding in antiestrogen treatment of breast cancer patients.
Mycoplasma pneumoniae infection: Basics
Authors: Saraya Takeshi
Published: April 2017

Mycoplasma pneumoniae (Mp) is one of the leading causes of community‐acquired pneumonia and can cause a number of extrapulmonary manifestations in the absence of pneumonia. In this regard, primary care physicians should know how to suspect, diagnose, and manage patients with Mp infection. This review gives a general overview of the basic clinical aspects of Mp infection with special reference to pneumonia, which will help further understanding of the disease.
Diffusion‐weighted imaging of hyperpolarized [13C]urea in mouse liver
Authors: Marco‐Rius Irene , Gordon Jeremy W. , Mattis Aras N. , Bok Robert , Delos Santos Romelyn , Sukumar Subramanian , Larson Peder E.Z. , Vigneron Daniel B. , Ohliger Michael A.
Published: April 2017

Purpose

To compare the apparent diffusion coefficient (ADC) of hyperpolarized (HP) [13C,15N]urea to the ADC of endogenous water in healthy and fibrotic mouse liver.

Materials and Methods

ADC measurements for water and [13C]urea were made in agarose phantoms at 14.1T. Next, the ADC of water and injected HP [13C,15N]urea were measured in eight CD1 mouse livers before and after induction of liver fibrosis using CCl4. Liver fibrosis was quantified pathologically using the modified Brunt fibrosis score and compared to the measured ADC of water and urea.

Results

In cell‐free phantoms with 12.5% agarose, water ADC was nearly twice the ADC of urea (1.93 × 10−3 mm2/s vs. 1.00 × 10−3 mm2/s). The mean ADC values of water and [13C,15N]urea in healthy mouse liver (±SD) were nearly identical [(0.75 ± 0.11) × 10−3 mm2/s and (0.75 ± 0.22) × 10−3 mm2/s, respectively]. Mean water and [13C,15N]urea ADC values in fibrotic liver (±SD) were (0.84 ± 0.22) × 10−3 mm2/s and (0.75 ± 0.15) × 10−3 mm2/s, respectively. Neither water nor urea ADCs were statistically different in the fibrotic livers compared to baseline (P = 0.14 and P = 0.99, respectively). Water and urea ADCs were positively correlated at baseline (R2 = 0.52 and P = 0.045) but not in fibrotic livers (R2 = 0.23 and P = 0.23).

Conclusion

ADC of injected hyperpolarized urea in healthy liver reflects a smaller change as compared to free solution than ADC of water. This may reflect differences in cellular compartmentalization of the two compounds. No significant change in ADC of either water or urea were observed in relatively mild stages of liver fibrosis.

Level of Evidence: 1

Technical Efficacy: Stage 1

J. Magn. Reson. Imaging 2018;47:141–151.
Diagnostic performance of different imaging modalities in the assessment of distant metastasis and local recurrence of tumor in patients with non‐small cell lung cancer
Authors: Ohno Yoshiharu , Yoshikawa Takeshi , Kishida Yuji , Seki Shinichiro , Koyama Hisanobu , Yui Masao , Kassai Yoshimori , Aoyagi Kota , Kaminaga Shigeo , Sugimura Kazuro
Published: April 2017

Purpose

To compare the diagnostic performance of positron emission tomography with [18F] fluoro‐2‐deoxy‐glucose (FDG‐PET) coregistered with magnetic resonance imaging (FDG‐PET/MRI), MRI with and without diffusion‐weighted imaging (DWI), FDG‐PET fused with computed tomography (FDG‐PET/CT) with brain contrast‐enhanced (CE‐) MRI, and routine radiological examination for assessment of postoperative recurrence in nonsmall‐cell lung cancer (NSCLC) patients.

Materials and Methods

96 consecutive postoperative NSCLC patients (52 men, 44 women; mean age 72 years) prospectively underwent whole‐body 3T MRI with and without DWI; PET/CTs and routine radiological examinations consisted of CE‐brain MRI, whole‐body CE‐CT, and bone scintigraphy. The patients were divided into a recurrence (n = 17) and a nonrecurrence (n = 79) group based on pathological and follow‐up examinations. All coregistered PET/MRIs were generated by proprietary software. The probability of recurrence was visually assessed on a per‐patient basis. Receiver operating characteristic analyses were used to compare the diagnostic performance of all methods. Finally, diagnostic capabilities were compared by means of McNemar's test.

Results

Areas under the curves (Azs) were significantly larger for PET/MRI and whole‐body MRI with DWI (Az = 0.99) than for PET/CT (Az = 0.92, P < 0.05) and conventional radiological examination (Az = 0.91, P < 0.05). Specificity and accuracy of PET/MRI and MRI with and without DWI were significantly higher than those of PET/CT (P < 0.05) and routine radiological examination (P < 0.05).

Conclusion

Whole‐body FDG‐PET/MRI and MRI with DWI were found to be more specific and accurate than FDG‐PET/CT and routine radiological examinations for assessment of recurrence in NSCLC patients, although MRI with and without DWI demonstrated slightly lower sensitivity than PET/CT.

Level of Evidence: 2

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2017;46:1707–1717.
Physics for clinicians: Fluid‐attenuated inversion recovery (FLAIR) and double inversion recovery (DIR) Imaging
Authors: Saranathan Manojkumar , Worters Pauline W. , Rettmann Dan W. , Winegar Blair , Becker Jennifer
Published: April 2017

A pedagogical review of fluid‐attenuated inversion recovery (FLAIR) and double inversion recovery (DIR) imaging is conducted in this article. The basics of the two pulse sequences are first described, including the details of the inversion preparation and imaging sequences with accompanying mathematical formulae for choosing the inversion time in a variety of scenarios for use on clinical MRI scanners. Magnetization preparation (or T2prep), a strategy for improving image signal‐to‐noise ratio and contrast and reducing T1 weighting at high field strengths, is also described. Lastly, image artifacts commonly associated with FLAIR and DIR are described with clinical examples, to help avoid misdiagnosis.

Level of Evidence: 5

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2017;46:1590–1600.
Aging does not alter tendon mechanical properties during homeostasis, but does impair flexor tendon healing
Authors: Ackerman Jessica E. , Bah Ibrahima , Jonason Jennifer H. , Buckley Mark R. , Loiselle Alayna E.
Published: April 2017

Aging is an important factor in disrupted homeostasis of many tissues. While an increased incidence of tendinopathy and tendon rupture are observed with aging, it is unclear whether this is due to progressive changes in tendon cell function and mechanics over time, or an impaired repair reaction from aged tendons in response to insult or injury. In the present study, we examined changes in the mechanical properties of Flexor Digitorum Longus (FDL), Flexor Carpi Ulnaris (FCU), and tail fascicles in both male and female C57Bl/6 mice between 3 and 27 months of age to better understand the effects of sex and age on tendon homeostasis. No change in max load at failure was observed in any group over the course of aging, although there were significant decreases in toe and linear stiffness in female mice from 3 to 15 months, and 3 to 27 months. No changes in cell proliferation were observed with aging, although an observable decrease in cellularity occurred in 31‐month old tendons. Given that aging did not dramatically alter tendon mechanical homeostasis we hypothesized that a disruption in tendon homeostasis, via acute injury would result in an impaired healing response. Significant decreases in max load, stiffness, and yield load were observed in repairs of 22‐month old mice, relative to 4‐month old mice. No changes in cell proliferation were observed between young and aged, however, a dramatic loss of bridging collagen extracellular matrix was observed in aged repairs suggest that matrix production, but not cell proliferation leads to impaired tendon healing with aging. Results © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2716–2724, 2017.
The ‘known’ genetic potential for microbial communities to degrade organic phosphorus is reduced in low‐pH soils
Authors: Lidbury Ian D. E. A. , Fraser Tandra , Murphy Andrew R. J. , Scanlan David J. , Bending Gary D. , Jones Alexandra M. E. , Moore Jonathan D. , Goodall Andrew , Tibbett Mark , Hammond John P. , Wellington Elizabeth M. H.
Published: April 2017

In soil, bioavailable inorganic orthophosphate is found at low concentrations and thus limits biological growth. To overcome this phosphorus scarcity, plants and bacteria secrete numerous enzymes, namely acid and alkaline phosphatases, which cleave orthophosphate from various organic phosphorus substrates. Using profile hidden Markov modeling approaches, we investigated the abundance of various non specific phosphatases, both acid and alkaline, in metagenomes retrieved from soils with contrasting pH regimes. This analysis uncovered a marked reduction in the abundance and diversity of various alkaline phosphatases in low‐pH soils that was not counterbalanced by an increase in acid phosphatases. Furthermore, it was also discovered that only half of the bacterial strains from different phyla deposited in the Integrated Microbial Genomes database harbor alkaline phosphatases. Taken together, our data suggests that these ‘phosphatase lacking’ isolates likely increase in low‐pH soils and future research should ascertain how these bacteria overcome phosphorus scarcity.
Regulation of Burkholderia cenocepacia biofilm formation by RpoN and the c‐di‐GMP effector BerB
Authors: Fazli Mustafa , Rybtke Morten , Steiner Elisabeth , Weidel Elisabeth , Berthelsen Jens , Groizeleau Julie , Bin Wu , Zhi Boo Zhao , Yaming Zhang , Kaever Volkhard , Givskov Michael , Hartmann Rolf W. , Eberl Leo , Tolker‐Nielsen Tim
Published: April 2017

Knowledge about the molecular mechanisms that are involved in the regulation of biofilm formation is essential for the development of biofilm‐control measures. It is well established that the nucleotide second messenger cyclic diguanosine monophosphate (c‐di‐GMP) is a positive regulator of biofilm formation in many bacteria, but more knowledge about c‐di‐GMP effectors is needed. We provide evidence that c‐di‐GMP, the alternative sigma factor RpoN (σ54), and the enhancer‐binding protein BerB play a role in biofilm formation of Burkholderia cenocepacia by regulating the production of a biofilm‐stabilizing exopolysaccharide. Our findings suggest that BerB binds c‐di‐GMP, and activates RpoN‐dependent transcription of the berA gene coding for a c‐di‐GMP‐responsive transcriptional regulator. An increased level of the BerA protein in turn induces the production of biofilm‐stabilizing exopolysaccharide in response to high c‐di‐GMP levels. Our findings imply that the production of biofilm exopolysaccharide in B. cenocepacia is regulated through a cascade involving two consecutive transcription events that are both activated by c‐di‐GMP. This type of regulation may allow tight control of the expenditure of cellular resources.
A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16‐Amino‐Acid Protein Causes Self‐inducible Paroxysmal Kinesigenic Dyskinesia
Authors: Kita Makoto , Kuwata Yasuhiro , Murase Nagako , Akiyama Yuichi , Usui Takeshi
Published: April 2017

Paroxysmal kinesigenic dyskinesia (PKD) is a sporadic or autosomal‐dominant, hereditary disorder characterized by brief, recurrent attacks of involuntary movements triggered by sudden, voluntary movement that generally develops during childhood and adolescence and is typically treated with carbamazepine. The proline‐rich transmembrane protein 2 (PRRT2) gene contains 4 exons that encode 340 amino acids as the major isoform, and recent research has identified PRRT2 as the primary causative gene in PKD, benign familial infantile epilepsy (BFIE), and infantile convulsions with PKD (PKD/IC). Here, the authors report the phenotype of a family with a novel p.E16X (c.46G>T) nonsense mutation of the PRRT2 gene that lacked almost a full allele. In this family, none of the individuals in the pedigree exhibited evidence of cognitive impairment: the elder brother had PKD/IC with migraine; the younger brother had PKD with ataxia; the father had PKD; both siblings experienced a sensory aura; and all 3 had a history of febrile seizures. This is the first report of a short nonsense mutation in PRRT2 and indicates that the manifestations of the disease, including other mutations to date, can be explained by haploinsufficiency and that 1 intact PRRT2 allele can allow normal cognitive development.
Experimental analysis and theoretical modeling of the mechanical behavior of starch‐grafted‐polypropylene/kenaf fibers composites
Authors: Phua Y.J. , Pegoretti A. , Mohd Ishak Z.A.
Published: April 2017

Mechanical properties of starch‐grafted‐polypropylene/kenaf fibers (KF) composites were investigated and compared to different theoretical models. In this work, the composites were prepared via melt compounding and compression molding processes at different KF loadings, that is, 10, 20, and 30 wt%. Tensile, fracture toughness and fatigue tests were performed. Generally, the mechanical properties increased with increasing kenaf fiber loadings. This is attributed to the good filler‐matrix interactions between KF and starch‐grafted‐polypropylene, as observed by scanning electron microscopy. Tensile properties were modeled using the rule of mixture, the Kelly‐Tyson and the Halpin‐Tsai models. Fatigue data were also modeled using different theoretical models to fit both S–N and normalized S–N curves with simple linear model and Boltzmann sigmoidal function. POLYM. COMPOS., 39:3289–3299, 2018. © 2017 Society of Plastics Engineers
Nanomechanical and nanoscratch performance of polystyrene/poly(methyl methacrylate)/multi‐walled carbon nanotubes nanocomposite coating
Authors: Fereidoon Abdolhosein , Katouzian Sobhan , Taraghi Iman , Paszkiewicz Sandra
Published: April 2017

This article describes how the nanoindentation procedure has been performed in order to present the effect of multi‐walled carbon nanotubes (MWCNTs) on the nanoscratch resistance of polystyrene/poly(methyl methacrylate) (PS/PMMA) coatings. The polymer nanocomposite coatings have been prepared using solution spin coating technique. Nanoindentation results reveal that the elastic modulus and hardness of the nanocomposites increase by 7.5% and 32%, respectively. Introduction of MWCNTs resulted in an increase of scratch hardness of the nanocomposites along with a decrease of the coefficient of friction. Moreover, the residual scratch exhibited greater reduction in the samples. Based on the obtained results it can be concluded that MWCNTs can improve the resistance capability of the PS/PMMA blends coatings to the nanoscratch phenomenon. POLYM. COMPOS., 39:E962–E968, 2018. © 2017 Society of Plastics Engineers
Lipopolysaccharide binding to the periplasmic protein LptA
Authors: Schultz Kathryn M. , Lundquist Tanner J. , Klug Candice S.
Published: April 2017

Lipopolysaccharide (LPS) and the periplasmic protein, LptA, are two essential components of Gram‐negative bacteria. LPS, also known as endotoxin, is found asymmetrically distributed in the outer leaflet of the outer membrane of Gram‐negative bacteria such as Escherichia coli and plays a role in the organism's natural defense in adverse environmental conditions. LptA is a member of the lipopolysaccharide transport protein (Lpt) family, which also includes LptC, LptDE, and LptBFG2, that functions to transport LPS through the periplasm to the outer leaflet of the outer membrane after MsbA flips LPS across the inner membrane. It is hypothesized that LPS binds to LptA to cross the periplasm and that the acyl chains of LPS bind to the central pocket of LptA. The studies described here are the first to comprehensively characterize and quantitate the binding of LPS by LptA. Using site‐directed spin‐labeling electron paramagnetic resonance (EPR) spectroscopy, data were collected for 15 spin‐labeled residues in and around the proposed LPS binding pocket on LptA to observe the mobility changes caused by the presence of exogenous LPS and identify the binding location of LPS to LptA. The EPR data obtained suggest a 1:1 ratio for the LPS:LptA complex and allow the first calculation of dissociation constants for the LptA–LPS interaction. The results indicate that the entire protein is affected by LPS binding, the N‐terminus unfolds in the presence of LPS, and a mutant LptA protein unable to form oligomers has an altered affinity for LPS.
Detection of prostate cancer‐specific transcripts in extracellular vesicles isolated from post‐DRE urine
Authors: Pellegrini Kathryn L. , Patil Dattatraya , Douglas Kristen J.S. , Lee Grace , Wehrmeyer Kathryn , Torlak Mersiha , Clark Jeremy , Cooper Colin S. , Moreno Carlos S. , Sanda Martin G.
Published: April 2017

Background: The measurement of gene expression in post‐digital rectal examination (DRE) urine specimens provides a non‐invasive method to determine a patient's risk of prostate cancer. Many currently available assays use whole urine or cell pellets for the analysis of prostate cancer‐associated genes, although the use of extracellular vesicles (EVs) has also recently been of interest. We investigated the expression of prostate‐, kidney‐, and bladder‐specific transcripts and known prostate cancer biomarkers in urine EVs.

Methods: Cell pellets and EVs were recovered from post‐DRE urine specimens, with the total RNA yield and quality determined by Bioanalyzer. The levels of prostate, kidney, and bladder‐associated transcripts in EVs were assessed by TaqMan qPCR and targeted sequencing.

Results: RNA was more consistently recovered from the urine EV specimens, with over 80% of the patients demonstrating higher RNA yields in the EV fraction as compared to urine cell pellets. The median EV RNA yield of 36.4 ng was significantly higher than the median urine cell pellet RNA yield of 4.8 ng. Analysis of the post‐DRE urine EVs indicated that prostate‐specific transcripts were more abundant than kidney‐ or bladder‐specific transcripts. Additionally, patients with prostate cancer had significantly higher levels of the prostate cancer‐associated genes PCA3 and ERG.

Conclusions: Post‐DRE urine EVs are a viable source of prostate‐derived RNAs for biomarker discovery and prostate cancer status can be distinguished from analysis of these specimens. Continued analysis of urine EVs offers the potential discovery of novel biomarkers for pre‐biopsy prostate cancer detection.
On the diagnosis of model error statistics using weak‐constraint data assimilation
Authors: Bowler N. E.
Published: April 2017

Outputs from a data assimilation system may be used to diagnose observation‐ and background‐error statistics, as has been demonstrated by previous researchers. In this study, that technique is extended to diagnose model error statistics using a weak‐constraint data assimilation. It deals with a set of observations over a time window and uses the temporal distribution to separate model errors from errors in the background forecast. In a set of idealized tests, this method is shown to be able to distinguish successfully between model and background errors. The success of this method depends on the prior assumptions included in the weak‐constraint data assimilation and how well these describe the true nature of the system being modelled. Other authors have demonstrated that it can be challenging to separate observation and background errors in diagnosis schemes. Some separation of these errors is possible within the context of four‐dimensional assimilation, provided that observation errors are known to be uncorrelated in time.
Smooth output feedback stabilization for a class of nonlinear systems with time‐varying powers
Authors: Chen Chih‐Chiang , Qian Chunjiang , Lin Xiangze , Sun Zong‐Yao , Liang Yew‐Wen
Published: April 2017

This paper investigates the global asymptotic stabilization problem for a class of nonlinear systems with time‐varying powers. First, adding a power integrator technique is revamped to design a smooth state feedback controller, which is implementable with only upper and lower bounds of the time‐varying powers. When the system state is not fully available and the time‐varying power is exactly known, a smooth output feedback controller constituted by a state feedback and a nonlinear state observer is constructed to globally stabilize the system. Copyright © 2017 John Wiley & Sons, Ltd.
Strategic NPV: Real Options and Strategic Games under Different Information Structures
Authors: Smit Han T. J. , Trigeorgis Lenos
Published: April 2017

Research summary: Among the most difficult firm strategic choices is the trade‐off between making a long‐term commitment or holding off on investment in the face of uncertainty. To operationalize strategic management theory under demand, technological and competitive uncertainty, we develop a Strategic Net Present Value (NPV) framework that integrates real options and game theory to quantify value components and interactions at the interface between NPV, real options, and strategic games. Our approach results in new propositions clarifying the way learning‐experience conditions, technological uncertainty, and proprietary information interact to tilt the balance in the interplay between wait‐and‐see flexibility and strategic commitment. As such, Strategic NPV adds to our understanding of the conditions where NPV, real options, or strategic thinking are more relevant.

Managerial summary: This study develops and elucidates implementation of a new valuation construct, “Strategic Net Present Value (NPV),” that integrates real options and game theory to more accurately portray strategic decisions underlying management theory. Among the most difficult firm strategic choices in capital intensive industries, such as energy, mining, chip manufacturing, and infrastructure development, is the trade‐off between making a long‐term commitment or holding off on investment in the face of demand, technological, and competitive uncertainties. The study provides new insights on the way various conditions, such as learning‐experience effects, technological uncertainty, and proprietary information, interact to tilt the balance in the interplay between commitment and wait‐and‐see flexibility. As such, Strategic NPV adds to our understanding of when NPV, real options, or strategic thinking matter more critically for decision making. Copyright © 2017 John Wiley & Sons, Ltd.