bluuebunny/crossref_metadata_2025 huggingface dataset:
Nickel‐Catalyzed Mizoroki–Heck‐Type Reactions of Unactivated Alkyl Bromides
Authors: Kwiatkowski Megan R. , Alexanian Erik J.
Published: October 2018

The development of a general, nickel‐catalyzed alkyl‐Mizoroki–Heck reaction of unactivated alkyl bromides is described. The mild reaction proceeds efficiently using a wide range of primary and secondary alkyl bromides, and examples of intermolecular cross‐couplings are provided. Reaction alkene regioselectivity is significantly enhanced over prior carbocyclizations using palladium catalysis. Mechanistic investigations are consistent with a direct carbocyclization in contrast to the auto‐tandem atom‐transfer cyclization and halide elimination previously observed with palladium catalysis.
Palladium‐Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature
Authors: Pan Fei , Boursalian Gregory B. , Ritter Tobias
Published: October 2018

Methods for the direct synthesis of difluoromethylated arenes are sparse, despite the importance of the difluoromethyl group in medical, agro‐, and materials chemistry. A palladium‐catalyzed decarbonylative cross‐coupling reaction of acid chlorides with a difluoromethyl zinc reagent is achieved to access difluoromethylated compounds. The transformation proceeds at room temperature and shows broad functional group tolerance, thus providing a general and efficient method for decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.
Biological evaluation of rare earth complexes bearing 1H‐imidazo[4,5‐f]‐1,10‐phenanthroline moiety as promising anticancer chemotherapeutics
Authors: Liu Yue , Zhou Xue‐Quan , Lu Jing , Li Si‐Tong , Nie Yan , Tian Jin‐Lei , Liu Xin , Yan Shi‐Ping
Published: October 2018

Six lanthanide(III) complexes with the 2‐(naphthalen‐1‐yl)‐1H‐imidazo[4,5‐f]‐1,10‐phenanthroline ligand have been synthesized and characterized using X‐ray crystallography. The central Ln(III) center displays a distorted square antiprismatic environment with a N2O6 donor set. To study the reactivity of the complexes with possible biological targets, spectroscopic studies and viscosity experiments were used to research their interactions with calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA), taken as model biomolecules. The six complexes are moderate intercalating agents to CT‐DNA and can quench the intrinsic fluorescence of BSA in a static quenching process. Low IC50 values of these complexes were measured using MTT assays on three human cancer cell lines. One of the complexes could induce apoptosis of BEL‐7404 cancer cells via the extrinsic pathway with high expression of caspase‐8, resulting in caspase‐3 activation. Furthermore, that same complex could significantly suppress BEL‐7404 cell proliferation via induced apoptosis with G2/M phase cell cycle.
31P NMR Method for Phospholipid Analysis in Krill Oil: Proficiency Testing—A Step toward Becoming an Official Method
Authors: Zailer Elina , Monakhova Yulia B. , Diehl Bernd W. K.
Published: October 2018

A high‐resolution 31P NMR method for determining the concentration of phospholipid (PL) species in krill oil was proficiency tested using an international interlaboratory study. Fourteen laboratories from five countries tested five different krill oil samples providing 17 datasets. Krill oil samples were prepared by the organizer using liquid–liquid extraction and sent to the participants who ran the nuclear magnetic resonance (NMR) analysis and evaluated the spectra. The relative standard deviation (RSD) among all the results provided by the participants varied between 2.1% and 3.3% for the phosphatidylcholine (PtdCho) content and between 2.8% and 12.3% for the sum of other PL. Afterward, an automated procedure was applied to all collected NMR data, which significantly improved the RSD values and provided reliable quantitative results for specific PL (PtdCho, 1‐lysophosphatidylcholine [LPC], 2‐LPS, PtdEtn, acylphosphatidylethanolamine [APE], and lysophosphatidylethanolamine [LPE]). The RSD varied between 1.6% and 2.7% for PtdCho and between 1.6% and 2.9% for the total phosphorus. Higher but acceptable values were obtained for 1‐LPC (5.1% to 8.9%), PtdEtn (7.0% to 10.5%), and LPE (5.7% to 16.5%) due to their small concentrations. The influence of different magnetic field strengths (400–600 MHz), probes, and slight differences in acquisition parameters was assessed as nonsignificant. PtdCho hydrolysis during 14 weeks before measurements was the major factor that affects the result distribution. This method was submitted to the AOCS to become an official AOCS method for krill oil analysis.
The Influence of Body Size and Bone Mass on Cortical Bone Histomorphometry in Human Ribs
Authors: Beresheim Amy C. , Pfeiffer Susan K. , Alblas Amanda
Published: October 2018

This study examines the influence of human adult body size and bone mass on cortical bone histomorphometry, and explores microstructural variation in mid‐thoracic ribs. The sample consists of 213 individuals (nfemale = 82, nmale = 131, mean age‐at‐death = 47.96 ± 15.71 years) from the Kirsten Skeletal Collection, Stellenbosch University, South Africa. Maximum femur length and femur maximum head diameter are used as proxies for height and weight; total cross‐sectional area, endosteal area, and cortical area are used to derive measures of bone mass. Histomorphometric variables include osteon population density (OPD) and osteon area (On.Ar). Partial correlations, controlling for age, test for significant relationships among variables. A hierarchical regression model is used to determine unique variable contributions to On.Ar and OPD. Body size measurements do not correlate with either bone mass or histomorphometric variables, suggesting that size‐standardization may not be necessary in studies of rib bone microstructure. Age is the most significant factor affecting OPD, while OPD is the best predictor of On.Ar. These findings suggest that age‐related secondary osteon crowding affects osteon geometry. Understanding the biological mechanisms that direct bone remodeling and determine microstructural variation is essential for interpreting histological data. Anat Rec, 301:1788–1796, 2018. © 2018 Wiley Periodicals, Inc.
Capturing B type acute lymphoblastic leukemia cells using two types of antibodies
Authors: İçöz Kutay , Gerçek Tayyibe , Murat Ayşegül , Özcan Servet , Ünal Ekrem
Published: October 2018

One way to monitor minimal residual disease (MRD) is to screen cells for multiple surface markers using flow cytometry. In order to develop an alternative microfluidic based method, isolation of B type acute lymphoblastic cells using two types of antibodies should be investigated. The immunomagnetic beads coated with various antibodies are used to capture the B type acute lymphoblastic cells. Single beads, two types of beads and surface immobilized antibody were used to measure the capture efficiency. Both micro and nanosize immunomagnetic beads can be used to capture B type acute lymphoblastic cells with a minimum efficiency of 94% and maximum efficiency of 98%. Development of a microfluidic based biochip incorporating immunomagnetic beads and surface immobilized antibodies for monitoring MRD can be an alternative to current cost and time inefficient laboratory methods. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2737, 2019
Address misconduct in subcultures via 5 key strategies
Authors: McCarthy Claudine
Published: October 2018

Addressing misconduct in socially exclusive, closed‐off student subcultures — such as fraternities, sororities, bands, and sports teams — ranks among the most challenging work faced by higher ed professionals. But implementing the right strategies can help you change the group culture, according to Gentry McCreary, Ph.D., consultant, and W. Scott Lewis, J.D., partner, both with The NCHERM Group, LLC. They spoke at the Association for Student Conduct Administration's annual conference.
Fluorescent, Recombinant‐Protein‐Conjugated, Near‐Infrared‐Emitting Quantum Dots for in Vitro and in Vivo Dual‐Color Molecular Imaging
Authors: Tsuboi Setsuko , Jin Takashi
Published: October 2018

Near‐infrared (NIR)‐emitting fluorescent probes are widely used for molecular imaging at the whole‐body level. However, NIR‐emitting fluorescent probes emitting over λ=700 nm are not suitable for molecular imaging at the cellular level, because most of the conventional fluorescence microscopes have very low optical sensitivity in the NIR region. Thus, to achieve fluorescence imaging at the cellular and whole‐body levels by using single probes, visible and NIR‐emitting dual‐color fluorescent probes are desirable. For dual‐color fluorescence molecular imaging, we synthesized fluorescent, recombinant‐protein‐conjugated, NIR‐emitting quantum dots (QDs), in which the recombinant protein consists of enhanced green fluorescent protein (EGFP) and the immunoglobulin binding domain (B1) of protein G. This dual‐color fluorescent QD probe binds the Fc region of immunoglobulin G (IgG) through its B1 domain at the QD surface and acts as a molecular‐imaging probe at both the cellular and whole‐body levels. In this paper, we present the synthesis of fluorescent, recombinant protein (HisEGFP‐GB1)‐conjugated, NIR‐emitting QDs and their application to the dual‐color molecular imaging of breast cancer cells in vitro and in vivo.
Effect of glucose and palmitate environment on proliferation and migration of PC3‐prostate cancer cells
Authors: Rezende Lívia Prometti , Galheigo Maria Raquel Unterkircher , Landim Breno Costa , Cruz Amanda Rodrigues , Botelho Françoise Vasconcelos , Zanon Renata Graciele , Góes Rejane Maira , Ribeiro Daniele Lisboa
Published: October 2018

Recent studies have been trying to find out how diet and metabolic changes such as dyslipidaemia, hyperglycaemia, and hyperinsulinaemia can stimulate cancer progression. This investigation aimed to evaluate the effect of high concentrations of fatty acids and/or glucose in tumour prostate cells, focusing on the proliferation/migration profile and oxidative stress. PC3 cells were treated with high concentration of saturated fatty acid (palmitate, 100 µM), glucose (220 mg/dL), or both for 24 or 48 h. Results demonstrated that PC3 cells showed a significant increase in proliferation after 48 h of treatment with glucose and palmitate+glucose. Cell proliferation was associated with reduced levels of AMPK phosphorylation in glucose group at 24 and 48 h of treatment, while palmitate group presented this result only after 48 h of treatment. Also, there was a significant increase in cell migration between time 0 and 48 h after all treatments, except in the control. Catalase activity was increased by palmitate in the beginning of treatment, while glucose presented a later effect. Also, nitrite production was increased by glucose only after 48 h, and the total antioxidant activity was enhanced by palmitate in the initial hours. Thus, we conclude that the high concentration of the saturated fatty acid palmitate and glucose in vitro influences PC3 cells and stimulates cellular activities related to carcinogenesis such as cell proliferation, migration, and oxidative stress in different ways. Palmitate presents a rapid and initial effect, while a glucose environment stimulates cells later on, maintaining high levels of cell proliferation.
SAPIEN valve for percutaneous transcatheter pulmonary valve replacement without “pre‐stenting”: A multi‐institutional experience
Authors: Morgan Gareth J. , Sadeghi Soraya , Salem Moris M. , Wilson Neil , Kay Joseph , Rothman Abraham , Galindo Alvaro , Martin Mary Hunt , Gray Robert , Ross Michael , Aboulhosn Jamil A. , Levi Daniel Steven
Published: October 2018

Objectives

To describe a multicenter experience of percutaneous transcatheter pulmonary valve replacement (TPVR) using the Edwards SAPIEN S3 valve without the use of a prior stent (“pre‐stenting”).

Background

The SAPIEN S3 and XT valves have durable cobalt–chromium stent frames which may allow for TPVR in large diameter dysfunctional right ventricular outflow tracts (RVOTs) without pre‐stenting the landing zone.

Methods

A retrospective review was performed of all patients with Congenital Heart Disease and dysfunctional RVOT who underwent TPVR using the SAPIEN valve without the use of a pre‐stent. Imaging data, procedural elements, and clinical follow‐up data were collected to evaluate short and intermediate‐term results.

Results

Fifty‐seven patients underwent percutaneous placement of the SAPIEN valve in the pulmonary position without the use of pre‐stenting. The anatomical substrate varied: native RVOTs (n = 41), conduits (n = 10), and bioprosthetic valves (n = 6). There were no cases in which the valve could not be implanted and no cases of valve embolization or misplacement. On follow‐up (range 1 month to 2.2 years, median 5.3 months), no patients had significant obstruction or regurgitation around the valve. There were no frame fractures. There were no procedural deaths. Major complications included severe aortic compression (n = 1) requiring surgical explantation and tricuspid valve injury requiring surgical intervention (n = 2).

Conclusions

This limited multi‐institutional experience demonstrates that the SAPIEN valve can be used for TPVR without the use of a pre‐stent without medium‐term risk of frame fracture, paravalvar leak, or embolization. Longer term follow‐up is required to fully assess this method.
Green Conversion of Microalgae into High‐Performance Sponge‐Like Nitrogen‐Enriched Carbon
Authors: Liu Yingying , Dai Gongxin , Zhu Lingjun , Wang Shurong
Published: October 2018

The selective conversion of biomass into high‐value carbon materials has recently been attracting increasing attraction. In this study, a microalga with a high nitrogen content, namely Spirulina platensis, was used as both the carbon and nitrogen precursors in the synthesis of sponge‐like nitrogen‐enriched carbon materials through a one‐step activation method with NaHCO3 as a green activator. The sponge‐like nitrogen‐enriched carbon materials obtained at different activation temperatures were systematically characterized by using SEM, N2 adsorption‐desorption, XRD, Raman, and XPS techniques. A series of tests were performed to investigate the electrochemical characteristics of the obtained carbon materials to determine their potential use as supercapacitors. The results show that sponge‐like nitrogen‐enriched carbon activated at 700 °C, which has a large BET surface area of 865 m2/g and a high nitrogen content of 7.5 wt%, gave the largest specific capacitance of 234.0 F/g at a current density of 1 A/g in a 6 M KOH electrolyte.
Rare‐Earth Metal Diimide Complexes via Alkylaluminate Templating, Including a Ceric Derivative
Authors: Thim Renita , Schädle Dorothea , Maichle‐Mössmer Cäcilia , Anwander Reiner
Published: October 2018

Protonolysis of lanthanide tris(tetramethylaluminate)s with two equivalents of 2,6‐diisopropylaniline affords LaIII and CeIII diimide compounds Ln[(μ‐NC6H3iPr2‐2,6)2AlMe2](thf)4 featuring a bidentate AlMe2‐linked diimido ligand. As revealed for the corresponding Ce(GaMe4)3‐reaction, formation of the diimide complexes proceeds via tetrametallic complexes of the type [Ce{(μ‐NC6H3iPr2‐2,6)(HNC6H3iPr2‐2,6)(MMe3)}]2 (Me=Al, Ga). Oxidation of the cerium(III) complex with hexachloroethane leads to a neutral CeIV diimide species. Partial protonolysis with phenylacetylene and hydrogenolysis via H3SiPh give conclusive insights into the reactive coordination sites of such diimide complexes.
Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators
Authors: Schierle Simone , Schmidt Jurema , Kaiser Astrid , Merk Daniel
Published: October 2018

Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist pranlukast on the farnesoid X receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub‐nanonmolar potency. The resulting FXR modulators lack any activity on CysLT1R and are characterized by high selectivity, high metabolic stability, and low toxicity. With their favorable in vitro profile, these SOSA‐derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.
Identification and Biological Evaluation of Novel Type II B‐RafV600E Inhibitors
Authors: Wang Peng‐Fei , Wang Ze‐Feng , Qiu Han‐Yue , Huang Yue , Hu Hui‐Min , Wang Zhong‐Chang , Zhu Hai‐Liang
Published: October 2018

The mitogen‐activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B‐RafV600E. New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B‐RafV600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3‐{3‐[4‐Chloro‐3‐(trifluoromethyl)phenyl]ureido}‐N‐[1‐(4‐methoxyphenyl)‐1H‐pyrazol‐4‐yl]benzamide was the most potent agent with IC50 values of 0.035±0.004 μm (B‐RafV600E kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B‐Raf inhibitor candidates.
Boolean Logic Gates Realized with Enzyme‐catalyzed Reactions – Unusual Look at Usual Chemical Reactions
Authors: Katz Evgeny
Published: October 2018

Research in the area of molecular computing systems, in the general framework of unconventional computing, has received high attention and resulted in rapid progress in formulating signal‐controlled switchable molecules capable to perform Boolean logic operations and basic arithmetic functions. Extension of this research to biomolecular systems allowed sophisticated computational functions much easier than using synthetic molecular and supramolecular species. The advantage of biomolecular systems comparing with synthetic molecular systems is in their complementarity and compatibility allowing easy assembling multi‐component systems from various biomolecules, thus increasing their functional complexity. While DNA‐based computing systems are promising faster computing than Si‐based electronics, at least for solving some combinatorial problems, due to massive parallel operation, enzyme‐based logic systems are less promising for computational applications in their narrow definition. However, they offer novel biosensing and bioactuation features operating in binary Yes/No format. The present review article overviews different kinds of enzyme logic gates exemplified with specific enzymatic reactions/cascades. Motivation for this research and its possible applications are discussed. The review will be helpful to researchers working in this specific area to see the comprehensive collection of logic operations performed by the enzyme reactions. The newcomers to the reviewed area will benefit from the example systems representing various logic functions systematically.
A Platform of Phenol‐Based Nitroxide Radicals as an “EPR Toolbox” in Supramolecular and Click Chemistry
Authors: Hauenschild Till , Hinderberger Dariush
Published: October 2018

A large number (63) of well‐defined nitroxide radicals, all phenol‐based TEMPO and PROXYL esters, were synthesized using different strategies based on well‐established Steglich esterifications. All of these radicals can be used as spin probes (SPs) and spin labels (SLs) for electron paramagnetic resonance (EPR) spectroscopy of supramolecular systems. Depending on the nature of the functional group(s) on each SP/SL, the synthesized nitroxide radicals serve as polyphilic molecular “toolbox” for the EPR‐spectroscopic detection and characterization of specific types of interactions, e. g. π–π interactions, sulfur‐sulfur interactions, hydrogen bonding, electrostatic and dipole‐dipole interactions, and van der Waals and hydrophobic interactions, in the presence of the selected supramolecular systems of interest (e. g. proteins, peptides). For each synthesized SP/SL the water solubility was gravimetrically determined for use in aqueous solution at pH 7.
SDN/NFV‐based handover management approach for ultradense 5G mobile networks
Authors: Gharsallah Amina , Zarai Faouzi , Neji Mahmoud
Published: October 2018

With the great increase of connected devices and new types of applications, mobile networks are witnessing exponential growth of traffic volume. To meet emerging requirements, it is widely agreed that the fifth‐generation mobile network will be ultradense and heterogeneous. However, the deployment of a high number of small cells in such networks poses challenges for the mobility management, including frequent, undesired, and ping‐pong handovers, not to mention issues related to increased delay and failure of the handover process. The adoption of software‐defined networking (SDN) and network function virtualization (NFV) technologies into 5G networks offers a new way to address the above‐mentioned challenges. These technologies offer tools and mechanisms to make networks flexible, programmable, and more manageable. The SDN has global network control ability so that various functions such as the handover control can be implemented in the SDN architecture to manage the handover efficiently. In this article, we propose a Software‐Defined Handover (SDHO) solution to optimize the handover in future 5G networks. In particular, we design a Software‐Defined Handover Management Engine (SDHME) to handle the handover control mechanism in 5G ultradense networks. The SDHME is defined in the application plane of the SDN architecture, executed by the control plane to orchestrate the data plane. Simulation results demonstrate that, compared with the conventional LTE handover strategy, the proposed approach significantly reduces the handover failure ratio and handover delay.
Cytomorphological features of cystic neutrophilic granulomatous mastitis on ThinPrep
Authors: Patel Ami , Sung Simon , Hoda Syed A. , Westblade Lars F. , D'Alfonso Timothy , Rao Rema
Published: October 2018

Granulomatous mastitis (GM) is an uncommon entity and challenging to distinguish from breast carcinoma, both clinically and upon imaging. Cystic neutrophilic granulomatous mastitis (CNGM) is a histologically distinct GM with clear “cystic” spaces (CS) surrounded by neutrophils and may contain Gram‐positive bacilli (such as Corynebacterium species). Cytologic features of GM, in particular CNGM, on ThinPrep (TP), are limited. We reviewed the cytological features of GM with a special focus on CNGM on TP. Ten cases with a concurrent/recent FNA and histologic diagnosis of GM or CNGM, or positive culture for Corynebacterium kroppenstedtii, were identified over an 11‐y period (2007‐2017). A double‐blinded review of the TP slides was performed by two independent cytopathologists. Data were analysed using Fisher's exact test. Six cases were histologically proven CNGM and 1 FNA only case had a positive culture for C. kroppenstedtii. Three had a histological diagnosis of GM. TP from the 7 CNGM cases demonstrated CS, including 1 case with a cellblock (CB) study showing well‐formed clear CS, while none of the non‐CNGM cases had CS (P = .01). Bacteria were identified within CS in 5 of 7 cases of CNGM. Multinucleated giant cells, granulomas, histiocytes, and neutrophils were variably observed. All histologically confirmed cases of CNGM showed distinct CS on TP. Cellblock study is a valuable adjunct to evaluate CNGM and for ancillary studies. Although our study was limited by a small sample size, our findings necessitate the need for studies with a larger cohort.
How Can We Understand Freshwater Soundscapes Without Fish Sound Descriptions?
Authors: Rountree Rodney A , Bolgan Marta , Juanes Francis
Published: October 2018

The ecological importance of the freshwater soundscape is just beginning to be recognized by society. Scientists are beginning to apply Passive Acoustic Monitoring (PAM) methods that are well established in marine systems to freshwater systems to map spatial and temporal patterns of behaviors associated with fish sounds as well as noise impacts on them. Unfortunately, these efforts are greatly hampered by a critical lack of data on the sources of sounds that make up the soundscape of freshwater habitats. A review of the literature finds that only 87 freshwater species have been reported to produce sounds in North America and Europe over the last 200 years, accounting for 5% of the known freshwater fish diversity. The problem is exacerbated by the general failure of researchers to report the detailed statistical descriptions of fish sound characteristics that are necessary to develop PAM programs. We suggest that publishers and editors should do more to encourage reporting of statistical properties of fish sounds. In addition, we call for research, academic, and government agencies to develop regional libraries of fish sounds to aid in PAM and anthropogenic noise impact studies.
Oxalate content of raw, wok‐fried, and juice made from bitter gourd fruits
Authors: Bong Wen‐Chun , Savage Geoffrey
Published: October 2018

The total, soluble, and insoluble oxalate contents of fresh and wok‐fried bitter gourd (Momordica charantia) fruits were extracted and measured using HPLC chromatography. Frozen bitter gourds were imported from Vietnam, and two cultivars characteristic of bitter gourd fruits grown in India and Malaysia were grown locally in the North Island of New Zealand. The mean total oxalate contents of ripe fruits from Vietnam, India, and Malaysia were 85.90 ± 8.60 mg/100 g wet matter (WM), while the mean total oxalates fell to 88.06 ± 0.95 mg/100 g FM when the fruits were wok‐fried. The mean soluble oxalate content of the total oxalate was 54.42% of the ripe fruits and 58.14% of the wok‐fried fruits. The three cultivars of bitter gourds were processed into juice by the addition of standard ingredients and then processed through a screw press to remove excess fiber. The final juices had an overall mean value of 27.11 mg of total oxalates/100 g WM; the mean soluble oxalate content was 85.5% of the total, which was much higher than that measured in the cooked gourds (mean 70.7%).
Glypican‐3‐Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma
Authors: Fu Ying , Urban Daniel J. , Nani Roger R. , Zhang Yi‐Fan , Li Nan , Fu Haiying , Shah Hamzah , Gorka Alexander P. , Guha Rajarshi , Chen Lu , Hall Matthew D. , Schnermann Martin J. , Ho Mitchell
Published: October 2018

Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican‐3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3‐specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody‐drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA‐damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3‐specific ADCs: hYP7‐DC and hYP7‐PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3‐positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7‐DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7‐DC in vitro and in vivo. Furthermore, single treatment of hYP7‐PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
Maternal serum uric acid concentration and pregnancy outcomes in women with pre‐eclampsia/eclampsia
Authors: Le Tam M. , Nguyen Long H. , Phan Nam L. , Le Duong D. , Nguyen Huy V.Q. , Truong Vinh Q. , Cao Thanh N.
Published: October 2018

Objectives

To determine the relationship between maternal serum uric acid levels and fetal/neonatal complications in women with pre‐eclampsia/eclampsia, and to establish a predictive threshold value.

Methods

A diagnostic test and historical cohort study conducted by prospective cross‐sectional data collection on pregnant women with pre‐eclampsia/eclampsia at Hue University Hospital, Vietnam, between March 2015 and July 2017. Pre‐eclampsia was diagnosed based on ACOG criteria. Serum uric acid levels were measured by enzymatic colorimetric testing using a Cobas c 501 analyzer (Roche Diagnostics, Mannheim, Germany). Fetal complications included intrauterine growth restriction, preterm delivery, fetal death, and neonatal death.

Results

There were 205 women enrolled. Serum uric acid at a cutoff of 393 μmol/L is a good predictor of fetal/neonatal complications (AUC 0.752), with 64.4% sensitivity and 79.5% specificity. High uric acid level (≥393 μmol/L) resulted in increased risk of preterm birth (OR 6.367, 95% CI 3.009–13.084), low Apgar scores (OR 5.514, 95% CI 1.877–16.198), intrauterine growth restriction (OR 7.188, 95% CI 3.592–14.382), and neonatal death (OR 7.818, 95% CI 1.614–37.867). There was no relationship between uric acid level and fetal death (OR 1.803, 95% CI 0.355–9.168).

Conclusions

Maternal serum uric acid concentration is a good predictor of fetal/neonatal outcomes in women with pre‐eclampsia/eclampsia.
Auditing the appropriateness of cesarean delivery using the Robson classification among women experiencing a maternal near miss
Authors: Saleh Gargari Soraya , Essén Birgitta , Fallahian Masoumeh , Mulic‐Lutvica Ajlana , Mohammadi Soheila
Published: October 2018

Objective

To evaluate appropriateness of cesarean delivery and cesarean delivery‐related morbidity among maternal near misses (MNMs) using the Robson ten‐group classification system.

Methods

In the present audit study, medical records were assessed for women who experienced MNM and underwent cesarean delivery at three university hospitals in Tehran, Iran, between March 1, 2012, and May 1, 2014. Local auditors assessed cesarean delivery indications and morbidity experienced. All records were re‐assessed using Swedish obstetric guidelines. Findings were reported using the Robson ten‐group classification system. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Results

Of the 61 women included, cesarean deliveries were more likely to be considered appropriate by local auditors compared with Swedish ones (OR 2.7, 95% CI 1.3–5.7). Cesarean delivery‐related morbidity was attributed to near‐miss events for 10 (16%) MNMs and was found to have aggravated 25 (41%). Of 16 women classified as Robson group 1–4, cesarean delivery‐related MNM was identified in 15 (94%), compared with 13 (43%) of 30 women in group 10. Cesarean delivery with appropriate indication was associated with very low likelihood of cesarean delivery‐related MNM (OR 0.2, 95% CI 0.1–0.6).

Conclusion

Cesarean delivery in the absence of appropriate indication could be an unsafe delivery choice. Audits using the Robson classification system facilitate understanding inappropriate cesarean delivery and its impact on maternal health.
Omnidirectional video delivery with decoder instance reduction
Authors: Kammachi‐Sreedhar Kashyap , Curcio Igor D.D.
Published: October 2018

The omnidirectional media streaming system as specified in motion pictures expert group (MPEG) is discussed. The paper provides a description of the viewport‐dependent delivery using adaptive bit rate streaming technology. It also describes the extractor method: an encapsulation technique defined in the ISO Base Media File Format. The use of the extractor technique reduces the number of decoder instances and also facilitates in providing an interoperable and standard conformant solution such that it enables the deployment of omnidirectional media applications in different heterogeneous devices.
Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice
Authors: Alam Imranul , Oakes Dana K , Reilly Austin M , Billingsley Caylin , Sbeta Shahed , Gerard‐O'Riley Rita L , Acton Dena , Sato Amy , Bellido Teresita , Econs Michael J
Published: October 2018

Glucocorticoids (GC) are commonly used for the treatment of a wide variety of autoimmune, pulmonary, gastrointestinal, and malignancy conditions. One of the devastating side effects of GC use is osteoporotic fractures, particularly in the spine and hip. Bisphosphonates (BP) are the most commonly prescribed pharmacological agents for the prevention and treatment of GC‐induced osteoporosis (GIO). However, GIO is marked by reduced bone formation and BP serves mainly to decrease bone resorption. The WNT signaling pathway plays a major role in bone and mineral homeostasis. Previously, we demonstrated that overexpression of WNT16 in mice led to higher bone mineral density and improved bone microarchitecture and strength. We hypothesized that WNT16 overexpression would prevent bone loss due to glucocorticoid treatment in mice. To test our hypothesis, we treated adult wild‐type and WNT16‐transgenic mice with vehicle and GC (prednisolone; 2.1 mg/kg body weight) via slow‐release pellets for 28 days. We measured bone mass and microarchitecture by dual‐energy X‐ray absorptiometry (DXA) and micro‐CT, and performed gene expression and serum biochemical analysis. We found that GC treatment compared with the vehicle significantly decreased femoral areal bone mineral density (aBMD), bone mineral content (BMC), and cortical bone area and thickness in both wild‐type and transgenic female mice. In contrast, the trabecular bone parameters at distal femur were not significantly changed by GC treatment in male and female mice for both genotypes. Further, we observed significantly lower level of serum P1NP and a tendency of higher level of serum TRAP in wild‐type and transgenic mice due to GC treatment in both sexes. Gene expression analysis showed lower mRNA levels of Wnt16, Opg, and Opg/Rankl ratio in GC‐treated female mice for both genotypes compared with the sex‐matched vehicle‐treated mice. These data suggest that although WNT16 overexpression resulted in higher baseline bone mineral density and bone volume per trabecular volume (BV/TV) in the transgenic mice, this was insufficient to prevent bone loss in mice due to glucocorticoid treatment. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population
Authors: Hughes Julie M , McKinnon Craig J , Taylor Kathryn M , Kardouni Joseph R , Bulathsinhala Lakmini , Guerriere Katelyn I , Popp Kristin L , Bouxsein Mary L , Proctor Susan P , Matheny Ronald W
Published: October 2018

Stress fractures are common in military personnel and endurance athletes, and nonsteroidal anti-inflammatory drug (NSAID) use is widespread in these populations. NSAIDs inhibit prostaglandin synthesis, which blunts the anabolic response of bone to physical activity and could therefore increase risk of stress fracture. The objective of this study was to determine whether prescribed NSAIDs were associated with stress fracture diagnoses among US Army soldiers. We also aimed to establish whether acetaminophen, an analgesic alternative to NSAIDs, was associated with stress fracture risk. A nested case-control study was conducted using data from the Total Army Injury and Health Outcomes Database from 2002 to 2011 (n = 1,260,168). We identified soldiers with a diagnosis of stress fracture (n = 24,146) and selected 4 controls per case matched on length of military service (n = 96,584). We identified NSAID and acetaminophen prescriptions 180 to 30 days before injury (or match date). We also identified soldiers who participated in basic combat training (BCT), a 10-week period of heightened physical activity at the onset of Army service. Among these individuals, we identified 9088 cases and 36,878 matched controls. Conditional logistic regression was used to calculate incident rate ratios (RR) for stress fracture with adjustment for sex. NSAID prescription was associated with a 2.9-fold increase (RR = 2.9, 95% confidence interval [CI] 2.8–2.9) and acetaminophen prescription with a 2.1-fold increase (RR = 2.1, 95% CI 2.0–2.2) in stress fracture risk within the total Army population. The risk was more than 5-fold greater in soldiers prescribed NSAIDs (RR = 5.3, 95% CI 4.9–5.7) and more than 4-fold greater in soldiers prescribed acetaminophen (RR = 4.4, 95% CI 3.9–4.9) during BCT. Our results reveal an association between NSAID and acetaminophen prescriptions and stress fracture risk, particularly during periods of heightened physical activity. Prospective observational studies and randomized controlled trials are needed to support these findings before clinical recommendations can be made. © 2018 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
Effect of Anti-TGF-β Treatment in a Mouse Model of Severe Osteogenesis Imperfecta
Authors: Tauer Josephine T , Abdullah Sami , Rauch Frank
Published: October 2018

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I encoding genes. Recent studies in mouse models of recessive OI, Crtap-/- mice, and dominant OI, +/G610C mice, found that application of a transforming growth factor beta (TGF-β) neutralizing antibody 1D11 rescues the bone phenotype. In the present study, we investigated TGF-β signaling in a mouse model of severe dominant OI with a high incidence of spontaneous fractures, Col1a1Jrt/+ mice, and the effect of TGF-β neutralizing antibody 1D11 on bone phenotype in 8-week-old mice. Col1a1Jrt/+ mice had elevated TGF-β signaling in bone tissue. Treatment of Col1a1Jrt/+ mice with 1D11 was associated with increased bone length but had no significant effect on bone mass or bone mechanical properties, and no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity) or resorption (tartrate-resistant acid phosphatase) were found. Our data thus indicate that the TGF-β neutralizing antibody 1D11 is not effective in a mouse model of dominant OI with a high incidence of spontaneous fractures. © 2018 American Society for Bone and Mineral Research.
Curved planar reformatting and convolutional neural network‐based segmentation of the small bowel for visualization and quantitative assessment of pediatric Crohn's disease from MRI
Authors: Lamash Yechiel , Kurugol Sila , Freiman Moti , Perez‐Rossello Jeannette M. , Callahan Michael J. , Bousvaros Athos , Warfield Simon K.
Published: October 2018

Background

Contrast‐enhanced MRI of the small bowel is an effective imaging sequence for the detection and characterization of disease burden in pediatric Crohn's disease (CD). However, visualization and quantification of disease burden requires scrolling back and forth through 3D images to follow the anatomy of the bowel, and it can be difficult to fully appreciate the extent of disease.

Purpose

To develop and evaluate a method that offers better visualization and quantitative assessment of CD from MRI.

Study Type

Retrospective.

Population

Twenty‐three pediatric patients with CD.

Field Strength/Sequence

1.5T MRI system and T1‐weighted postcontrast VIBE sequence.

Assessment

The convolutional neural network (CNN) segmentation of the bowel's lumen, wall, and background was compared with manual boundary delineation. We assessed the reproducibility and the capability of the extracted markers to differentiate between different levels of disease defined after a consensus review by two experienced radiologists.

Statistical Tests

The segmentation algorithm was assessed using the Dice similarity coefficient (DSC) and boundary distances between the CNN and manual boundary delineations. The capability of the extracted markers to differentiate between different disease levels was determined using a t‐test. The reproducibility of the extracted markers was assessed using the mean relative difference (MRD), Pearson correlation, and Bland–Altman analysis.

Results

Our CNN exhibited DSCs of 75 ± 18%, 81 ± 8%, and 97 ± 2% for the lumen, wall, and background, respectively. The extracted markers of wall thickness at the location of min radius (P = 0.0013) and the median value of relative contrast enhancement (P = 0.0033) could differentiate active and nonactive disease segments. Other extracted markers could differentiate between segments with strictures and segments without strictures (P < 0.05). The observers' agreement in measuring stricture length was >3 times superior when computed on curved planar reformatting images compared with the conventional scheme.

Data Conclusion

The results of this study show that the newly developed method is efficient for visualization and assessment of CD.

Level of Evidence: 4

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2019;49:1565–1576.
Use of induced pluripotent stem cells (iPSCs) and cerebral organoids in modeling the congenital infection and neuropathogenesis induced by Zika virus
Authors: Majolo Fernanda , Marinowic Daniel Rodrigo , Moura Adriana Ávila , Machado Denise Cantarelli , da Costa Jaderson Costa
Published: October 2018

Infection with Zika virus (ZIKV) was recently demonstrated to be associated with damage to the central nervous system, especially microcephaly and the Guillain‐Barré syndrome. This finding had alarmed public health agencies and mobilized institutions around the world to search for more information about the virus, its effects, pathophysiological mechanisms, and potential immunizations and treatments. Given the increasing interest in using iPSCs and cerebral organoids to model the congenital infection and neuropathogenesis induced by ZIKV, the aim of this review was to present an up‐to‐date summary of the publications on the association of ZIKV with microcephaly, using iPSCs and organoids. According to our review, the number of studies has decreased concomitantly with a decrease in the number of cases. The presence of subclinical lesions at birth, which may eventually present cognitive or behavioral problems in the future, suggests that persistent research efforts on the virus should be undertaken by the global health community till the threat is completely wiped out.
Citrulline Generation Test: What Does It Measure?
Authors: Mohammad Mahmoud A. , Didelija Inka C. , Stoll Barbara , Marini Juan C.
Published: October 2018

Background

The citrulline generation test (CGT) has been proposed as a tool to determine gut function. However, the increase in plasma citrulline concentration that follows a bolus dose of alanyl‐glutamine may also result from a reduction in citrulline clearance due to competition with glutamine for transport.

Materials and Methods

A swine model was developed, and stable isotope tracers were used to determine the mechanism behind the increase in plasma citrulline that follows a bolus dose of alanyl‐glutamine. Plasma concentrations and enrichments were determined, and a non–steady‐state model was used to calculate rates of appearance, disappearance, and conversion.

Results

The pig model recapitulated the increase in plasma citrulline observed in humans after a dose of alanyl‐glutamine. The dipeptide was rapidly hydrolyzed to its constitutive amino acids. Both citrulline plasma concentration and citrulline rate of appearance increased by ≈45% after the bolus dose of alanyl‐glutamine. The conversion of citrulline to arginine and the rate of appearance of arginine also increased. Glutamine contributed up to 25% ± 2% of the rate of appearance of citrulline. No changes in the rate of disappearance of citrulline were observed.

Conclusion

Our results indicate that a single bolus dose of alanyl‐glutamine increases plasma citrulline concentration by increasing citrulline production without any effect on citrulline disposal. Our findings strongly indicate that the CGT assesses the metabolic response of the gut and that CGT can become a useful tool to evaluate gut mass and function.
Children with unilateral cochlear nerve canal stenosis have bilateral cochleovestibular anomalies
Authors: Vilchez‐Madrigal Luis D. , Blaser Susan I. , Wolter Nikolaus E. , James Adrian L. , Papsin Blake C. , Gordon Karen A. , Cushing Sharon L. , Propst Evan J.
Published: October 2018

Objectives/Hypothesis

To investigate the cochleovestibular apparatus bilaterally in children with isolated unilateral bony cochlear nerve canal (bCNC) stenosis.

Study Design

Retrospective review.

Methods

Imaging studies of children with unilateral bCNC stenosis (<1.0 mm) on computed tomography imaging (N = 36) were compared with controls imaged due to trauma without temporal bone injury (N = 32). Twenty‐six measurements were obtained in each ear, assessing the bony internal auditory canal (IAC), cochlea, and vestibular end‐organs, and were analyzed using one‐way analysis of variance for intersubject comparisons and paired t tests for intrasubject comparisons with a Bonferroni adjustment for multiple comparisons (P = .0006).

Results

Patients with bCNC stenosis had a smaller IAC (P < .000) and cochlea (P < .000) on the stenotic side as compared with controls. Although the vestibular end‐organ was also smaller in bCNC ears, this difference was not significant. The contralateral ear also had a smaller bCNC (P < .000) and cochlea (P < .000) as compared with controls, although to a lesser degree than the stenotic side.

Conclusions

Children with unilateral bCNC stenosis have abnormal biometry of both the cochlea and the vestibular end‐organ in the affected and the normal contralateral ear as compared with controls.

Level of Evidence

3b

Laryngoscope, 129:2403–2408, 2019