bluuebunny/crossref_metadata_2025 huggingface dataset:
Mouse trigeminal neurons respond to kokumi substances
Authors: Leijon Sara C.M. , Chaudhari Nirupa , Roper Stephen D.
Published: February 2019

1.

Using in vivo confocal Ca2+ imaging, we investigated whether oral application of kokumi substances elicits responses in trigeminal somatosensory ganglion neurons of the mouse. Our results show that 100 μM γEVG (γ-Glu-Val-Gly), a potent kokumi stimulus, evokes responses in a very small fraction (0.6 %) of neurons in area V3 (oral sensory field) of the trigeminal ganglion. By comparison, cooled artificial saliva elicited thermal-evoked responses in >7 % of V3 trigeminal ganglion neurons. γEVG-evoked responses were small and quite variable, with latencies ranging from 2 to over 200 sec. Co-application of the calcium sensing receptor (CaSR) inhibitor NPS-2143 significantly decreased γEVG-evoked activity. Furthermore, we show that 4 additional kokumi substances evoked responses in mouse trigeminal ganglion neurons. All neurons responding to kokumi compounds were small cells, with mean diameters below 20 μm. In summary, our data show that certain physiological and pharmacological properties of responses to kokumi compounds can be recorded from sensory neurons in the trigeminal ganglion of living mice. Thus, sensory neurons in the somatosensory trigeminal ganglia may transmit signals from the oral cavity to the central nervous system to generate the texture perceptions that are part of the enigmatic sensations evoked by kokumi substances.
Age-structure as key to delayed logistic proliferation of scratch assays
Authors: Bobadilla Ana Victoria Ponce , Carraro Thomas , Byrne Helen M. , Maini Philip K. , Alarcón Tomás
Published: February 2019

Scratch assays are in-vitro methods for studying cell migration. In these experiments, a scratch is made on a cell monolayer and recolonisation of the scratched region is imaged to quantify cell migration rates. Typically, scratch assays are modelled by reaction diffusion equations depicting cell migration by Fickian diffusion and modelling proliferation by a logistic term. In a recent paper (Jin, W. et al. Bull Math Biol (2017)), the authors observed experimentally that during the early stage of the recolonisation process, there is a disturbance phase where proliferation is not logistic, and this is followed by a growth phase where proliferation appears to be logistic. The authors did not identify the precise mechanism that causes the disturbance phase but showed that ignoring it can lead to incorrect parameter estimates. The aim of this work is to show that a non-linear age-structured population model can account for the two phases of proliferation in scratch assays. The model consists of an age-structured cell cycle model of a cell population, coupled with an ordinary differential equation describing the resource concentration dynamics in the substrate. The model assumes a resource-dependent cell cycle threshold age, above which cells are able to proliferate. By studying the dynamics of the full system in terms of the subpopulations of cells that can proliferate and the ones that can not, we are able to find conditions under which the model captures the two-phase behaviour. Through numerical simulations we are able to show that the resource concentration in the substrate regulates the biphasic dynamics.
Topological data analysis reveals principles of chromosome structure throughout cellular differentiation
Authors: Sauerwald Natalie , Shen Yihang , Kingsford Carl
Published: February 2019

Three-dimensional chromosome structure has a significant influence in many diverse genomic processes and has recently been shown to relate to cellular differentiation. Many methods for describing the chromosomal architecture focus on specific substructures such as topologically-associating domains (TADs) or compartments, but we are still missing a global view of all geometric features of chromosomes. Topological data analysis (TDA) is a mathematically well-founded set of methods to derive robust information about the structure and topology of data sets, making it well-suited to better understand the key features of chromosome structure. By applying TDA to the study of chromosome structure through differentiation across three cell lines, we provide insight into principles of chromosome folding generally, and observe structural changes across lineages. We identify both global and local differences in chromosome topology through differentiation, identifying trends consistent across human cell lines.

Availability

Scripts to reproduce the results from this study can be found at https://github.com/Kingsford-Group/hictda

Contact

carlk@cs.cmu.edu
Optimal Scheduling of Bevacizumab and Pemetrexed/cisplatin Dosing in Non-Small Cell Lung Cancer
Authors: Schneider Benjamin K , Boyer Arnaud , Ciccolini Joseph , Barlesi Fabrice , Wang Kenneth , Benzekry Sebastien , Mochel Jonathan P
Published: February 2019

Bevacizumab-pemetrexed/cisplatin (BEV-PEM/CIS) is a first line therapeutic for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab potentiates PEM/CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV-PEM/CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV-PEM/CIS pharmacodynamic modeling in NSCLC-bearing mice to estimate the optimal gap in the scheduling of sequential BEV-PEM/CIS. We predicted the optimal gap in BEV-PEM/CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy loss in scheduling BEV-PEM/CIS at too great of a gap is much less than the efficacy loss in scheduling BEV-PEM/CIS at too short of a gap.
Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells
Authors: Polak Marta E , Sirvent Sofia , Clayton Kalum , Davies James , Vallejo Andres F. , Wu Zhiguo , Woo Jeongmin , Riddell Jeremy , Stumpf Patrick , Rose-Zerilli Matthew , West Jonathan , Pujato Mario , Chen Xiaoting , Woelk Christopher H. , MacArthur Ben , Ardern-Jones Michael , Friedmann Peter S , Weirauch Matthew T. , Singh Harinder
Published: February 2019

Langerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.
Spatiotemporal Coupling of Vessel Cavitation and Discharge of Stored Xylem Water in a Tree Sapling
Authors: Knipfer Thorsten , Reyes Clarissa , Earles J. Mason , Berry Z. Carter , Johnson Daniel M. , Brodersen Craig R. , McElrone Andrew J.
Published: February 2019

Water discharge from stem internal storage compartments is thought to minimize the risk of vessel cavitation. Based on this concept, one would expect that water storage compartments involved in the buffering of xylem tensions empty before the onset of vessel cavitation under drought stress, and potentially refill after soil saturation. However, scant in vivo data exist that elucidate this localized spatiotemporal coupling. In this study on intact saplings of American chestnut (Castanea dentata), x-ray computed microtomography (microCT) showed that the xylem matrix surrounding vessels releases stored water and becomes air-filled either concurrent to or after vessel cavitation under progressive drought stress. Among annual growth rings, the xylem matrix of the current year remained largely water-filled even under severe drought stress. In comparison, microtomography images collected on excised stems showed that applied pressures of much greater than 0 MPa were required to induce water release from the xylem matrix. Viability staining highlighted that water release from the xylem matrix was associated primarily with emptying of dead fibers. Refilling of the xylem matrix and vessels was detected in intact saplings when the canopy was bagged and stem water potential was close to 0 MPa, and in leafless saplings over the winter period. In conclusion, this study indicates that the bulk of water stored in the xylem matrix is released after the onset of vessel cavitation, and suggests that capillary water contributes to overall stem water storage under drought but is not used primarily for the prevention of drought-induced vessel cavitation in this species.
Crystal structure, Hirshfeld surface analysis and frontier molecular orbital analysis of (E)-4-bromo-N′-(2,3-dichlorobenzylidene)benzohydrazide
Authors: Sivajeyanthi Palaniyappan , Jeevaraj Muthaiah , Edison Bellarmin , Balasubramani Kasthuri
Published: February 2019

The title Schiff base compound, C14H9BrCl2N2O, displays a trans or E configuration with respect to the C=N bond, with a dihedral angle 15.7 (2)° formed between the benzene rings. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds, forming chains along [001] which enclose R
1
2(6) loops. The intermolecular interactions were investigated by Hirshfeld surfaces analysis and two-dimensional fingerprint plots. The DFT-B3LYP/6–311 G++(d,p) method was used to determine the HOMO–LUMO energy levels.
Diethyl 3,3′-[(4-fluorophenyl)methylidene]bis(1H-indole-2-carboxylate)
Authors: Li Yu-Long , Zhou Jin , Zhong Kai-Long , Shi Xing-Hao , Zhang Zhi-Yuan , Jiang Hong , Sun Hong-Shun
Published: February 2019

In the title compound, C29H25FN2O4, the mean planes of the indole ring systems (r.m.s. deviations = 0.0107 and 0.0158 Å) are approximately perpendicular to each other, subtending a dihedral angle of 87.43 (16)°. The 4-fluorophenyl ring is twisted by 77.6 (2) and 83.0 (2)° with respect to the two indole ring systems. In the crystal, molecules are linked by N—H...O hydrogen bonds, forming layers parallel to the (001) plane. The layers are linked by C—H...π interactions, forming a supramolecular three-dimensional network.
(Methanol-κO)bis(thiocyanato-κN)[2,4,6-tris(pyridin-2-yl)-1,3,5-triazine-κ3N2,N1,N6]nickel(II) methanol monosolvate
Authors: Ha Kwang
Published: February 2019

In the structure of the title compound, [Ni(NCS)2(C18H12N6)(CH3OH)]·CH3OH, the NiIIion is six-coordinated in an octahedral coordination environment defined by three N atoms from a 2,4,6-tris(pyridin-2-yl)-1,3,5-triazine ligand, two N atoms from two mutuallycis-positioned SCN−anions and one O atom from a methanol ligand. The complex and methanol solvent molecules are linked by intermolecular hydrogen bonds. In the crystal, the complex molecules are stacked in columns parallel to thebaxis.
Varying the spatial arrangement of synthetic herbivore‐induced plant volatiles and companion plants to improve conservation biological control
Authors: Jaworski Coline C. , Xiao Da , Xu Qingxuan , Ramirez‐Romero Ricardo , Guo Xiaojun , Wang Su , Desneux Nicolas
Published: February 2019

Conservation biological control aims to control pests by promoting wild populations of natural enemies. One challenge is to attract and retain efficient natural enemies in crop fields, which often are a suboptimal environment. Towards this goal, the attract‐and‐reward strategy relies on combining attractive synthetically produced herbivore‐induced plant volatiles (HIPVs) with companion plants (non‐crop plants which provide alternative resources to the targeted natural enemies). Although severely overlooked, the spatial arrangement of HIPV dispensers and rewards inside crop fields may strongly influence the foraging behaviour and persistence of natural enemies and thus the success of this pest management strategy.

We tested the impact of two contrasting spatial arrangements of HIPV dispensers and rewards, alternatively inside and around a block of target apple trees, on the efficacy of the biological control of Aphis citricola populations by the common predatory ladybird Propylea japonica in apple orchards in northern China. We used synthetic methyl salicylate (MeSA) as an attractant and the companion plant Calendula officinalis as a reward. To better understand how the spatial arrangement of MeSA dispensers and companion plants affected the attraction and foraging behaviour of adult ladybirds, we conducted indoor experiments in a flight mill, an olfactometer and a wind‐tunnel.

Blocks of target trees treated with MeSA dispensers inside and companion plants around provided the most efficient pest control in orchards, compared with the opposite spatial arrangement.

The synthetic MeSA dispenser and the companion plant synergistically attracted ladybirds in the olfactometer and enhanced their flight activity in the flight mill. In the wind‐tunnel, MeSA served as a spatial cue for ladybirds to find nearby prey, while companion plants were sought in the absence of prey.

Synthesis and applications. This study aims to further improve aphid control in apple orchards through a careful spatial arrangement of herbivore‐induced plant volatiles dispensers (HIPVs) and rewards (companion plants) in optimized attract‐and‐reward strategies. Without such assessment, these strategies may be hazardous even with well‐identified targeted natural enemies. Associated lab experiments highlight that interactions between HIPVs and companion plants influence ladybird foraging pattern, and that their spatial arrangement can modulate the ability of such key predators to find their prey.
An Olympic‐sized Challenge: Effect of Organizational Pathology on Maintaining and Repairing Organizational Legitimacy in Sports Governing Bodies
Authors: Anastasiadis Stephanos , Spence Laura J.
Published: February 2019

Private organizations increasingly wield public authority, with substantial impact on the lives of individual persons. Such authority is often paired with enhanced public scrutiny and decreased trust in the relevant organization, leading to a loss of legitimacy. This paper uses sports governing bodies to contribute to the literature on governance by developing theory on the interaction between organizational legitimacy and pathological internal structures. It takes a nuanced view of legitimacy and extends a model of organizational pathology. While primarily conceptual, the paper uses the well‐documented cases of the International Olympic Committee and, to a lesser extent, FIFA to illustrate how organizational pathology can not only undermine an organization's legitimacy, but can also interfere with its ability to perceive a path to legitimacy repair, even when it recognizes the necessity of doing so. The paper concludes with recommendations for practice and suggestions for future research looking beyond sports governing bodies.
Is Investor Attention for Sale? The Role of Advertising in Financial Markets
Authors: MADSEN JOSHUA , NIESSNER MARINA
Published: February 2019

Prior research documents capital market benefits of increased investor attention to accounting disclosures and media coverage; however, little is known about how investors and markets respond to attention‐grabbing events that reveal little nonpublic information. We use daily firm advertising data to test how advertisements, which are designed to attract consumers' attention, influence investors' attention and financial markets (i.e., spillover effects). Exploiting the fact that firms often advertise at weekly intervals, we use an instrumental variables approach to provide evidence that print ads, especially in business publications, trigger temporary spikes in investor attention. We further find that trading volume and quoted dollar depths increase on days with ads in a business publication. We contribute to research on how management choices influence firms' information environments, determinants and consequences of investor attention, and consequences of advertising for financial markets.
Early referral for endoscopy is the most appropriate management strategy in cases of food bolus obstruction
Authors: Fulforth James M , Chen Amanda J , Falvey James D
Published: February 2019

Objective

To investigate the characteristics of patients presenting with oesophageal food bolus obstruction (FBO) who achieve early resolution of symptoms, and to assess the impact of medical therapies on the overall time course of FBO.

Methods

A retrospective observational study was performed in a university teaching hospital with regional acute endoscopy services. Patients presenting with symptoms of FBO were identified through clinical coding and demographic, clinical and endoscopic data extracted from the electronic medical record. The primary outcome was the time to resolution defined as the earliest of symptom resolution, endoscopic or surgical intervention or discharge.

Results

A total of 116 patients presented with symptoms of FBO. Twenty‐seven (23.3%) had early resolution of symptoms and were discharged from the ED without acute endoscopy, the remainder were admitted for further management. Patients discharged from the ED presented to hospital sooner after the onset of symptoms (137 vs 288 min, P < 0.05), but did not differ from those admitted in any other characteristic. Seventy‐one (61.2%) patients received medical therapy. There was no statistical difference in the time to resolution between those who received medical therapy and those who did not. Furthermore, the use of medical therapy was associated with a delay in referral for endoscopy (140 vs 100 min, P < 0.05).

Conclusions

Time from symptom onset to presentation is the only predictor of early resolution from FBO, while medical therapy is ineffective in relieving obstruction and may delay definitive therapy. We recommend the use of an institutional management plan to facilitate early access to endoscopy in cases of FBO.
Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging
Authors: Semba Richard D. , Zhang Pingbo , Adelnia Fatemeh , Sun Kai , Gonzalez‐Freire Marta , Salem Norman , Brennan Nicholas , Spencer Richard G. , Fishbein Kenneth , Khadeer Mohammed , Shardell Michelle , Moaddel Ruin , Ferrucci Luigi
Published: February 2019

The decrease in skeletal muscle mitochondrial oxidative capacity with age adversely affects muscle strength and physical performance. Factors that are associated with this decrease have not been well characterized. Low plasma lysophosphatidylcholines (LPC), a major class of systemic bioactive lipids, are predictive of aging phenotypes such as cognitive impairment and decline of gait speed in older adults. Therefore, we tested the hypothesis that low plasma LPC are associated with impaired skeletal muscle mitochondrial oxidative capacity. Skeletal muscle mitochondrial oxidative capacity was measured using in vivo phosphorus magnetic resonance spectroscopy (31P‐MRS) in 385 participants (256 women, 129 men), aged 24–97 years (mean 72.5) in the Baltimore Longitudinal Study of Aging. Postexercise recovery rate of phosphocreatine (PCr), kPCr, was used as a biomarker of mitochondrial oxidative capacity. Plasma LPC were measured using liquid chromatography–tandem mass spectrometry. Adults in the highest quartile of kPCr had higher plasma LPC 16:0 (p = 0.04), 16:1 (p = 0.004), 17:0 (p = 0.01), 18:1 (p = 0.0002), 18:2 (p = 0.002), and 20:3 (p = 0.0007), but not 18:0 (p = 0.07), 20:4 (p = 0.09) compared with those in the lower three quartiles in multivariable linear regression models adjusting for age, sex, and height. Multiple machine‐learning algorithms showed an area under the receiver operating characteristic curve of 0.638 (95% confidence interval, 0.554, 0.723) comparing six LPC in adults in the lower three quartiles of kPCr with the highest quartile. Low plasma LPC are associated with impaired mitochondrial oxidative capacity in adults.
Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants
Authors: Norman Elisabeth , Kindblom Jenny M. , Rane Anders , Berg Ann‐Cathrine , Schubert Ulf , Hallberg Boubou , Fellman Vineta
Published: February 2019

Aim

Fentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5 μg/mL for procedural pain.

Methods

Preterm infants were given 0.5 (n = 20, median gestational age 26.5; range 23.3–34.1 weeks) and 2 μg/kg (n = 8, 27.4; 25.3–30.7 weeks) fentanyl, respectively, before skin‐breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24 hours. Physiologic parameters were monitored and pain scores assessed.

Results

The median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35 ng/mL at 15–31 minutes, two and four hours and the half‐lives were 1.6 to 20.5 or 4.1 to 32.6 hours for the low‐ and high‐dose groups, respectively. A significant correlation was seen between weight at study inclusion and half‐life (Spearman′s r = −0.9, p < 0.001), volume of distribution (r = −0.8, p < 0.01) and clearance (r = −0.9, p < 0.01) in the low‐dose group (n = 9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated.

Conclusion

The inter‐individual variation of fentanyl pharmacokinetics is large in preterm infants, and the dose of 0.5 μg/kg seems not effective for skin‐breaking procedures.
Preserved cardiovascular homeostasis despite blunted acetylcholine‐induced dilation in mice with endothelial muscarinic M3 receptor deletion
Authors: Rhoden Alexandra , Speiser Jakob , Geertz Birgit , Uebeler June , Schmidt Kjestine , de Wit Cor , Eschenhagen Thomas
Published: February 2019

Aim

Muscarinic acetylcholine receptors (AChMR1‐5) are fundamental for cellular responses upon release of the neurotransmitter acetylcholine (ACh) from parasympathetic nerve fibers. ACh is the prototypical agonist stimulating endothelium‐dependent dilation, but most blood vessels lack parasympathetic innervation, raising the question as to the physiologic function of endothelial AChMR in vivo. Global deletion of AChM3R revealed a role in ACh‐induced vasodilation in vitro and food uptake, but overall cardiovascular homeostasis has not been examined thoroughly.

Methods

To characterize the function of endothelial AChM3R in vivo, we deleted AChM3R specifically in endothelial cells with an inducible or a non‐inducible Cre‐loxP system, driven by the endothelium‐specific promoters VE‐cadherin (indEC‐M3R−/−) or TIE2 (tek2; EC‐M3R−/−) and examined arteriolar dilation in the cremaster microcirculation, arterial pressure and cardiac function in these mice in vivo.

Results

In both EC‐M3R−/−, ACh‐induced dilation was strongly impaired in arterioles in vivo, while responses to other dilators were mostly preserved. However, arterial pressure (indEC‐M3R−/−) and arteriolar tone as a surrogate for peripheral vascular resistance did not differ between EC‐M3R−/− and control mice. Aged EC‐M3R−/− mice (74‐78 weeks) did not differ in body weight, heart weight, cardiac structure or contractile function from controls.

Conclusion

We conclude that AChM3R elicits the endothelium‐dependent dilation upon ACh also in arterioles in vivo. Despite this prominent role, the endothelial deletion of AChM3R does not affect overall cardiovascular homeostasis. Thus, their physiologic function in endothelial cells remains obscure.
Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach
Authors: Tang Dan , Song Bai‐Li , Yan Miao , Zou Jian‐Jun , Zhang Min , Zhou Hua‐Ying , Wang Feng , Xiao Yi‐Wen , Xu Ping , Zhang Bi‐Kui , Chen Xi‐Jing , Xiang Da‐Xiong , Linh Banh Hoan
Published: February 2019

Voriconazole is a broad‐spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (Vd) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.
What makes the α1A‐adrenoceptor gene product assume an α1L‐adrenoceptor phenotype?
Authors: White Carl W. , da Silva Junior Edilson Dantas , Lim Linzi , Ventura Sabatino
Published: February 2019

The α1A‐adrenoceptor is abundantly expressed in the lower urinary tract and is the principal therapeutic target for the symptomatic treatment of lower urinary tract symptoms in men. Prazosin has a lower affinity for the lower urinary tract α1A‐adrenoceptor than α1A‐adrenoceptors found in other parts of the body. This has led to the lower urinary tract α1A‐adrenoceptor being subclassified as an α1L‐adrenoceptor. It was demonstrated that this pharmacologically distinct α1L‐adrenoceptor is a product of the α1A‐adrenoceptor gene, but the mechanism by which this altered phenotype is achieved remains a mystery. Hypotheses for this altered pharmacology include the presence of an interacting protein such as cysteine‐rich with EGF‐like domain (CRELD) 1 or other GPCRs such as the CXCR2 chemokine or 5‐HT1B receptor. Alternatively, the influence of breast cancer resistance protein (BCRP) efflux transporters on the pharmacology of α1A‐adrenoceptors has also been investigated. These and other hypotheses will be described and discussed in this review.

Linked Articles

This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc
Sulfasalazine could modulate the CD44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer
Authors: Ogihara Koichiro , Kikuchi Eiji , Okazaki Shogo , Hagiwara Masayuki , Takeda Toshikazu , Matsumoto Kazuhiro , Kosaka Takeo , Mikami Shuji , Saya Hideyuki , Oya Mototsugu
Published: February 2019

The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9‐xCT system in order to enhance cisplatin (CDDP)‐induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer‐specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho‐p38MAPK protein expression by SSZ with or without CDDP were assessed in MBT‐2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT‐2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT‐2V cells by inhibiting CD44v9 expression and upregulating phospho‐p38MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT‐2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.
Development of miRNA‐based therapeutic approaches for cancer patients
Authors: Takahashi Ryou‐u , Prieto‐Vila Marta , Kohama Isaku , Ochiya Takahiro
Published: February 2019

Over the past few decades, siRNA and miRNA have attracted a great deal of attention from researchers and clinicians. These molecules have been extensively studied from the standpoint of developing biopharmaceuticals against various diseases, including heart disease, diabetes and cancers. siRNA suppresses only a single target, whereas each miRNA regulates the expression of multiple target genes. More importantly, because miRNA are also secreted from cancer cells, and their aberrant expression is associated with tumor development and progression, they represent not only therapeutic targets but also promising biomarkers for diagnosis and prognosis. Therefore, miRNA may be more effective tools against cancers, in which multiple signal pathways are dysregulated. In this review, we summarize recent progress in the development of miRNA therapeutics for the treatment of cancer patients, and describe delivery systems for oligonucleotide therapeutics.
Growth hormone therapy and short stature‐related distress: A randomized placebo‐controlled trial
Authors: Shemesh‐Iron Moran , Lazar Liora , Lebenthal Yael , Nagelberg Nessia , Tenenbaum Ariel , Ezra Revital , Leffler Nir , Yackobovitch‐Gavan Michal , Schoenberg‐Taz Michal , Phillip Moshe
Published: February 2019

Context

Growth hormone (GH) treatment of short healthy children is based on the belief that short stature is associated with psychosocial problems and a diminished quality of life.

Objective

To determine the impact of GH therapy on psychosocial well‐being and the ability of psychological metrics to define short stature‐related distress.

Methods

Sixty prepubertal boys with idiopathic short stature (age: 10.0 ± 1.4 years, height‐SDS: −2.38 ± 0.3) were enrolled in this 4‐year intervention study (1‐year double‐blinded, randomized, placebo‐controlled [GH/placebo‐2:1] and 3‐year open‐labelled GH therapy). Explicit (conscious/voluntary) psychological metrics (Pediatric Quality of Life Inventory [PedsQL], Silhouette Apperception Test [SAT], Rosenberg Self‐Esteem Scale [RSES], Child Behavior Checklist [CBCL]) and implicit (unconscious/involuntary) psychological metrics (Single‐Category Implicit Association Test for height [SC‐IAT‐H], Height Perception Picture Test [HPPT]). Psychosocial evaluations were performed at study entry, after 1 and 4 years.

Results

At study entry, PedsQL of boys with idiopathic short stature was lower than Israeli norms (P = 0.001). After 1‐year blinded intervention, only the GH‐treated boys improved their actual and anticipated adult height perception (SAT, P < 0.001 and P = 0.022) with reduced short stature‐related distress (SC‐IAT‐H, P < 0.001). At study end, RSES and SC‐IAT‐H improved significantly (P < 0.001), with no change in PedsQL and CBCL.

Conclusions

Our finding of improved psychosocial functioning only in the GH‐treated boys after 1‐year blinded intervention suggests that it was the GH therapy, rather than being enrolled in a clinical trial, which contributed to the outcome. Long‐term open‐labelled GH treatment significantly improved height perception and self‐esteem. Future studies are needed to fully assess the relevance of complementing the routinely used explicit self‐report measures with the implicit measures.
Modeling vanishing white matter disease with patient‐derived induced pluripotent stem cells reveals astrocytic dysfunction
Authors: Zhou Ling , Li Peng , Chen Na , Dai Li‐Fang , Gao Kai , Liu Yi‐Nan , Shen Li , Wang Jing‐Min , Jiang Yu‐Wu , Wu Ye
Published: February 2019

Aims

Vanishing white matter disease (VWM) is an inherited leukoencephalopathy in children attributed to mutations in EIF2B1–5, encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B). Although the defects are in the housekeeping genes, glial cells are selectively involved in VWM. Several studies have suggested that astrocytes are central in the pathogenesis of VWM. However, the exact pathomechanism remains unknown, and no model for VWM induced pluripotent stem cells (iPSCs) has been established.

Methods

Fibroblasts from two VWM children were reprogrammed into iPSCs by using a virus‐free nonintegrating episomal vector system. Control and VWM iPSCs were sequentially differentiated into neural stem cells (NSCs) and then into neural cells, including neurons, oligodendrocytes (OLs), and astrocytes.

Results

Vanishing white matter disease iPSC‐derived NSCs can normally differentiate into neurons, oligodendrocytes precursor cells (OPCs), and oligodendrocytes in vitro. By contrast, VWM astrocytes were dysmorphic and characterized by shorter processes. Moreover, δ‐GFAP and αB‐Crystalline were significantly increased in addition to increased early and total apoptosis.

Conclusion

The results provided further evidence supporting the central role of astrocytic dysfunction. The establishment of VWM‐specific iPSC models provides a platform for exploring the pathogenesis of VWM and future drug screening.
A cellular blue nevus with pigmented epithelioid melanocytoma‐like pattern on the ipsilateral upper arm associated with a congenital plaque‐type blue nevus on the hand
Authors: Lee Min Young , Jin Suna , Lee Kyung‐Hwa , Park Min Ho , Jung Sung Taek , Rubin Adam , Yun Sook Jung
Published: February 2019

A 36‐year‐old man presented with a subcutaneous nodule on the right upper arm. A small nodule had developed 8 years earlier, and grew in size, accompanied by a tingling sensation and numbness. In addition, he had a bluish irregular patch on the right hand since birth, which crossed from the palm to the dorsal hand. Skin biopsies from the hand showed a heavily pigmented melanocyte proliferation in the dermis with perieccrine, perivascular, and perineural involvement, and a diagnosis of congenital plaque‐type blue nevus was made. The tumor on the arm was located closely along the median nerve, and was observed as a large black pedunculated round tumor. Histopathologically, the tumor on the arm consisted of densely packed tissue with nevoid cells without atypia in the larger nodular part, and heavily pigmented spindle and epithelioid melanocytes in the slender stalk area, which was diagnosed as cellular blue nevus with pigmented epithelioid melanocytoma‐like pattern. Next‐generation sequencing revealed GNAQ mutations in the hand lesion, and in the lesions on the arm. This case suggests that the areas of skin following the same neural distribution of a congenital plaque‐type blue nevus on the extremities should be followed up for secondary changes.
Functional Evaluation of Eating Difficulties Scale to predict oral motor skills in infants with neurodevelopmental disorders: a longitudinal study
Authors: Cavallini Anna , Provenzi Livio , Scotto Di Minico Giunia , Sacchi Daniela , Gavazzi Lidia , Amorelli Valeria , Borgatti Renato
Published: February 2019

Aim

To assess the predictive validity of the Functional Evaluation of Eating Difficulties Scale (FEEDS) on long‐term eating developmental outcomes in infants with neurodevelopmental disorders.

Method

In total, 144 infants (69 females, 75 males) aged 0 to 12 months (mean [SD] 5.34mo [3.42]) with neurodevelopmental disorders and requiring enteral nutrition support, hospitalized between January 2004 and December 2017, were included. The FEEDS was administered at the onset of hospitalization. Follow‐up evaluations of feeding modalities occurred at discharge and at 6 months, 12 months, and 24 months after discharge. FEEDS score was tested as a predictor of infants’ feeding modality (percutaneous endoscopic gastrostomy, nasogastric tube, mixed, oral feeding) and time to autonomous oral feeding. Percentages of false‐positive and negative cases were checked.

Results

Lower FEEDS scores significantly predicted infants’ feeding modality (0.40≤R2≤0.61). A 1‐point increase in FEEDS score was associated with increased risk (6%–14%; p<0.05) of being non‐autonomous feeders at the different follow‐up points in infants who had a FEEDS score above the clinical cut‐off.

Interpretation

The FEEDS appears to be a clinically valid assessment to predict the presence of eating difficulties in infants with neurodevelopmental disabilities.

What this paper adds

Functional Evaluation of Eating Difficulties Scale (FEEDS) significantly predicted eating difficulties in infants with neurodevelopmental disabilities.

Lower FEEDS score is significantly associated with autonomous feeding at the 24‐month follow‐up.

FEEDS cut‐off identified infants at low‐risk and high‐risk for eating disorder.
Hand Assessment for Infants: normative reference values
Authors: Ek Linda , Eliasson Ann‐Christin , Sicola Elisa , Sjöstrand Lena , Guzzetta Andrea , Sgandurra Giuseppina , Cioni Giovanni , Krumlinde‐Sundholm Lena
Published: February 2019

Aim

To create normative reference values for unilateral and bilateral use of the hands, using the Hand Assessment for Infants (HAI), a newly developed criterion‐referenced assessment measuring hand use in infants aged 3 months to 12 months at risk of cerebral palsy (CP).

Method

In total, 489 HAI assessments of typically developing infants (243 females, 246 males), aged 3 months to 10 months (mean 6mo 14d [SD 2mo 5d]), were collected in Italy and Sweden. Normative growth curves based on mean and SDs were created, as well as skill acquisition curves for each test item. Correlation to age and differences between groups based on sex and nationality, as well as differences between the right and the left hand, were investigated.

Results

The growth curves showed a steady increase in mean value and a decrease in SD over age. There were no differences between groups based on sex or nationality. There was a negligible mean difference (0.1 raw score) between the right and left hands.

Interpretation

HAI normative reference values are now available, which can assist in identifying deviating hand use for each month of age, as well as a side difference between hands in infants at risk of CP.

What this paper adds

A Hand Assessment for Infants (HAI) result greater than 2SD below the mean indicates atypical hand use.

Skill acquisition curves describe the age at which typically developing infants master the HAI items.

Most typically developing infants do not demonstrate asymmetry in hand use.
Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring
Authors: Jones Hannah F , Ho Alvin C C , Sharma Suvasini , Mohammad Shekeeb S , Kothur Kavitha , Patel Shrujna , Brilot Fabienne , Guastella Adam J , Dale Russell C ,   Immune‐Neurodevelopment (Imm‐Nd) Study Group
Published: February 2019

Epidemiological studies, animal models, and case–control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive–compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4–15y]; six males and two females) referred over a 2‐year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre‐existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing‐remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli.

What this paper adds

Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring.

Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.
The Istanbul programme of action for the least developed countries: What does it add?
Authors: Diallo Oumar , Diarra Cheick S. , Katjomuise Kavazeua U.
Published: February 2019

Motivation

Every ten years, the member states of the United Nations agree on a decennial Programme of Action (PoA) intended to advance the development agenda of the least developed countries (LDCs). As this PoA is expected to expand on its predecessor, the question is whether this additionality holds for Istanbul Programme of Action (IPoA), which covers the period 2011–2020.

Purpose

The purpose of the article is to review the Istanbul Programme of Action and to contrast it with its predecessor: the Brussels Programme of Action.

Approach and methods

In comparing these two PoAs, we use qualitative and quantitative approaches and draw on recent literature pertaining to international development co‐operation.

Findings

Using these methodologies, we identify several novelties in the IPoA, including the focus on previously neglected issues that are important for LDCs' long‐term. We show, however, that the IPoA retains some of the shortcomings of its predecessors, while its structure and options of setting goals and targets create a wedge between development aspirations and the means of implementation.

Policy implications

Advancing the development agenda of LDCs requires re‐committing to achieving some of the new features in the IPoA and addressing its shortcomings in the 2021–2030 Programme of Action, which will be adopted at the 2021 Fifth United Nations Conference on LDCs.
Association of cardiorespiratory fitness on interhemispheric hippocampal and parahippocampal functional connectivity
Authors: Ikuta Toshikazu , Loprinzi Paul D.
Published: February 2019

Interhemispheric functional connectivity is associated with cognitive functioning. Although previous work has evaluated the association of cardiorespiratory fitness on cognitive function, there has been a limited investigation of the association of cardiorespiratory fitness on the functional connectivity of memory‐related brain structures. As such, the objective of this study was to examine the association between cardiorespiratory fitness and parahippocampal and hippocampal interhemispheric functional connectivity. Data from the Nathan Kline Institute‐Rockland Sample (NKI‐RS) were utilized. Our analysis consisted of 284 participants (Mage = 43 years; 62% female). Cardiorespiratory fitness was objectively measured using a cycle ergometer protocol. Parahippocampal and hippocampal interhemispheric functional connectivity were assessed from fMRI. Higher cardiorespiratory fitness was associated with greater parahippocampal (β = 0.004; CI, 0.00009 to 0.008, p = 0.04), but not hippocampal (β = 0.001; CI, −0.002 to 0.005, p = 0.44) interhemispheric functional connectivity. In conclusion, enhanced cardiorespiratory fitness may facilitate parahippocampal interhemispheric functional connectivity.
Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells
Authors: Park Sang‐Min , Hwang Chae Young , Cho Sung‐Hwan , Lee Daewon , Gong Jeong‐Ryeol , Lee Soobeom , Nam Sohee , Cho Kwang‐Hyun
Published: February 2019

Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild‐type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these five genes can increase CTX sensitivity in KRAS WT cells. Interestingly, we further found that GNB5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation.
Organizational processes and gender integration in operational military units: An Israel Defense Forces case study
Authors: Ben‐Shalom Uzi , Lewin Eyal , Engel Shimrit
Published: February 2019

This study examines collective action by men and women in operational military units deployed on Israel's borders. Gender integration is generally perceived by soldiers and commanders in these units as a trivial matter rather than an issue for discussion or a disadvantage. The integration results from organizational qualities, which include military leadership with accumulated experience in gender integration; division of labour between men and women that gradually develops during protracted training; screening processes within the units; and professional development of commanders. Our findings negate a large corpus of sociological literature on gender integration in military organizations. We discuss the micro‐social processes that enable or deter mixed‐gender integration in operational units. Our findings are presented as an alternative to arguments on the inevitable marginality of women in the military and that equality is neither a prerequisite of a cohesive mixed‐gender unit nor a barrier for the inclusion of women into combat units.
Silence‐breaking butterfly effect: Resistance towards the military within #MeToo
Authors: Alvinius Aida , Holmberg Arita
Published: February 2019

Systemic violence against women in the military has existed for decades, but they have mostly refrained from public resistance. However, in the context of the #MeToo movement in Sweden, 1768 women published a call for an end to violence and sexual harassment in the military. We analyse this call as a public resistance effort against the military and find that #MeToo is: (i) challenging the norms of the hyper‐masculine military organization, making resistance towards it visible; and (ii) resisting the practices of sexual harassment and lack of responsibility in the military organization. The military organization is questioned when it comes to norms and practices, but there are variations in whether the social order of the military is truly challenged. Still, the call highlights the fragmentation of this ‘last bastion of masculinity’. More research is needed on the erosion of the militarized norms and practices and the effects of the call.