bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of sweet potato endogenous amylase activation on in vivo energy bioavailability and acceptability of soy‐enriched orange‐fleshed sweet potato complementary porridges
Authors: Birungi Catherine , Nabubuya Agnes , Mukisa Ivan Muzira
Published: April 2018

Energy bioavailability can be influenced by food matrix factors and processing conditions or treatments. In this study, the effects of endogenous sweet potato amylase enzyme activation and slurry solids content of soy‐enriched orange‐fleshed sweet potato (OFSP) porridges on in vivo energy bioavailability (energy, weight gain, and feed efficiency ratio) and porridge acceptability were determined. Fifty‐six weanling albino rats were randomly assigned to two blocks each having eight groups of seven rats. The rats were housed in individual cages in a well‐ventilated animal house. The intervention block had rats fed on activated porridges (held at 75°C for 15 min), while rats in the control block were fed on nonactivated porridges (boiled at 90–95°C for 10 min). The rats were fed for 28 days on 50 ml of porridge per rat per day. The four groups per block were each fed on porridges with varying amounts of total solids content (10%, 15%, 20%, and 25%). Weight gain, energy bioavailability, and feed efficiency ratio were determined at the end of the feeding period. Consumer acceptability of activated and nonactivated porridges at 25% solids content was determined using a nontrained human panel (n = 40). Activation of amylases did not significantly (p > .05) affect the bioavailable energy, cumulative weight gain, and feed efficiency of the rats. Increasing slurry solids content of activated and nonactivated porridges significantly (p < .05) increased feed efficiency ratio (−14.6 ± 11.7 to 102.3 ± 2.3), weight gain (−1.4 to 5.6 g ± 1.9 g), and bioavailable energy (702.8 ± 16.2 to 1242.8 ± 12.2 kcal). Activation of amylases reduced porridge viscosity but did not significantly influence the overall acceptability. This work demonstrates the opportunity of utilizing sweet potato amylases to facilitate the preparation of complementary porridges with appropriate viscosity and increased energy density.
Market uncertainty and market orders in futures markets
Authors: Chang Matthew C. , Tsai Chih‐Ling , Wu Rebecca Chung‐Fern , Zhu Ning
Published: April 2018

In this paper, we employ a unique dataset from Taiwan to investigate the order type choices made by individual and institutional investors over periods of high market uncertainty. Our studies show that individuals change their behavior during periods of high market uncertainty by submitting more market orders and sell orders. In contrast, institutions are less influenced by market uncertainty. Institutional trades can alleviate, but not reverse, this increase in individuals' market orders during periods of high market uncertainty. These findings suggest that the composition of investor clientele plays an important role in understanding asset returns and volatility in emerging markets.
Correlation of TET2 SNP rs2454206 with improved survival in children with acute myeloid leukemia featuring intermediate‐risk cytogenetics
Authors: Wang Xingjuan , Chen Xi , Yang Zhenzhen , Dou Hu , Lu Ling , Bi Junqin , Zou Lin , Yu Jie , Bao Liming
Published: April 2018

Single nucleotide polymorphisms (SNPs) may influence the disease course and outcome of hematologic neoplasms. SNP rs2454206 is common in the TET2 gene, which plays a role in epigenetic regulation of myelopoiesis. Few investigations examined the role of TET2 SNP rs2454206 in acute myeloid leukemia (AML) and none of those studies was performed in Chinese populations. Here, we report the prevalence and clinical relevance of TET2 SNP rs2454206 in 254 Chinese patients with childhood AML. Our data demonstrate that TET2 SNP rs2454206AG/GG is associated with improved overall survival and event‐free survival in AML patients with intermediate‐risk cytogenetics features. The prognostic impact of TET2 SNP rs2454206AG/GG was independent of other common AML risk factors, such as age, white blood cell count, and FLT3‐ITD. No difference in TET2 expression levels in AML with TET2 SNP rs2454206AA and TET2 SNP rs2454206AG/GG was detected, indicating that TET2 SNP rs2454206 status does not affect TET2 expression in pediatric AML.
Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis
Authors: Terada Kazuki , Yamaguchi Hiroki , Ueki Toshimitsu , Usuki Kensuke , Kobayashi Yutaka , Tajika Kenji , Gomi Seiji , Kurosawa Saiko , Saito Riho , Furuta Yutaka , Miyadera Keiki , Tokura Taichiro , Marumo Atsushi , Omori Ikuko , Sakaguchi Masahiro , Fujiwara Yusuke , Yui Shunsuke , Ryotokuji Takeshi , Arai Kunihito , Kitano Tomoaki , Wakita Satoshi , Fukuda Takahiro , Inokuchi Koiti
Published: April 2018

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next‐generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3‐ITD‐negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5‐year overall survival (OS) (13.6% vs. 55.0%, P = 0.0021) and relapse‐free survival (RFS) (14.3% vs. 44.5%, P = 0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P = 0.0038, P = 0.0463) for both OS and RFS. In cases of AML that are FLT3‐ITD‐negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor.
Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop
Authors: Mouton‐Liger François , Rosazza Thibault , Sepulveda‐Diaz Julia , Ieang Amélie , Hassoun Sidi‐Mohamed , Claire Emilie , Mangone Graziella , Brice Alexis , Michel Patrick P. , Corvol Jean‐Christophe , Corti Olga
Published: April 2018

Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2−/− and Pink1−/− mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2−/− and Pink1−/− cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target.
Analyzing medical costs with time‐dependent treatment: The nested g‐formula
Authors: Spieker Andrew , Roy Jason , Mitra Nandita
Published: April 2018

As medical expenses continue to rise, methods to properly analyze cost outcomes are becoming of increasing relevance when seeking to compare average costs across treatments. Inverse probability weighted regression models have been developed to address the challenge of cost censoring in order to identify intent‐to‐treat effects (i.e., to compare mean costs between groups on the basis of their initial treatment assignment, irrespective of any subsequent changes to their treatment status). In this paper, we describe a nested g‐computation procedure that can be used to compare mean costs between two or more time‐varying treatment regimes. We highlight the relative advantages and limitations of this approach when compared with existing regression‐based models. We illustrate the utility of this approach as a means to inform public policy by applying it to a simulated data example motivated by costs associated with cancer treatments. Simulations confirm that inference regarding intent‐to‐treat effects versus the joint causal effects estimated by the nested g‐formula can lead to markedly different conclusions regarding differential costs. Therefore, it is essential to prespecify the desired target of inference when choosing between these two frameworks. The nested g‐formula should be considered as a useful, complementary tool to existing methods when analyzing cost outcomes.
Association between nasopharyngeal carcinoma and risk of optic neuropathy: A population‐based cohort study
Authors: Fan Chao‐Yueh , Jen Yee‐Min , Su Yuan‐Chih , Chao Hsing‐Lung , Lin Chun‐Shu , Huang Wen‐Yen , Lin Miao‐Jung , Kao Chia‐Hung
Published: April 2018

Background

The purpose of this study was to assess the predictive factors of optic neuropathy among patients with nasopharyngeal carcinoma (NPC).

Methods

The analysis included 16 297 patients with NPC and 65 187 controls. Each patient with NPC was randomly frequency‐matched with 4 individuals without NPC by age, sex, and index year. Cox proportional hazard models were applied to measure the hazard ratios (HRs) and 95% confidence intervals (CIs) of optic neuropathy development associated with NPC.

Results

The risk of optic neuropathy was significantly higher in the NPC cohort (adjusted HR [aHR] 3.42; 95% CI 2.85‐4.09; P < .001). Independent risk factors for optic neuropathy among patients with NPC included stroke (aHR 1.7; 95% CI 1.07‐2.7; P = .03) and receipt of chemotherapy (aHR 1.55; 95% CI 1.17‐2.06; P = .002).

Conclusion

The risk of optic neuropathy was significantly higher in patients with NPC than in the general population.
Optimization of immunolabeling and clearing techniques for indelibly labeled memory traces
Authors: Pavlova Ina P. , Shipley Shannon C. , Lanio Marcos , Hen René , Denny Christine A.
Published: April 2018

Recent genetic tools have allowed researchers to visualize and manipulate memory traces (i.e., engrams) in small brain regions. However, the ultimate goal is to visualize memory traces across the entire brain in order to better understand how memories are stored in neural networks and how multiple memories may coexist. Intact tissue clearing and imaging is a new and rapidly growing area of focus that could accomplish this task. Here, we utilized the leading protocols for whole‐brain clearing and applied them to the ArcCreERT2 mice, a murine line that allows for the indelible labeling of memory traces. We found that CLARITY and PACT greatly distorted the tissue, and iDISCO quenched enhanced yellow fluorescent protein (EYFP) fluorescence and hindered immunolabeling. Alternative clearing solutions, such as tert‐Butanol, circumvented these harmful effects, but still did not permit whole‐brain immunolabeling. CUBIC and CUBIC with Reagent‐1A produced improved antibody penetration and preserved EYFP fluorescence, but also did not allow for whole‐brain memory trace visualization. Modification of CUBIC with Reagent‐1A resulted in EYFP fluorescence preservation and immunolabeling of the immediate early gene (IEG) Arc in deep brain areas; however, optimized memory trace labeling still required tissue slicing into mm‐thick tissue sections. In summary, our data show that CUBIC with Reagent‐1A* is the ideal method for reproducible clearing and immunolabeling for the visualization of memory traces in mm‐thick tissue sections from ArcCreERT2 mice.
Extraction, isolation, and concentration of calprotectin antigen (S100A8/S100A9) from granulocytes
Authors: Nilsen Tom , Haugen Siri Helen , Larsson Anders
Published: April 2018

Background

Calprotectin is a promising biomarker for granulocyte activation. It is mainly measured in faeces as a marker for inflammatory bowel disease. A limitation is that there is no widely accepted calibrator.

Aim

To establish a method for purification of calprotectin from human granulocytes that is easily reproducible, reliable, and could contribute to a better agreement between different calprotectin methods.

Methods and results

Calprotectin was purified from granulocyte extracts using ion‐exchange chromatography. The granulocytes were separated from blood bags. The purity was analysed by analysing pixel density of a picture of the sodium dodecyl sulfate polyacrylamide gel electrophoresis and by size exclusion chromatography. The calprotectin concentration of the pure antigen solution was determined using Biuret method. The purity was >95% for 3 preparations, and their concentrations were 1079, 1080, and 1813 mg/L.

Conclusion

It is possible to reproducibly prepare highly purified calprotectin antigen from human granulocytes. The preparations can be used for preparing calibrators, controls for immunological calprotectin assays, and immunisation for raising antibodies against human calprotectin in hens.
A TGF‐β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16‐associated oropharyngeal cancer
Authors: Tao Ye , Sturgis Erich M. , Huang Zhigang , Sun Yan , Dahlstrom Kristina R. , Wei Qingyi , Li Guojun
Published: April 2018

TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site may alter TGF‐β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF‐β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer‐free controls in the non‐Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF‐β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never‐smokers (OR, 165.9; 95% CI, 28.6–960.4) or never‐drinkers (OR, 196.0; 95% CI, 28.2–1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3–87.0 vs. OR, 6.0; 95% CI, 1.7–17.9, respectively). The significant associations between this polymorphism and HPV16‐associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF‐β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16‐associated oral cancer, particularly in OPSCC subjects who are never‐smokers, never‐drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.
Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes
Authors: Webb Matthew W. , Sun Jianping , Sheard Michael A. , Liu Wei‐Yao , Wu Hong‐Wei , Jackson Jeremy R. , Malvar Jemily , Sposto Richard , Daniel Dylan , Seeger Robert C.
Published: April 2018

Tumor‐associated macrophages can promote growth of cancers. In neuroblastoma, tumor‐associated macrophages have greater frequency in metastatic versus loco‐regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high‐risk patients who have MYCN‐non‐amplified disease. The contribution of cytotoxic T‐lymphocytes to anti‐neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T‐cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF‐1R can improve the response to chemotherapy. In vitro, CSF‐1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co‐injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14+ and CD163+ cells and mouse F4/80+ cells after CSF‐1R blockade. In subcutaneous or intra‐renal models in immunodeficient NSG or NOD/SCID mice, CSF‐1R blockade alone did not affect tumor growth or mouse survival. However, when combined with cyclophosphamide plus topotecan, the CSF‐1R inhibitor BLZ945, either without or with anti‐human and anti‐mouse CSF‐1 mAbs, inhibited neuroblastoma growth and synergistically improved mouse survival. These findings indicate that depletion of tumor‐associated macrophages from neuroblastomas can be associated with increased chemotherapeutic efficacy without requiring a contribution from T‐lymphocytes, suggesting the possibility that combination of CSF‐1R blockade with chemotherapy might be effective in patients who have limited anti‐tumor T‐cell responses.
Transition Metal‐Catalyzed Benzannulation towards Naturally Occurring Carbazole Alkaloids
Authors: Zhang Xue , Ma Shengming
Published: April 2018

In this account, we will summarize our recent progress on development of Pt‐ or Au‐catalyzed benzannulation of 1‐indolyl‐2,3‐allenols for the efficient construction of carbazole skeleton via a metal carbene intermediate and its application towards the synthesis of naturally occurring carbazole alkaloids. The strategy enjoys the outstanding regioselectivity, atom economy, mild reaction conditions, substrate scope, functional group tolerance.
[1, 2]‐Migration Reactions Catalyzed by Gold Complexes and their Applications in Total Synthesis
Authors: Holzschneider Kristina , Kirsch Stefan F.
Published: April 2018

The area of cascade reactions, initiated by the transition metal‐catalyzed activation of π‐systems and coupled with a 1,2‐migration step is of considerable interest in current organic chemistry research. In this article, recent advances in the field are highlighted, focusing on gold as the activating π‐acid. Cascade reactions with 1,2‐shifts of alkyl groups as migrating agents are mainly presented, but also selected 1,2‐aryl migrations and miscellaneous examples are depicted. With the reactions discussed, molecules of high structural complexity become readily accessible. Examples are shown where the reactions were used as the key steps of total synthesis endeavours.
E‐cigarettes: voltage‐ and concentration‐dependent loss in human lung adenocarcinoma viability
Authors: Otręba Michał , Kośmider Leon , Knysak Jakub , Warncke Jared D. , Sobczak Andrzej
Published: April 2018

E‐cigarettes are used by millions of people despite the fact that the harmful effect of aerosol emitted from these products to the human organism is still not clear. In this paper, toxicity of vapor generated using different solutions and battery output voltage on A549 cells viability is presented. The obtained EC50 values for commercially available propylene glycol/glycerol solution 1:1 e‐liquids based on 3.2 V (0.127%), 4.0 V (0.112%) and 4.8 V (0.038%) were about 1.5–4.5 times higher than in tobacco smoke (0.0086%). Furthermore, it was shown that the increase of battery output voltage decreased A549 cell viability. In addition, commercially available extracts were more cytotoxic than laboratory made extracts. Owing to the expansiveness of e‐cigarettes, it is very important to estimate their impact on public health. Our results not only confirm less cytotoxicity of e‐liquid aerosol than cigarette smoke, but also demonstrate that solutions used in e‐liquids and, for the first time, battery output voltage have a significant impact on cytotoxicity of e‐cigarette vapor. Thus, the results of this study are very important for the current and future legal regulations on e‐cigarettes.
Inside Cover: Internalization kinetics and cytoplasmic localization of functionalized diatomite nanoparticles in cancer cells by Raman imaging (J. Biophotonics 4/2018)
Authors: Managò Stefano , Migliaccio Nunzia , Terracciano Monica , Napolitano Michela , Martucci Nicola M. , De Stefano Luca , Rendina Ivo , De Luca Anna Chiara , Lamberti Annalisa , Rea Ilaria
Published: April 2018

The internalization kinetics and intracellular spatial distribution of functionalized diatomite nanoparticles in human lung epidermoid carcinoma cell line have been investigated by confocal fluorescence and Raman microscopy. In this context, Raman imaging due to its non‐destructive, chemically selective and label‐free working principle provides evidence that the nanovectors are internalized and co‐localize with lipid environments, suggesting an endocytic internalisation route. Nanoparticle uptakes and intracellular persistence are observed up to 72 hours, without damage to cell viability or morphology.

Further details can be found in the article by Stefano Managò et al. (e201700207)

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Evaluating size‐dependent relaxivity of PEGylated‐USPIOs to develop gadolinium‐free T1 contrast agents for vascular imaging
Authors: Khandhar Amit P. , Wilson Gregory J. , Kaul Michael G. , Salamon Johannes , Jung Caroline , Krishnan Kannan M.
Published: April 2018

Ultra‐small superparamagnetic iron oxide (USPIO) nanoparticles provide a safer alternative to gadolinium‐based contrast agents (GBCAs) in T1‐weighted MR imaging. MRI contrast behavior of USPIOs depends on their magnetic properties, which in turn depend on their physicochemical composition. Identifying and tailoring USPIO structural characteristics that influence proton relaxation in MRI is crucial to developing effective gadolinium‐free T1 contrast agents. Here, we present a systematic empirical evaluation of the relationship between USPIO size and MRI relaxivity (r1 and r2 values). Monodisperse USPIO cores, with precisely controlled core diameter (dC) were synthesized via the thermal decomposition of iron(III)‐oleate precursor. USPIOs with dC = 6.34, 7.58, 8.58, and 9.50nm, were dispersed in aqueous phase via ligand exchange with silane or dopamine‐modified polyethylene glycol (PEG) polymers. Relaxivity characterization in a 1.5 T clinical MRI scanner showed the r2/r1 ratio increased linearly with USPIO core diameter (R2 = 0.95), but varied little with both hydrodynamic diameter (dH) and PEG molecular weight. One sample, DOPA‐6‐20 (6.34nm USPIO cores coated with 20 kDa dopamine‐modified PEG), provided the lowest r2/r1 value (3.44) and thus promise as a potential T1 contrast agent. In a preliminary study, we evaluated DOPA‐6‐20 for in vivo angiography imaging in a mouse with a 7 T scanner and observed strong T1‐weighted enhancement of the mouse blood pool. Key anatomical features in the vascular network were visible even 5 min after intravenous administration. Using empirical data, we have presented the basis of a structure–property relationship that can help develop optimized USPIO‐based T1 contrast agents. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2440–2447, 2018.
Engineered natural and synthetic polymer surfaces induce nuclear deformation in osteosarcoma cells
Authors: Antmen Ezgi , Ermis Menekse , Demirci Utkan , Hasirci Vasif
Published: April 2018

Cell‐substrate interactions involve constant probing of microenvironment by cells. One of the responses of cells to environmental cues is to change the conformation of their cytoplasm and nucleus. We hypothesized that surface chemistry and topography could be engineered to make these differences significant enough. When designing the substrates that would accentuate these differences, we prepared surfaces carrying cell adhesive biological cues arranged in specific patterns. Collagen type I and poly(lactic acid‐co‐glycolic acid) (PLGA) were used to represent substrates with biological cues and those without, and these materials were decorated with four square prism micropillars with different dimensions. The nuclear deformations were analyzed using some descriptors. Nucleus area and solidity were the best descriptors in distinguishing the substrates in terms of biological cues, while nucleus area, solidity, and circularity were more sensitive to the interpillar distances. Another distinguishing factor tested was the duration of contact. Nucleus area was the only descriptor sensitive to nuclear deformation change with time. PLGA was more suitable in nuclear conformation analysis while collagen was better in cell adhesion and proliferation. These deformations lead to changes in the molecular processes and further studies are needed to better understand cell mechanobiology. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 366–376, 2019.
Content of distinct metals in periprosthetic tissues and pseudosynovial joint fluid in patients with total joint arthroplasty
Authors: Kuba Martin , Gallo Jiří , Pluháček Tomáš , Hobza Martin , Milde David
Published: April 2018

This prospective study examined the content of metals released from total joint arthroplasty into joint fluid, whole blood and periprosthetic tissues. We determined the levels of Ti, V, Nb, Co, Cr, and Mo, using inductively coupled plasma mass spectrometry, in samples from patients who underwent reoperation of total hip or knee arthroplasty. All of the patients (n = 117) included in the study had either metal on polyethylene or ceramic on polyethylene‐bearing pairs. First, our results conclusively showed that the majority of released metals were deposited in periprosthetic tissues. In this context, the bloodstream turned out to be an ineffective biomarker of the effects occurring in local tissues. Second, there was a clear time‐dependent nature of metallic accumulation. Based on our extensive dataset, we found significantly elevated levels of the released metals in joint fluid and periprosthetic tissues originating from loosened implants compared to stable ones, as well as recognizable differences between the groups with stable implants and aseptic loosening. Finally, it was proved that the concentrations of metals decreased dependent on the distance of the tissue from the implant. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 454–462, 2019.
Efficacy of Switching From Teriparatide to Bisphosphonate or Denosumab: A Prospective, Randomized, Open‐Label Trial
Authors: Niimi Rui , Kono Toshibumi , Nishihara Atsushi , Hasegawa Masahiro , Kono Toshihiko , Sudo Akihiro
Published: April 2018

There is no consensus on an optimal treatment after daily teriparatide (TPTD). We performed a prospective, randomized, open‐label, 12‐month trial to investigate the efficacy of follow‐up treatment after daily TPTD treatment for Japanese patients. Three‐hundred patients were enrolled in this study. Patients received oral bisphosphonate (BP) including alendronate (ALN; 35 mg/week) and minodoronate (MINO; 50 mg/month), or subcutaneous denosumab (60 mg/6 month). The primary efficacy measure was bone mineral density (BMD) responses in the lumbar spine (LS) and femoral neck (FN). Lumbar spine BMD increased by 1.3 ± 5.1% in the ALN subgroups, 0.5 ± 4.6% in the MINO subgroups, and 4.3 ± 3.5% in the denosumab subgroups. Femoral neck BMD increased by 0.7 ± 4.6% in the ALN subgroups, 0.2 ± 4.6% in the MINO subgroups, and 1.4 ± 3.4% in the denosumab subgroups. Lumbar spine BMD increases were significantly greater in the denosumab subgroup than the BP subgroups. There were no significant differences in FN BMD increases among the three subgroups. Lumbar spine BMD increases were significantly greater in the denosumab subgroup than the BP subgroups, whereas FN BMD increases were not significant. Denosumab treatment was more effective in increasing BMD and therefore has the potential benefit of fracture prevention. Further research is warranted to determine the optimal treatment after daily TPTD. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Severely Impaired Bone Material Quality in Chihuahua Zebrafish Resembles Classical Dominant Human Osteogenesis Imperfecta
Authors: Fiedler Imke A.K. , Schmidt Felix N. , Wölfel Eva M. , Plumeyer Christine , Milovanovic Petar , Gioia Roberta , Tonelli Francesca , Bale Hrishikesh A. , Jähn Katharina , Besio Roberta , Forlino Antonella , Busse Björn
Published: April 2018

Excessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Because the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how OI manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/+) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as a suitable animal model of classical dominant OI, showing skeletal deformities, altered mineralization patterns, and a smaller body size. This study assessed the bone quality properties of Chi/+ at multiple length scales using micro-computed tomography (micro-CT), histomorphometry, quantitative back-scattered electron imaging, Fourier-transform infrared spectroscopy, nanoindentation, and X-ray microscopy. At the skeletal level, the Chi/+ displays smaller body size, deformities, and fracture calli in the ribs. Morphological changes at the whole bone level showed that the vertebrae in Chi/+ had a smaller size, smaller thickness, and distorted shape. At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to wild-type zebrafish. The alterations in the cellular, compositional, and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties, which promote an increase in overall bone fragility in Chi/+. The quantitative assessment of bone quality in Chi/+ thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant OI. © 2018 American Society for Bone and Mineral Research.
Retracted: Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90
Authors: Tao Hua , Chen Yuan‐Yuan , Sun Zong‐Wen , Chen Hua‐Lin , Chen Ming
Published: April 2018

Esophageal carcinoma is aggressive in nature and its prognosis is largely dependent on the degree of invasion. Histone deacetylase 6 (HDAC6), as the most unique member of HDACs family, has the positive activity to promote initiation and progression of various cancers via targeting multiple non‐histone proteins in cytoplasm. In this study, we found that HDAC6 was over‐expressed in three esophageal cancer cell lines (KYSE140, KYSE170, KYSE180) when compared to non‐carcinoma esophageal epithelial cell HEEC‐1. Then two HDAC6 specific siRNAs and HDAC6 inhibitor tubastatin A greatly suppressed KYSE140 and KYSE180 cells proliferation and migration, and the inhibition of cell motility was accompanied by elevated acetylation of α‐tubulin, a target of HDAC6. Consistently, the microtubulin skeleton was stabilized after HDAC6 knockdown or inhibition. In addition, acetylation status of HSP90, another HDAC6 target, was also increased towards HDAC6 knockdown or inhibition by co‐immunoprecipitation assay. Besides, co‐treatment of HSP90 inhibitor (PU‐H71) and HDAC6 inhibitor (tubastatin A) induced a stronger cell migration inhibition compared to administration of either drug alone. Furthermore, cell proliferation of KYSE140 and KYSE180 were also compromised in response to combination of HDAC6 and HSP90 inhibitors. Additionally, co‐administration of HSP90 inhibitor and HDAC6 inhibitor strongly inhibited tumor growth in vivo. Taken together, our results indicated that HDAC6 is a promising target by inhibiting HSP90 function in ESCC.
Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells
Authors: Wang Lele , Zhao Linlin , Wei Guo , Saur Dieter , Seidler Barbara , Wang Junyan , Wang Chuanxin , Qi Tonggang
Published: April 2018

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating disease with the 5‐year survival rate less than 6%. In this study, we investigated if inhibiting protein synthesis directly with homoharringtonine (HHT) could induce acute apoptosis in pancreatic cancer cells through quick depletion of multiple short‐lived critical members of the central proteome, example, PSMD11(26S proteasome non‐ATPase regulatory subunit 11). It was shown that although HHT could inhibit proliferation and growth of MiaPaCa‐2 and PANC‐1 cells in a time‐ and dose‐dependent manner, only part of pancreatic cancer cells could be induced to die through acute apoptosis. Mechanistic studies showed that HHT could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. Inhibiting MEK1/ERK1/2 pathway with sorafenib could improve the cytotoxity of HHT in vitro and in a genetically engineered mouse model of pancreatic cancer. These results suggest that quick induction of PSMD11 or other acute apoptosis inhibitors through activation of the MEK1/ERK1/2 signaling pathway may be one of the important surviving mechanism which can help pancreatic cancer cells avoid acute apoptosis, it may have significant implications for the targeted therapy of pancreatic ductal adenocarcinoma.
MiR‐370 inhibits vascular inflammation and oxidative stress triggered by oxidized low‐density lipoprotein through targeting TLR4
Authors: Tian Dan , Sha Yin , Lu Jing‐Min , Du Xian‐Jin
Published: April 2018

Atherosclerosis, as a chronic cardiovascular disease, still remains a serious threat to human health. Inflammation and oxidative stress are commonly involved in various stages of atherosclerosis development. MicroRNAs are reported to play important roles in macrophages, which can respond to inflammation and oxidative stress. In our current study, we focused on the biological roles of miR‐370 in atherosclerosis. According to the previously research, miR‐370 was downregulated in AS mice models. Oxidized low‐density lipoprotein (Ox‐LDL) is regarded as a crucial regulator of atherosclerosis and we observed that miR‐370 was decreased by ox‐LDL dose‐dependently and time‐dependently in THP‐1 cells. Then, it was found that miR‐370 overexpression was able to inhibit inflammation molecules including IL‐6 and IL‐1β. Meanwhile, ROS levels, and malondialdehyde (MDA) were also restrained by miR‐370 mimics in vitro. Toll‐like receptor 4 (TLR4) has been implicated in many inflammation diseases. It can serve as a target of miR‐370 and TLR4 expression was greatly increased in ox‐LDL‐incubated THP‐1 cells in a time and dose dependent manner. The negative correlation was validated using a dual‐luciferase reporter assay in our study. In conclusion, our present study revealed that miR‐370 can reduce inflammatory reaction and inhibit the ROS production by targeting TLR4 in THP‐1 cells.
A group of tissue‐specific microRNAs contribute to the silencing of CUX1 in different cell lineages during development
Authors: Xu Hui , He Jie‐Hua , Xu Shi‐Jun , Xie Shu‐Juan , Ma Li‐Ming , Zhang Yin , Zhou Hui , Qu Liang‐Hu
Published: April 2018

Cut‐like homeobox 1 (CUX1) is a highly conserved homeoprotein that functions as a transcriptional repressor of genes specifying terminal differentiation. We previously showed that liver‐specific microRNA‐122 (miR‐122) regulates the timing of liver development by silencing CUX1 post‐transcriptionally. Since the CUX1 protein is expressed in a subset of embryonic tissues, we hypothesized that it is regulated by specific microRNAs (miRNAs) in each cell type during development. Using a large‐scale screening method, we identified ten tissue‐specific miRNAs from different cell lineages that directly targeted CUX1. An analysis of the interaction between heart‐specific microRNA‐208a (miR‐208a) and CUX1 in the hearts of developing mouse embryos and in P19CL6 cells undergoing cardiac differentiation indicated that CUX1 is regulated by miR‐208a during heart development and cardiomyocyte differentiation. Functional analysis of miR‐208a in P19CL6 cells using lentiviral‐mediated over‐expression showed that it regulates the transition between cellular proliferation and differentiation. These results suggest that these tissue‐specific miRNAs might play a common role in timing the progression of terminal differentiation of different cell lineages, possibly by silencing the differentiation repressor CUX1.
Tannic acid modulates fibroblast proliferation and differentiation in response to pro‐fibrotic stimuli
Authors: Pattarayan Dhamotharan , Sivanantham Ayyanar , Bethunaickan Ramalingam , Palanichamy Rajaguru , Rajasekaran Subbiah
Published: April 2018

In response to tissue injury, fibroblasts migrate into the wound, where they undergo proliferation and differentiation. The persistence of these differentiated fibroblasts (myofibroblasts) is associated with excessive scarring in various organs. We aimed to investigate the effects of Tannic acid (TA) on fibroblast proliferation and differentiation, and found that TA inhibited fibroblast differentiation as assessed by reduced expression of α‐smooth muscle actin, N‐cadherin, and type‐1‐collagen. TA also prevented the TGF‐β1‐induced alteration in the expression of two classes of genes involved in the remodeling of extracellular matrix (ECM) proteins, namely matrix metalloproteinases (Mmp‐2 and ‐9) and tissue inhibitors of metalloproteinases (Timp‐1 and ‐3). Further, TA suppressed TGF‐β1‐induced cell proliferation and induced cell cycle arrest at G0/G1 phase via targeting Cyclins expression. Finally, TA exerted its inhibitory effects by decreasing the phosphorylation of Smad and ERK signaling. In sum, our results suggesting that TA may be a potential therapeutic agent for pathological fibrosis.
The effect of plant lectins on the survival and malignant behaviors of thyroid cancer cells
Authors: Kaptan Engin , Sancar‐Bas Serap , Sancakli Aylin , Bektas Suna , Bolkent Sehnaz
Published: April 2018

Altered or aberrant glycosylation is a common phenomenon in cancer cells and it originates from changes in the expression of the enzymes, glycosyltransferase, and glycosidase which up‐regulate in response to some oncogenes in the glycan synthesis pathway. In this present study, it has been aimed to determine the alteration of sialic acid and fucose expressions in the cell surface of human thyroid carcinoma cells and investigate the changes in tumorigenic and malignant characters after treating them with specific plant lectins. Our study showed that the cell surface glycan chains of anaplastic 8305C, follicular FTC‐133, and papillary K1 thyroid carcinoma cells were rich in α‐2,6, α‐2,3, sialic acid, and α‐1,6 fucose residues. When the cells were treated with specific doses of Maackia amurensis lectin II (MAL), Sambucus nigra agglutinin (SNA), and Aleuria aurantia lectin (AAL) which have specific binding capacity for the detected glycan residues, respectively their cancerous traits changed dramatically. Remarkable findings obtained from MAL treatment leading to necrosis in 8505C cells without any toxicity for normal thyroid epithelial cells but it had proliferative effect on K1 and FCT‐133 cells. Besides, MAL and SNA treatment decreased the mobility of 8505C and K1 cells. MAL and SNA lectins dramatically reduced the endothelial affinity of the cells and AAL significantly attenuated that of 8050C and K1 cells but not FTC‐133. These results suggest that altered cell surface glycosylation in thyroid cancer seems to be a strong candidate for developing new therapeutic strategies.
Retracted: miR‐200c, a tumor suppressor that modulate the expression of cancer stem cells markers and epithelial‐mesenchymal transition in colorectal cancer
Authors: Karimi Dermani Fateme , Amini Razieh , Saidijam Massoud , Najafi Rezvan
Published: April 2018

Colorectal cancer (CRC) is the most frequently diagnosed cancer and the most common gastrointestinal cancer worldwide. Due to the presence of populations of cancer stem cells (CSCs) that cause recurrence, the possibility of cancer treatment is very low. The aim of current study was to evaluate the inhibitory role of miR‐200c on EMT, CSCs markers and β‐catenin in HCT‐116 and SW48 cell lines. The expression of miR‐200c, EMT‐related genes, CSCs markers, and β‐catenin were quantified by qRT‐PCR. Further, expression of β‐catenin and EMT‐related proteins, and migration were analyzed by Western blot, and migration assay kit, respectively. Spheroid formation assay was used to enrich colorectal CSCs from colorectal cancer cell lines. LNA‐anti‐miR‐200c suppressed the endogenous miR‐200c in transfected cells compared with the control. qRT PCR and Western blot analysis of LNA‐anti‐miR‐200c transfected cells revealed a considerable increase in CSCs markers, vimentin, ZEB‐1, N‐cadherin, and β‐catenin expression, with a concomitant reduction in E‐cadherin expression level. Migration and sphere forming ability of HCT‐116 and SW48 cells increased in transfected cells. The results of current study revealed that downregulation of miR‐200c may be an important factor for the overexpression of CSCs markers and EMT related genes via β‐catenin upregulation in CRC.
Disulfiram/copper targets stem cell‐like ALDH+ population of multiple myeloma by inhibition of ALDH1A1 and Hedgehog pathway
Authors: Jin Na , Zhu Xiaojian , Cheng Fanjun , Zhang Liling
Published: April 2018

Multiple myeloma stem cells (MMSCs) have been considered as the major cause resulting in relapse. Eradicating MMSCs may be an effective strategy to improve the outcome of multiple myeloma (MM). Increased activity of aldehyde dehydrogenase (ALDH) has been found in MMSCs, but whether inhibiting ALDH activity can eliminate MMSCs remains unknown. Disulfiram (DS) has been reported as an inhibitor of ALDH, and increasing studies showed it has anti‐cancer effects in a copper (Cu)‐dependent manner. In this study, we isolated ALDH+ cells of MM by Aldefluor assay and demonstrated they possessed tumorigenesis capacities in vitro and in vivo. Next, we investigated the effects of DS with or without Cu on suppressing the stemness of MM both in vitro and in vivo. We found that DS/Cu eliminated the stem cell‐like ALDH+ cells. Furthermore, we demonstrated that DS/Cu inhibited the expression of stem cell transcription factors NANOG and OCT4, and abolished the clonogenicity of MM. We also showed that DS/Cu reduced the tumor growth and inhibited stemness of MM in xenograft model. We further found the specific target of DS/Cu is ALDH1A1 and DS/Cu inhibited the Hedgehog (Hh) pathway transcription factors Gli1 and Gli2 regulated by ALDH1A1 at least in part. Our data suggest that DS/Cu can inhibit the ALDH+ stem cell‐like cells through ALDH1A1 and Hh pathway, which may be a promising therapeutic agent in eradicating stem cell‐like cells of MM.
Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway
Authors: Zhang Yuan , Liu Yufeng , Xu Xueju
Published: April 2018

Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma‐associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)‐based chemotherapy and ADR‐resistant AML cells was examined by qRT‐PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively. The protein levels of hypoxia‐inducible factor 1α (HIF‐1α) and hexokinase 2 (HK2) were determined by Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the relationships between UCA1, HK2, and miR‐125a. We found that UCA1 expression was upregulated following ADR‐based chemotherapy. Knockdown of UCA1 increased the cytotoxic effect of ADR and inhibited HIF‐1α‐dependent glycolysis in ADR‐resistant AML cells. Additionally, UCA1 functioned as a ceRNA of miR‐125a by directly binding to miR‐125a. HK2, a target of miR‐125a, was positively regulated by UCA1 in HL60 and HL60/ADR cells. More notably, UCA1 overexpression overturned miR‐125‐mediated inhibition on HIF‐1α‐dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2‐deoxy‐glucose (2‐DG) exposure inhibited HIF‐1α‐dependent glycolysis, and attenuated UCA1‐induced increase of chemoresistance in HL60 and HL60/ADR cells. We conclude that knockdown of UCA1 plays a positive role in overcoming the chemoresistance of pediatric AML, through suppressing glycolysis by the miR‐125a/HK2 pathway, contributing to a better understanding of the molecular mechanism of chemoresistance in AML.
A Novel GJB2 compound heterozygous mutation c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) causes sensorineural hearing loss in a Chinese family
Authors: Shi Xi , Zhang Yan , Qiu Shiwei , Zhuang Wei , Yuan Na , Sun Tiantian , Gao Jian , Qiao Yuehua , Liu Ke
Published: April 2018

Objective

To investigate whether a novel compound heterozygous mutations c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) in GJB2 result in hearing loss.

Methods

Allele‐specific PCR‐based universal array (ASPUA) screening and sequence analysis were applied to identify these mutations. 3D model was built to perform molecular dynamics (MD) simulation to verify the susceptibility of the mutations. Furthermore, WT‐ and Mut‐GJB2 DNA fragments, containing the mutation of c.257C>G and c.176del16 were respectively cloned and transfected into HEK293 and spiral ganglion neuron cell (SGNs) by lenti‐virus delivery system to indicate the subcellular localization of the WT‐ and Mut‐CX26 protein.

Results

A novel compound heterozygous mutation c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) in GJB2 was identified in a Chinese family, in which 4 siblings with profound hearing loss, but the fifth child is normal. By ASPUA screening and sequencing, a compound heterozygote mutations in GJB2 c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) were identified in these four deaf children, each of the mutated GJB2 gene were inherited from their parents. There is no mutation of GJB2 gene identified in the normal child. Besides, the compound heterozygous mutation GJB2 c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) could lead to the alterations of the subcellular localization of each corresponding mutated CX26 protein and could cause the hearing loss, which has been predicted by MD simulation and verified in both 293T and SGNs cell line.

Conclusion

The c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) compound mutations in GJB2 detected in this study are novel, and which may be associated with hearing loss in this Chinese family.