bluuebunny/crossref_metadata_2025 huggingface dataset:
Β‐actin does not show the characteristics of a reference protein in human cortex
Authors: Parkin Georgia M. , Udawela Madhara , Gibbons Andrew , Dean Brian
Published: October 2018

Levels of a reference protein must be the same as a proportion of total protein in all tissues and, in the study of human diseases, cannot vary with factors such as age, gender or disease pathophysiology. It is increasingly apparent that there may be few, if any, proteins that display the characteristics of a reference protein within the human central nervous system (CNS). To begin to challenge this hypothesis, we used Western blotting to compare variance in levels of the “gold standard” reference protein, β‐actin, in Brodmann's area 9 from 194 subjects to variance of total transferred protein measured as intensity of Ponceau S staining. The coefficient of variance of sum intensity measurements for β‐actin levels across all donors was 47% compared to 24 and 27% for the sum intensity of Ponceau S staining measured using two different detection techniques. These data strongly suggest that the level of β‐actin, proportional to total protein, is not constant in human cortex which raises further doubt about the use of reference proteins to normalise data in human CNS studies. Considering our data, we suggest an alternative approach to presenting data from Western blotting of human CNS.
Spatial patterns of mercury contamination and associated risk to piscivorous wading birds of the south central United States
Authors: Gerstle Christopher T. , Drenner Ray W. , Chumchal Matthew M.
Published: October 2018

Piscivorous birds are top predators in aquatic ecosystems and are vulnerable to mercury (Hg) exposure and associated adverse health effects. In some areas of North America, the health risk posed to piscivorous birds by Hg contamination has not been characterized because concentrations of Hg in bird tissues have not been extensively monitored. When data on Hg in tissues of piscivorous birds are not available, the concentration of Hg in the blood of piscivorous birds can be estimated from the concentration of Hg in prey fish. We used concentrations of Hg in different lengths of a proxy prey fish, bluegill (Lepomis macrochirus), to estimate the concentration of Hg in the blood of 4 species of adult piscivorous wading birds (little blue herons [Egretta caerulea], green herons [Butorides virescens], great egrets [Ardea albus], and great blue herons [Ardea herodias]) in 14 ecoregions of the south central United States. The 4 species of birds consume different sizes of fish with different concentrations of Hg and were predicted to have different concentrations of Hg in their blood, with little blue herons < green herons < great egrets < great blue herons. For each species of bird, there were significant differences in average estimated concentrations of Hg in blood between ecoregions, with estimated concentrations of Hg in blood increasing with Hg deposition. The level of predicted risk varied with ecoregion and bird species and was highest for great blue herons. We recommend that future studies of Hg contamination of piscivorous wading birds of the southern United States focus on great blue herons in water bodies within ecoregions that have high Hg deposition. Environ Toxicol Chem 2019;38:160–166. © 2018 SETAC

Abstract

Estimated Hg concentration in bird blood. Photo credit: PhotoL, iStock.
Corticospinal tract degeneration in ALS unmasked in T1‐weighted images using texture analysis
Authors: Ishaque Abdullah , Mah Dennell , Seres Peter , Luk Collin , Johnston Wendy , Chenji Sneha , Beaulieu Christian , Yang Yee‐Hong , Kalra Sanjay
Published: October 2018

The purpose of this study was to investigate whether textures computed from T1‐weighted (T1W) images of the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS) are associated with degenerative changes evaluated by diffusion tensor imaging (DTI). Nineteen patients with ALS and 14 controls were prospectively recruited and underwent T1W and diffusion‐weighted magnetic resonance imaging. Three‐dimensional texture maps were computed from T1W images and correlated with the DTI metrics within the CST. Significantly correlated textures were selected and compared within the CST for group differences between patients and controls using voxel‐wise analysis. Textures were correlated with the patients' clinical upper motor neuron (UMN) signs and their diagnostic accuracy was evaluated. Voxel‐wise analysis of textures and their diagnostic performance were then assessed in an independent cohort with 26 patients and 13 controls. Results showed that textures autocorrelation, energy, and inverse difference normalized significantly correlated with DTI metrics (p < .05) and these textures were selected for further analyses. The textures demonstrated significant voxel‐wise differences between patients and controls in the centrum semiovale and the posterior limb of the internal capsule bilaterally (p < .05). Autocorrelation and energy significantly correlated with UMN burden in patients (p < .05) and classified patients and controls with 97% accuracy (100% sensitivity, 92.9% specificity). In the independent cohort, the selected textures demonstrated similar regional differences between patients and controls and classified participants with 94.9% accuracy. These results provide evidence that T1‐based textures are associated with degenerative changes in the CST.
Partially impaired functional connectivity states between right anterior insula and default mode network in autism spectrum disorder
Authors: Guo Xiaonan , Duan Xujun , Suckling John , Chen Heng , Liao Wei , Cui Qian , Chen Huafu
Published: October 2018

Time‐invariant resting‐state functional connectivity studies have illuminated the crucial role of the right anterior insula (rAI) in prominent social impairments of autism spectrum disorder (ASD). However, a recent dynamic connectivity study demonstrated that rather than being stationary, functional connectivity patterns of the rAI vary significantly across time. The present study aimed to explore the differences in functional connectivity in dynamic states of the rAI between individuals with ASD and typically developing controls (TD). Resting‐state functional magnetic resonance imaging data obtained from a publicly available database were analyzed in 209 individuals with ASD and 298 demographically matched controls. A k‐means clustering algorithm was utilized to obtain five dynamic states of functional connectivity of the rAI. The temporal properties, frequency properties, and meta‐analytic decoding were first identified in TD group to obtain the characteristics of each rAI dynamic state. Multivariate analysis of variance was then performed to compare the functional connectivity patterns of the rAI between ASD and TD groups in obtained states. Significantly impaired connectivity was observed in ASD in the ventral medial prefrontal cortex and posterior cingulate cortex, which are two critical hubs of the default mode network (DMN). States in which ASD showed decreased connectivity between the rAI and these regions were those more relevant to socio‐cognitive processing. From a dynamic perspective, these findings demonstrate partially impaired resting‐state functional connectivity patterns between the rAI and DMN across states in ASD, and provide novel insights into the neural mechanisms underlying social impairments in individuals with ASD.
Breast cancer‐specific survival by clinical subtype after 7 years follow‐up of young and elderly women in a nationwide cohort
Authors: Johansson Anna L.V. , Trewin Cassia B. , Hjerkind Kirsti Vik , Ellingjord‐Dale Merete , Johannesen Tom Børge , Ursin Giske
Published: October 2018

Age and tumor subtype are prognostic factors for breast cancer survival, but it is unclear which matters the most. We used population‐based data to address this question. We identified 21,384 women diagnosed with breast cancer at ages 20–89 between 2005 and 2015 in the Cancer Registry of Norway. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A‐like (ER+PR+HER2‐), luminal B‐like HER2‐negative (ER+PR‐HER2‐), luminal B‐like HER2‐positive (ER+PR+/‐HER2+), HER2‐positive (ER‐PR‐HER2+) and triple‐negative (TNBC) (ER‐PR‐HER2‐). Cox regression estimated hazard ratios (HR) for breast cancer‐specific 7‐year survival by age and subtype, while adjusting for year, grade, TNM stage and treatment. Young women more often had HER2‐positive and TNBC tumors, while elderly women (70–89) more often had luminal A‐like tumors. Compared to age 50–59, young women had doubled breast cancer‐specific mortality rate (HR = 2.26, 95% CI 1.81–2.82), while elderly had two to five times higher mortality rate (70–79: HR = 2.25, 1.87–2.71; 80–89: HR = 5.19, 4.21–6.41). After adjustments, the association was non‐significant among young women but remained high among elderly. Young age was associated with increased breast cancer‐specific mortality among luminal A‐like subtype, while old age was associated with increased mortality in all subtypes. Age and subtype were strong independent prognostic factors. The elderly always did worse, also after adjustment for subtype. Tumor‐associated factors (subtype, grade and stage) largely explained the higher breast cancer‐specific mortality among young. Future studies should address why luminal A‐like subtype is associated with a higher mortality rate in young women.
Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French Network of Cancer Registries (FRANCIM) data
Authors: Tron Laure , Belot Aurélien , Fauvernier Mathieu , Remontet Laurent , Bossard Nadine , Launay Ludivine , Bryere Joséphine , Monnereau Alain , Dejardin Olivier , Launoy Guy ,   the French Network of Cancer Registries (FRANCIM)
Published: October 2018

Social inequalities are concerning along the cancer continuum. In France, social gradient in health is particularly marked but little is known about social gradient in cancer survival. We aimed to investigate the influence of socioeconomic environment on cancer survival, for all cancers reported in the French Network of Cancer Registries. We analyzed 189,657 solid tumors diagnosed between 2006 and 2009, recorded in 18 registries. The European Deprivation Index (EDI), an ecological index measuring relative poverty in small geographic areas, assessed social environment. The EDI was categorized into quintiles of the national distribution. One‐ and five‐year age‐standardized net survival (ASNS) were estimated for each solid tumor site and deprivation quintile, among men and among women. We found that 5‐year ASNS was lower among patients living in the most deprived areas compared to those living in the least deprived ones for 14/16 cancers among men and 16/18 cancers among women. The extent of cancer survival disparities according to deprivation varied substantially across the cancer sites. The reduction in ASNS between the least and the most deprived quintile reached 34% for liver cancer among men and 59% for bile duct cancer among women. For pancreas, stomach and esophagus cancer (among men), and ovary and stomach cancer (among women), deprivation gaps were larger at 1‐year than 5‐year survival. In conclusion, survival was worse in the most deprived areas for almost all cancers. Our results from population‐based cancer registries data highlight the need for implementing actions to reduce social inequalities in cancer survival in France.
Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation
Authors: Kruber Philip , Angay Oguzhan , Winkler Anja , Bösl Michael R. , Kneitz Susanne , Heinze Katrin G. , Gessler Manfred
Published: October 2018

Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes DROSHA and DGCR8 have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the in vivo role of DROSHA mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA carrying a tumor‐specific E1147K mutation that acts in a dominant negative manner. Both types of mutation induce striking changes in miRNA patterns. Six2‐cre mediated deletion of Drosha in nephron progenitors led to perinatal lethality with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions via Wt1‐creERT2 resulted in a milder phenotype with viable offspring that developed proteinuria after 2–4 weeks, but no evidence of tumor formation. Activation of the DROSHA‐E1147K transgene via Six2‐cre, on the other hand, induced a more severe phenotype with apoptosis of progenitor cells, proteinuria and glomerular sclerosis. The severely growth retarded mice died within the first 2 months of life, confirming the predicted dominant‐negative effect of DROSHA‐E1147K in vivo. While our data underscores the importance of a viable self‐renewing progenitor pool for kidney development, there was no evidence of tumor formation through impaired DROSHA function. This suggests that either additional alterations in mitogenic or antiapoptotic pathways are needed for malignant transformation, or premature loss of a susceptible target cell population and early lethality prevent WT formation.
Cancer‐associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma
Authors: Kashima Hajime , Noma Kazuhiro , Ohara Toshiaki , Kato Takuya , Katsura Yuki , Komoto Satoshi , Sato Hiroaki , Katsube Ryoichi , Ninomiya Takayuki , Tazawa Hiroshi , Shirakawa Yasuhiro , Fujiwara Toshiyoshi
Published: October 2018

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer‐associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP+ CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.
Activin A improves retinal pigment epithelial cell survival on stiff but not soft substrates
Authors: White Corina E. , Kwok Bryan , Olabisi Ronke M.
Published: October 2018

In several retinal degenerative disease pathologies, such as dry age‐related macular degeneration (AMD), the retinal pigment epithelium (RPE) cell monolayer becomes dysfunctional. Promising tissue engineering treatment approaches implant RPE cells on scaffolds into the subretinal space. However, these approaches are not without challenges. Two major challenges that must be addressed are RPE dedifferentiation and the inflammatory response to cell/scaffold implantation. Design and optimization of scaffold cues for the purpose of RPE transplantation remain relatively unexplored, specifically the mechanical properties of the scaffolds. Prior work from our group indicated that by varying substrate moduli significant differences could be induced in cell cytoskeleton structure, cellular activity, and expression of inflammatory markers. We hypothesized that Activin A would provide rescue effects for cells demonstrating dedifferentiated characteristics. Results demonstrated that for cells on low modulus scaffolds, the mechanical environment was the dominating factor and Activin A was unable to rescue these cells. However, Activin A did demonstrate rescue effects for cells on high modulus scaffolds. This finding indicates that when cultured on scaffolds with an appropriate modulus, exogenous factors, such as Activin A, can improve RPE cell expression, morphology, and activity, while an inappropriate scaffold modulus can have devastating effects on RPE survival regardless of chemical stimulation. These findings have broad implications for the design and optimization of scaffolds for long‐term successful RPE transplantation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2871–2880, 2018.
Evaluation of cytotoxicity and antimicrobial activity of an injectable bone substitute of carrageenan and nano hydroxyapatite
Authors: González Ocampo Jazmín I. , Bassous Nicole , Ossa Orozco Claudia P. , Webster Thomas J.
Published: October 2018

A successful post‐surgical implant is associated with accelerated recovery periods, involving the efficient regeneration of lost or non‐viable tissue and a reduction in microbial growth. Alternatively, the long‐term success of an implant is guided by the selection of an engineered biomimetic material that is biocompatible, non‐biodegradable, and stable at the site of implantation, without invoking any non‐essential or undesirable biological responses. The potential for developing an injectable bone substitute (IBS) was investigated here. In particular, carrageenan (CG) and nano‐hydroxyapatite (nHA) injectable composites were fabricated by chemical cross‐linking, and the in vitro behavior of mammalian cells and bacteria on the IBS surface structures were evaluated. Formulations consisting of 1%, 1.5%, and 2.5% CG and 60% nHA by weight were then evaluated for their interactions with human osteoblasts (or bone forming cells). MTS viability testing indicated that osteoblast adhesion and viability on the IBS were excellent and uniform among various formulation types. Bacteria assays were also performed to assess antimicrobial functions on the CG/nHA composite against both Gram‐negative and Gram‐positive strains. A higher CG content, as found in some samples, correlated with improved Pseudomonas aeruginosa growth inhibition, although other bacteria strains appeared unaffected by the IBS. In summary, this study highlights CG/nHA composites as innovative biomaterials that should be further studied for reduced bacteria activity and promoted osteoblast responses which was achieved without using pharmaceutical drugs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2984–2993, 2018.
Modulating matrix‐multicellular response using polysucrose‐blended with poly‐L‐lactide or polydioxanone in electrospun scaffolds for skin tissue regeneration
Authors: Chummun Itisha , Bhaw‐Luximon Archana , Jhurry Dhanjay
Published: October 2018

Polysucrose (PSuc) is hydrophilic, has excellent biocompatibility with cells as a density gradient and is resistant to enzymes. Its use in electrospun mats for tissue engineering applications has not been investigated due to its amorphous nature. For spinnability and robustness, polysucrose was blended with poly‐L‐lactide (PLLA) and polydioxanone (PDX) respectively and electrospun into nanofibrous mats. Interaction with cells was assessed using L929 mouse fibroblasts and HaCaT keratinocytes separately and in co‐culture. Effect of parameters such as porosity, fiber diameter, surface wettability and mechanical properties of mats on cell‐scaffold interactions was studied. Depending on nature and composition of mats, fibroblasts showed dendritic, spindle or round cell morphologies along with the formation of lamellipodia, filopodia, fibrillar or fiber‐like projections of 100 nm and 200–300 nm in diameter respectively from the periphery or center of cells. Granular extracellular matrix was formed on both PLLA‐PSuc and PDX‐PSuc 50–50 seeded with keratinocytes. Growth of keratinocytes was enhanced in co‐culture with fibroblasts with the formation of a skin‐like layer. Both cells showed the ability to form multilayer structures. The mats maintained their physical integrity during the period of study. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3275–3291, 2018.
A novel approach to devise the therapy for ventricular fibrillation by epicardial delivery of lidocaine using active hydraulic ventricular attaching support system: An experimental study in rats
Authors: Yasmeen Sufia , Liao Xiaoqian , Khan Farhan Ullah , Ihsan Awais Ullah , Li Xue , Li Cunyu , Chen Dingding , Yu Feng , Wang Zhijie , Sembatya Kiganda Raymond , Mikrani Reyaj , Zhou Xiaohui
Published: October 2018

Active hydraulic ventricular attaching support system (ASD) placed around the heart is not only a novel, nontransplant surgical device used for epicardial administration of drugs like lidocaine, but also a promising treatment option for ventricular fibrillation (VF) and arrhythmias. We hypothesize that lidocaine in 5 mg/kg dose released by ASD significantly improves the VF in the rat model. Sprague‐Dawley (SD) rats were selected and were divided into four groups, intravenous injection (IV), epicardial infusion (EI), ASD, and control. ASD group was further divided into four subgroups for different lidocaine doses (i) ASD+A group (10 mg/kg), (ii) ASD+B group (5 mg/kg), (iii) ASD+C group (1 mg/kg), and (iv) ASD+D group (0.1 mg/kg). VF was induced with calcium chloride injection and was confirmed by electrocardiogram (ECG) in all the groups. VF was treated with different doses of lidocaine using different modes of administration. Data were analyzed using the SPSS 19.0 Chi‐square tests and one‐way analysis of variance (ANOVA). The Kaplan–Meier curve for OS was compared to the Logrank test based on the survival time. P < 0.05 was considered as statistically significant. ASD + B group (5 mg/kg) showed significantly reduced sgroup. The time of first sinus rhythm recovered (15.96 ± 21.77 min) and ▵T‐SOD in plasma (−42.02 ± 26.99 U/mL) was significantly different than that of control, IV, and EI groups. ▵T‐SOD in plasma for all ASD‐treated groups was smaller than the control and IV groups. This study proves that ASD with 5 mg/kg lidocaine dose appears as a promising therapeutic platform for treating VF in rats. Furthermore, ASD may also have potential for treating VF or other cardiovascular disease with different therapeutic agents. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1722–1731, 2019.
Gamma‐secretase inhibitor suppressed Notch1 intracellular domain combination with p65 and resulted in the inhibition of the NF‐κB signaling pathway induced by IL‐1β and TNF‐α in nucleus pulposus cells
Authors: Huang Yao , Mei Wei , Chen Jian , Jiang Tao , Zhou Zheng , Yin Guoyong , Fan Jin
Published: October 2018

In this experiment, the cross‐talk betweenNotch and the NF‐κB signaling pathway was examined to reveal the mechanism of slowing down the type II collagen (ColII) and aggrecan degeneration affected by inflammatory cytokines. The expression levels of ColII and aggrecan in the intervertebral disc were observed through immunohistochemistry and hematoxylin‐eosin staining+alcian blue staining, respectively. The expression levels of ColII, aggrecan, Runx2, and NF‐κB in the nuclei of human nucleus pulposus cells (hNPCs) in each group, as well as the phosphorylation and acetylation levels of p65, were examined through Western blot analysis. The 293T cells were transfected with a plasmid containing the overexpressed relative domain of Notch1 intracellular domain (NICD1), and immunoprecipitation (IP) was performed to observe the combination of NICD1 and p65. HNPCs were transfected with a lentiviral‐contained overexpression lacking the ANK region of NICD1, and IP was performed to observe the combination of NICD1 and p65. The expression of ColII and aggrecan in the intervertebral disc culture increased when γ‐secretase inhibitor N‐[N‐(3,5‐difluorophenacetyl)‐1‐alanyl]‐Sphenylglycine t‐butyl ester (DAPT) was added to the disc culture medium. Western blot revealed that DAPT inhibited p65 phosphorylation and acetylation, and the p65 and p50 levels in the nucleus decreased. NICD1 was found to be combined with p65 in contrast to the reverse consequences after ANK domain deletion in hNPCs. In nucleus pulposus cells, the combination of p65 and the ANK domain of NICD1 is a critical procedure for the degeneration related to the NF‐κB signaling pathway activation induced by IL‐1β and TNF‐α.
Betulinic acid inhibits cell proliferation, migration, and inflammatory response in rheumatoid arthritis fibroblast‐like synoviocytes
Authors: Wang Jing , Zhao Qing
Published: October 2018

Betulinic acid (BA), a pentacyclic triterpene derived from the bark of the white birch tree, has been reported to have a variety of pharmacological effects, including antioxidant, anti‐inflammatory, antitumor, immunomodulatory, and antiarthritis properties. However, the role of BA in rheumatoid arthritis (RA) remains unclear. Thus, the objective of this study was to examine the effects of BA on RA fibroblast‐like synoviocytes (RA‐FLS) proliferation, migration, and inflammatory response, and further explore the potential underlying mechanisms. Our results showed that BA inhibited the proliferation, migration, and invasion of RA‐FLSs. BA also attenuated tumor necrosis factor‐α (TNF‐α), enhanced matrix metalloproteinases (MMPs) expression, and inflammatory cytokines production in RA‐FLS. Furthermore, BA prevented the activation of Akt/NF‐κB pathway in RA‐FLS exposed to TNF‐α. In conclusion, these findings indicated that BA inhibits cell proliferation, migration, and inflammatory response in RA‐FLS; and the Akt/NF‐κB signaling pathway was involved in the protective effect of BA on RA‐FLS. Thus, BA might be a potential therapeutic agent for the treatment of RA.
Inactivation of ATF‐2 enhances epithelial‐mesenchymal transition and gemcitabine sensitivity in human pancreatic cancer cells
Authors: Wu Xingda , Liu Zhe , Guo Kejia , Ma Gang , Song Shaowei
Published: October 2018

Objective

This work aimed to study the activating transcription factor 2 or AMP‐dependent transcription factor‐2 (ATF‐2) inhibition mediated gemcitabine sensitivity in human pancreatic cancer cells.

Methods

The protein and messenger RNA expressions of ATF‐2 in 42 pancreatic cancer tissues and adjacent nontumorous tissues were detected. Kaplan‐Meier survival analysis was performed based on the expression level of ATF‐2 protein in tumor tissues. Then the pancreatic cancer cells were transduced with ATF‐2‐expressing lentivirus and small interfering RNAs (siRNAs) to investigate the effect of ATF‐2 on pancreatic cancer cell invasion, epithelium to mesenchyme transition, apoptosis, and gemcitabine sensitivity.

Results

The expression of phosphorylated (p)‐ATF‐2 protein was upregulated in pancreatic cancer tissues compared with adjacent nontumorous tissues. Patients with relative higher p‐ATF‐2 level showed significantly lower survival time. Then we found that the transfection ATF‐2 siRNA into BxPC3 cells inhibited cell proliferation, invasion, and epithelium to mesenchyme transition, but enhanced cell apoptosis. These changes could be enhanced by the additional administration of gemcitabine. In addition, we confirmed that the overexpression of ATF‐2 in Panc‐1 cells promoted cell invasion and epithelium to mesenchyme transition.

Conclusion

We concluded that inhibition‐promoted ATF‐2 expression was responsible for epithelium to mesenchyme transition and invasion of pancreatic cancer cells, while the inhibition of ATF‐2 confers to gemcitabine sensitivity in human pancreatic cancer cells in vitro.
Urea‐modulated UT‐B urea transporter internalization is clathrin‐ and caveolae‐dependent in infantile hemangioma‐derived vascular endothelial cells
Authors: Xiao Li , Liu Dakan , Zuo Song , Zhu Xiaoshuang , Wang Yanlin , Dong Changxian
Published: October 2018

The aim of this study was to investigate the manner of urea‐modulated UT‐B urea transporter (UT) internalization in infantile hemangioma‐derived vascular endothelial cells (HemECs). The immunohistochemistry assay was performed to identify infancy hemangioma‐derived endothelial cell line (XPTS‐1) cells. Cell toxicity was detected with the 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide (MTT) assay. Quantitative real‐time polymerase chain reaction and Western blot analysis were measured to analyze the expression of UT‐B. UT‐B internalization was observed by confocal microscopy. The clathrin inhibitor chlorpromazine (CPZ) and caveolin endocytic disrupter methyl‐β‐cyclodextrin (MβCD) were used in XPTS‐1 cells transfected with UT‐B‐GFP to repress endocytosis. Urea‐promoted UT‐B expression in a concentration‐dependent manner in an infantile XPTS‐1 cell line. CPZ and MβCD significantly inhibited UT‐B protein internalization. The pretreatment of UT‐B‐GFP cells with adaptor protein2 (AP2)‐μ2‐siRNA and caveolin‐siRNA significantly inhibited UT‐B protein internalization. Our findings suggested that urea‐mediated UT‐B UT internalization is clathrin and caveolae dependent in infantile HemECs.
RETRACTED: H19 suppresses the growth of hepatoblastoma cells by promoting their apoptosis via the signaling pathways of miR‐675/FADD and miR‐138/PTK2
Authors: Ge Lili , Zhang Xianwei , Hu Shengnan , Song Yinsen , Kong Jinghui , Zhang Bo , Yang Xiaoang
Published: October 2018

Background

The objective of this study was to clarify the molecular pathways involved in hepatitis B virus (HBV)‐induced hepatoblastoma.

Method

The expression of factors in different signaling pathways (H19, miR‐675, miR‐138, protein tyrosine kinase 2 [PTK2], fas‐associated death domain [FADD], hypoxia‐inducible factor 1‐alpha [HIFIA], focal adhesion kinase [FAK], caspase‐8, and caspase‐3) was compared between HBV (+) and HBV (−) groups using quantitative real‐time polymerase chain reaction and Western blot analysis. Subsequently, immunohistochemistry (IHC) and TdT‐mediated dUTP Nick‐End Labeling (TUNEL) assays were used to verify the expression of above proteins in HBV (+) and HBV (−) groups. Computational analysis was conducted to predict the target genes of miR‐675 and miR‐138, whose regulatory relationships were then clarified using luciferase assays and cell transfection studies.

Result

The expression of H19, miR‐675, PTK2, HIFIA, and FAK was increased in the HBV (+) group, while the expression of miR‐138, FADD, caspase‐8, and caspase‐3 was decreased in the HBV (+) group. FADD and PTK2 were identified as target genes of miR‐675 and miR‐138, respectively. In addition, miR‐675 was upregulated while miR‐138 was downregulated by X protein (HBx).

Conclusion

In summary, the results of this study revealed the molecular pathways involved in HBV‐induced hepatoblastoma. In the presence of HBV, HBX upregulated the expression of H19 through HIFIA. Consecutively, overexpressed H19 upregulated the expression of PTK2 via targeting miR‐138 and downregulated the expression of FADD via targeting miR‐675. Finally, increased expression of PTK2 and reduced expression of FADD both led to the inhibition of cell apoptosis, thus promoting the tumorigenesis of hepatoblastoma.
Retracted: Long noncoding RNA HOTAIR knockdown inhibits autophagy and epithelial–mesenchymal transition through the Wnt signaling pathway in radioresistant human cervical cancer HeLa cells
Authors: Guo Xinggang , Xiao Hongqi , Guo Sihong , Li Jing , Wang Yuxia , Chen Jie , Lou Ge
Published: October 2018

Cervical cancer is one of the most common female malignancies around the world, and radiation resistance is a major obstacle to cancer therapy. Previously, overexpression of the long noncoding ribonucleic acid (RNA) (lncRNA) HOX transcript antisense RNA (HOTAIR) has been found to be associated with the invasion and metastasis capacities of several epithelial cancers, including cervical cancer. To gain insights into the molecular mechanisms of HOTAIR in cervical cancer resistance to radiotherapy, we investigated cellular autophagy and epithelial‐to‐mesenchymal transition (EMT) in radioresistant human cervical cancer HeLa cells when HOTAIR was suppressed. HOTAIR levels were quantified in cancerous and noncancerous cervical tissues obtained from 108 patients with cervical cancer. Next, we inhibited HOTAIR by RNA interference and activated the Wnt signaling pathway by LiCl in radioresistant HeLa cells to investigate the regulatory mechanisms for the HOTAIR mediating Wnt signaling pathway. We determined that the upregulated HOTAIR may contribute to cervical cancer progression. We found that the short interfering ribonucleic acid (siRNA)‐mediated knockdown of HOTAIR disturbed the Wnt signaling pathway, reduced autophagy, inhibited EMT, decreased cell proliferation, and induced apoptosis in radioresistant HeLa cells. It is worthy to note that the combination treatment of siRNA‐HOTAIR and LiCl demonstrated that the activation of the Wnt signaling pathway is responsible for the beneficial effect of HOTAIR knockdown in enhancing sensitivity to radiotherapy in radioresistant HeLa cells. Together, our results revealed an important role of HOTAIR in regulating cervical cancer resistance to radiotherapy. Functional suppression of HOTAIR could enhance sensitivity to radiotherapy by reduction of autophagy and reversal of EMT through the suppression of the Wnt signaling pathway.
Tet methylcytosine dioxygenase 1 promotes hypoxic gene induction and cell migration in colon cancer
Authors: Ma Ling , Qi Tianyang , Wang Shensen , Hao Miao , Sakhawat Ali , Liang Tianya , Zhang Lin , Cong Xianling , Huang Yinghui
Published: October 2018

Ten‐eleven translocation 1 (TET1), a widely reported DNA demethylation protein, has been associated with tumorigenesis and metastasis. However, whether TET1 is an oncogene or tumor suppressor gene has been controversial; the mechanism of how TET1 affects cancer progression remains unclear. The current study aims to investigate how TET1 is changed in the tumor microenvironment and to explore the mechanisms of how TET1 affects colon cancer progression. Because hypoxia prevails on solid tumors, we established an important connection between hypoxia and DNA demethylation in tumorigenesis. By qPCR and RNA interference (RNAi) technology, we found that hypoxia increased TET1 expression with a hypoxia‐inducible factor‐1‐alpha (HIF‐1α)‐dependent manner. By CHIP‐qPCR and pyrosequencing technology, we demonstrated that TET1 regulated the target gene expression of HIF‐1α through HIF‐1α binding to hypoxia‐responsive elements (HREs), and HIF‐1α binding to HREs depended on CpG methylation levels. By Cell Counting Kit‐8 (CCK‐8) and transwell assay, we showed that loss of TET1 did not affect cell proliferation but inhibited migration. We also identified two novel gene mutants of TET1 in 120 paired tumor/normal tissue specimens by DNA sequencing and found that TET1 E2082K mutant blocked the TET1‐enhanced cell migration. Our results showed that the downregulation of TET1 rescued the abnormally high levels of gene expression resulting from hypoxia in tumors and reduced the migration activity of tumor cells, suggesting a therapeutic role by interference with TET1 in colon cancer treatment. By demonstrating that hypoxia upregulated TET1 and that TET1 drove HIF‐1α‐responsive genes, we showed that an epigenetic mechanism and tumor microenvironment‐driven models coexisted and mutually affected colon cancer.
HOTAIR promotes osteosarcoma development by sponging miR‐217 and targeting ZEB1
Authors: Wang Bing , Qu Xing‐Long , Liu Jiaxiang , Lu Junhui , Zhou Zong‐Yu
Published: October 2018

Long noncoding RNAs (lncRNAs) have drawn increasing attention because of the role which they play in various diseases, including osteosarcoma. So far, the function and mechanism of HOTAIR in osteosarcoma are unclear. In our study, we observed that HOTAIR was elevated accompanied with a decrease of miR‐217 and an increase of ZEB1 in human osteosarcoma cells including U2OS, MG63, Saos‐2, and SW1353 compared with human osteoblast cell line hFOB. In addition, the subsequent functional assay exhibited that silencing HOTAIR could significantly repress osteosarcoma cell growth, migration, invasion, and induce cell apoptosis capacity, which indicated that HOTAIR exerted an oncogenic role in osteosarcoma. Moreover, it was revealed by using bioinformatics analysis that HOTAIR can be targeted by microRNA‐217 (miR‐217). miR‐217 has been recognized as a crucial tumor suppressive gene in cancers. We verified that mimics of miR‐217 were able to suppress the osteosarcoma development. Furthermore, real‐time quantitative PCR showed that HOTAIR siRNA increased miR‐217 expression. Besides these, ZEB1 was identified as a downstream gene of miR‐217 and we found that HOTAIR can mediate osteosarcoma progress by upregulating ZEB1 expression via acting as a competitive endogenous RNA (ceRNA) via miR‐217. Taken these together, our findings in this study indicated that HOTAIR/miR‐217/ZEB1 axis, as a novel research point can provide new insights into molecular mechanism of osteosarcoma development.
LINC00961 restrains cancer progression via modulating epithelial–mesenchymal transition in renal cell carcinoma
Authors: Chen Dongming , Zhu Meng , Su Huang , Chen Jiexun , Xu Xianlin , Cao Changchun
Published: October 2018

Recently, long noncoding RNA have been identified as new gene regulators and prognostic biomarkers in various cancers, including renal cell carcinoma (RCC). The expression and biological roles of LINC00961 have been reported in many human cancers. However, up to date, no study of LINC00961 has been shown in RCC. Currently, we aimed to investigate the function of LINC00961 in RCC progression. Interestingly, we observed that LINC00961 could act as a novel biomarker in predicting the diagnosis of RCC. Then, we found that LINC00961 was greatly downregulated in RCC cell lines (Caki‐1, Caki‐2, 786‐O, A498, and ACHN cells) compared with normal renal cell lines (HK‐2 cells). Then, 786‐O cells and ACHN cells were infected with LV‐LINC00961. As displayed in our current study, LINC00961 overexpression could obviously suppress the proliferation and survival of RCC cells in vitro. In addition, RCC cell apoptosis was greatly induced and cell cycle progression was blocked in G1 phase by upregulation of LINC00961 in 786‐O cells and ACHN cells. Subsequently, we found that LV‐LINC00961 was able to restrain RCC cell migration and cell invasion capacity. Meanwhile, the messenger RNA and protein expression levels of epithelial–mesenchymal transition (EMT)‐associated markers Slug and N‐cadherin in RCC cell lines were dramatically inhibited by overexpressing LINC00961. Finally, the in vivo experiment was carried out and we observed that LINC00961 could inhibit RCC development through modulating EMT process. Taken these together, it was indicated in our study that LINC00961 was involved in RCC progression through targeting EMT pathway.
Narrative review of the effects of antidiabetic drugs on albuminuria
Authors: Yaribeygi Habib , Atkin Stephen L. , Katsiki Niki , Sahebkar Amirhossein
Published: October 2018

Diabetes mellitus is the most prevalent metabolic disorder worldwide. Glycemic control is the main focus of antidiabetic therapy. However, there are data suggesting that some antidiabetic drugs may have intrinsic beneficial renal effects and protect against the development and progression of albuminuria, thus minimizing the risk of diabetic nephropathy. These pharmacological agents can suppress upstream molecular pathways involved in the pathophysiology of diabetes‐induced renal dysfunction such as oxidative stress, inflammatory responses, and apoptosis. In this narrative review, the pathophysiology of albuminuria in patients with diabetic nephropathy is discussed. Furthermore, the renoprotective effects of antidiabetic drugs, focusing on albuminuria, are reviewed.
Inhibition of the formation of autophagosome but not autolysosome augments ABT‐751‐induced apoptosis in TP53‐deficient Hep‐3B cells
Authors: Wei Ren‐Jie , Wu Wen‐Ren , Pan Cheng‐Tang , Yu Chun‐Yen , Li Chien‐Feng , Chen Lih‐Ren , Liang Shih‐Shin , Shiue Yow‐Ling
Published: October 2018

Abstarct

The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel antimicrotubule drug, ABT‐751, in a tumor protein p53 (
TP53)‐deficient hepatocellular carcinoma‐derived Hep‐3B cells. A series of in vitro assays indicated that ABT‐751 caused the disruption of the mitotic spindle structure, collapse of mitochondrial membrane potential, generation of reactive oxygen species, DNA damage, G
2/M cell cycle arrest, inhibition of anchorage‐independent cell growth and apoptosis in Hep‐3B cells accompanied by alteration of the expression levels of several DNA damage checkpoint proteins and cell cycle regulators. Subsequently, ABT‐751 triggered apoptosis along with markedly upregulated several proapoptotic proteins involving in extrinsic, intrinsic, and caspase‐mediated apoptotic pathways. A pan‐caspase inhibitor suppressed ABT‐751‐induced apoptosis. ABT‐751 also induced autophagy soon after the occurrence of apoptosis through the suppression of AKT serine/threonine kinase/mechanistic target of rapamycin signaling pathway. Exogenous expression of the
TP53 gene significantly incurred both apoptosis and autophagy in Hep‐3B cells. Pharmacological inhibition of autophagosome (early autophagy) but not autolysosome (late autophagy) enhanced ABT‐751‐induced apoptosis in
TP53‐deficient Hep‐3B cells. Our study provided a new strategy to augment ABT‐751‐induced apoptosis in
TP53‐deficient cells.
The C‐terminal flanking peptide of neuropeptide Y (NPY) is not essential for seizure‐suppressant actions of prepro‐NPY overexpression in male rats
Authors: Soud Katia , Jørgensen Søren Heide , Woldbye David Paul Drucker , Sørensen Andreas Toft
Published: October 2018

The full coding sequence of neuropeptide Y (NPY), prepro‐NPY, is sequentially metabolized into three peptides; an N‐terminus 28‐amino acid signaling peptide, the NPY peptide itself (NPY1‐36), and a 30‐amino acid C‐terminus peptide, known as the C‐terminal flanking peptide of neuropeptide‐Y (CPON). While the signaling peptide directs intracellular trafficking and NPY1‐36 is well characterized, the biological function of CPON is unknown. This is noteworthy because CPON is co‐stored and co‐released along with NPY1‐36 and could thus potentially serve important functions. To assess the role of CPON, we adapted a viral genetic approach using two different vector designs encoding NPY, but where the CPON coding sequence was excluded from one of the vectors. Thus, the effect of CPON was indirectly assessed. Male rats received intrahippocampal injections of either a vector encoding NPY1‐39 whose metabolism yields NPY1‐36 and not CPON, or a prepro‐NPY vector encoding both NPY1‐36 and CPON. A third vector encoding EGFP served as control. We subsequently studied to what extent CPON might affect seizure susceptibility and memory performance, respectively, to address two important questions to evaluate the potential of NPY gene therapy in epilepsy. Both NPY vectors, as compared to EGFP control, were found to be equally effective at suppressing acute kainate–induced seizures, and both did not influence learning and memory performance in the Morris water maze. Thus CPON itself does not appear to aid actions governed by vector–mediated overexpression of NPY1‐36 within the hippocampus. Whether CPON serves other important functions remains to be determined.
Histological and histomorphometric evaluation of hydroxyapatite‐based biomaterials in surgically created defects around implants in dogs
Authors: Attia Mai S. , Mohammed Hend M. , Attia Mohammed G. , Hamid Mohamed A. Abd El , Shoeriabah Eatemad A.
Published: October 2018

Background

The present study evaluated histologically and histometrically the efficacy of micro‐, nano‐, or mixed‐composite of hydroxyapatite (HA) graft in treatment of surgically created defects around dental implants in mongrel dogs.

Methods

Immediate implant was used after extraction of the lower third premolar in mongrel male dogs. Critical‐size defects were created in intact proximal alveolar bone to each implant. The defects were divided randomly into four groups of two animals based on biomaterials used for treatment: 1) received no treatment (negative control); 2) defects treated with nano‐HA bone graft; 3) defects treated with micro‐HA bone graft; and 4) defects treated with a mixed composite of micro‐HA and nano‐HA. Animals were sacrificed at 2 months and histologic and histometric evaluation was performed.

Results

The amount of new bone formed with nano‐HA bone graft was highly more significant than that obtained by a micro‐ or mixed‐composite of hydroxyapatite. Defects treated by mixed hydroxyapatite showed the greatest value in mean area percentage of collagen fibers using Masson trichrome stain.

Conclusions

The present study demonstrated that nano‐hydroxyapatite bone graft was better than micro‐HA or mixed‐HA bone graft in new bone formation in standardized surgically created defects around dental implants. However, longer period is necessary to determine the time taken for complete resorption of bone graft materials and their replacement with new bone.
Effects of methods of hydration of a biphasic ceramic graft on bone regeneration of extraction socket defects
Authors: Santos Igor Guimarães Barros Paulinelli , de Santana Carolina Miler Mattos , Alves Adriana Therezinha Neves Novelino , de Uzeda Marcelo José Pinheiro Gueded , Calasans‐Maia Mônica Diuana , de Santana Ronaldo Barcellos
Published: October 2018

Background

Alveolar volumetric changes are inherent to the healing process after tooth extraction and filling of the extraction site with biomaterials can reduce these volumetric changes and provide a more favorable environment for the future prosthetic restoration with implants. Among the biomaterials available, biphasic ceramic compounds have shown promissing clinical results, however, histologic evaluation of bone tissue response to different hydration and incorporation methods are limited. The objective of this study was to comparatively evaluatein vivothe osteoconductive potential of the biphasic ceramic bone substitute (SBC) composed of beta‐tricalcium phosphate and hydroxyapatite after different hydration methodologies in rat extraction sockets.

Methods

Wistar rats (n = 20) were randomly distributed in two subgroups (G1, G2) according to the hydration methods used. After extraction of the right upper central incisor the alveoli were filled with SBC hydrated by two different methods. Group 1: biomaterial hydrated in blood; Group 2: biomaterial hydrated in physiologic saline. The animals were euthanized after 1 and 6 weeks for removal of the bone blocks containing the biomaterial and were submitted to histologic processing. Five‐μm‐thick demineralized sections of the samples were stained with hematoxylin and eosin (HE) and subjected to histomorphometric analysis.

Results

Bone formation was limited 7 days after the extraction procedure and increased in both groups between 7 and 42 days from surgery, demonstrating a time dependent increase of bone volume throughtout the experimental period (p < 0.05).

Conclusions

The hydration of SBC with saline significantly increased new bone formation and reduced connective tissue volume after 42 days demonstrating that hydration method may significantly influence bone healing in such defects, and, thus should be carefully performed.