bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of cysteine‐glutamate transporter and CD44 for prediction of recurrence and survival in patients with oral cavity squamous cell carcinoma
Authors: Lee Jae Ryung , Roh Jong‐Lyel , Lee Sun Mi , Park Yangsoon , Cho Kyung‐Ja , Choi Seung‐Ho , Nam Soon Yuhl , Kim Sang Yoon
Published: October 2018

Background

This study analyzed the expression of CD44 and cystine‐glutamate transporter SLC7A11 (xCT) in primary oral cavity squamous cell carcinoma (SCC) and the relationships of expression to tumor recurrence and patient survival.

Methods

Associations between CD44 and xCT expression and clinicopathologic results were analyzed in 231 patients with oral cavity SCC. Cox proportional hazard analyses were used to identify factors associated with recurrence‐free survival (RFS), disease‐specific survival (DSS), and overall survival (OS).

Results

Overexpression of CD44 and/or xCT was associated with advanced T classification, perineural invasion, and lymphovascular invasion (P < .05 each). High expression of xCT was also associated with nodal metastasis and depth of invasion (P < .01 each). Multivariate analysis indicated that high expression of xCT and both xCT and CD44 were independent predictors of poor RFS, DSS, and OS (P < .05 each).

Conclusion

Overexpression of xCT or xCT plus CD44 may predict posttreatment recurrence and survival in patients with oral cavity SCC.
Transoral surgery using the Flex Robotic System: Initial experience in the United States
Authors: Persky Michael J. , Issa Mohamad , Bonfili Jennifer R. , Goyal Neerav , Goldenberg David , Duvvuri Umamaheswar
Published: October 2018

Background

This multicenter, retrospective review documents the initial experience using the Flex system for transoral surgery in 2 United States academic centers.

Methods

All patients who underwent transoral robotic surgery using the Medrobotics Flex Robotic System (Raynham, MA) between September 2015 and May 2017 were reviewed. Rates of successful surgery and complications were evaluated.

Results

Thirty‐six men and 32 women were enrolled in the study. The average age was 55.6 years (range 17‐82 years). The Flex system was used successfully in surgery of the tongue base, the palatine tonsils, the supraglottis, the glottis, the hypopharynx, the oral tongue, and the soft palate. Only 6 cases (7.6%) required readmission after discharge. There were no intraoperative or immediate postoperative complications, with no cases of intraoperative hemorrhage.

Conclusion

To the best of our knowledge, this is the first study in the United States evaluating the use of the Flex system to safely resect lesions in the oral cavity, larynx, and pharynx.
Estimating dominant runoff modes across the conterminous United States
Authors: Buchanan Brian , Auerbach Daniel A. , Knighton James , Evensen Darrick , Fuka Daniel R. , Easton Zachary , Wieczorek Michael , Archibald Josephine A. , McWilliams Brandon , Walter Todd
Published: October 2018

Effective natural resource planning depends on understanding the prevalence of runoff generating processes. Within a specific area of interest, this demands reproducible, straightforward information that can complement available local data and can orient and guide stakeholders with diverse training and backgrounds. To address this demand within the contiguous United States (CONUS), we characterized and mapped the predominance of two primary runoff generating processes: infiltration‐excess and saturation‐excess runoff (IE vs. SE, respectively). Specifically, we constructed a gap‐filled grid of surficial saturated hydraulic conductivity using the Soil Survey Geographic and State Soil Geographic soils databases. We then compared surficial saturated hydraulic conductivity values with 1‐hr rainfall‐frequency estimates across a range of return intervals derived from CONUS‐scale random forest models. This assessment of the prevalence of IE versus SE runoff also incorporated a simple uncertainty analysis, as well as a case study of how the approach could be used to evaluate future alterations in runoff processes resulting from climate change. We found a low likelihood of IE runoff on undisturbed soils over much of CONUS for 1‐hr storms with return intervals <5 years. Conversely, IE runoff is most likely in the Central United States (i.e., Texas, Louisiana, Kansas, Missouri, Iowa, Nebraska, and Western South Dakota), and the relative predominance of runoff types is highly sensitive to the accuracy of the estimated soil properties. Leveraging publicly available data sets and reproducible workflows, our approach offers greater understanding of predominant runoff generating processes over a continental extent and expands the technical resources available to environmental planners, regulators, and modellers.
Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene‐set analysis
Authors: Berrandou Takiy , Mulot Claire , Cordina‐Duverger Emilie , Arveux Patrick , Laurent‐Puig Pierre , Truong Thérèse , Guénel Pascal
Published: October 2018

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene‐set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case–control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.
Short half‐life of HPV16 E6 and E7 mRNAs sensitizes HPV16‐positive tonsillar cancer cell line HN26 to DNA‐damaging drugs
Authors: Wu Chengjun , Nilsson Kersti , Zheng Yunji , Ekenstierna Camilla , Sugiyama Natsuki , Forslund Ola , Kajitani Naoko , Yu Haoran , Wennerberg Johan , Ekblad Lars , Schwartz Stefan
Published: October 2018

Here we show that treatment of the HPV16‐positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan‐induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down‐regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1‐negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half‐life of the HPV16 E6 and E7 mRNAs renders HPV16‐driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.
3D‐printed polycaprolactone scaffold mixed with β‐tricalcium phosphate as a bone regenerative material in rabbit calvarial defects
Authors: Pae Hyung‐Chul , Kang Joo‐Hyun , Cha Jae‐Kook , Lee Jung‐Seok , Paik Jeong‐Won , Jung Ui‐Won , Kim Byung‐Hoon , Choi Seong‐Ho
Published: October 2018

Defect‐specific bone regeneration using 3‐dimensional (3D) printing of block bone has been developed. Polycaprolactone (PCL) is biocompatible polymer that can be used as 3D scaffold. The aim of this study is to assess the biocompatibility and osteogenic efficacy of 3D printed PCL scaffold and to evaluate the effectiveness of β‐tricalcium phosphate (β‐TCP) addition in PCL scaffold. In this work, four circular defects (diameter: 8 mm) in rabbit calvarium were randomly assigned to (1) negative control (control), (2) PCL block (PCL), (3) PCL mixed with 10 wt% β‐TCP (PCL/β‐TCP), and (4) PCL/β‐TCP plus collagen membrane (PCL/β‐TCP + M). Animals were euthanized at 2 (n = 5) and 8 weeks (n = 5). Results indicated that in micro‐CT, PCL/β‐TCP + M showed the highest total augmented volume and new bone volume at 8 weeks, but there was no significant difference among four groups. Histomorphometrically, PCL, PCL/β‐TCP, and PCL/β‐TCP + M showed the significantly higher total augmented area compared to the control. PCL/β‐TCP + M showed the highest new bone area but not statistically higher than the control. New bone formation deep inside the scaffold was observed only in β‐TCP added scaffold. PCL showed high biocompatibility with great volume maintenance. Addition of β‐TCP to PCL seemed to increase hydrophilicity and osteoconductivity. Developments in 3D‐printed PCL material are expected. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1254–1263, 2019.
Dysregulation of FTX/miR‐545 signaling pathway downregulates Tim‐3 and is responsible for the abnormal activation of macrophage in cirrhosis
Authors: Liu Xia , Li Cong , Zhu Jie , Li Wenshuai , Zhu Qiang
Published: October 2018

Background

Accumulating evidence has suggested the involvement of miR‐545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR‐545 and lncRNA FTX in hepatitis B virus (HBV)‐related cirrhosis.

Method

The level of Tim‐3, TLR‐4, and endotoxin was detected in CD14+, CD14
+CD16
+, and CD14
+CD16
− monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF‐a), interleukin‐6 (IL‐6), IL‐1β, and Nuclear factor kB (NF‐kB). In‐silico analysis, luciferase assay, real‐time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR‐545 and Tim‐3.

Results

The levels of Tim‐3, Tim‐3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim‐3 was also decreased in the CD14
+CD16
− monocytes isolated from patients with cirrhosis, whereas the level of Tim‐3 in CD14
+CD16
+ monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR‐4 was highly expressed in CD14
+CD16
+ monocytes isolated from patients with cirrhosis, whereas Tim‐3 was negatively regulated by endotoxin and the correlation coefficient was ‐0.5287. After the LPS stimulation, although the level of TNF‐a, IL‐6, IL‐1β, and NF‐kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim‐3, but a higher level of miR‐545. Moreover, miR‐545 directly bound to the 3′untranslated region (3′UTR) of Tim‐3 and inhibited the luciferase activity of cells cotransfected with miR‐545 mimics and wild‐type 3′UTR of Tim‐3. Furthermore, FTX downregulated the expression of miR‐545, TNF‐a, IL‐6, IL‐1β, and NF‐kB, but upregulated the expression of Tim‐3.

Conclusion

The results of this study confirmed the effect of FTX, miR‐545, and Tim‐3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV‐related cirrhosis.
Total flavonoids from Smilax glabra Roxb blocks epithelial‐mesenchymal transition and inhibits renal interstitial fibrosis by targeting miR‐21/PTEN signaling
Authors: Luo Qihan , Cai Zhaowei , Tu Jue , Ling Yun , Wang Dejun , Cai Yueqin
Published: October 2018

Background

Smilax glabra Roxb, a traditional Chinese herb, has been widely used in folk medicine. The current study was performed to investigate the protective effect of
S. glabra Roxb extract, pure total flavonoids from
Smilax glabra Roxb (PTFS), on renal interstitial fibrosis (RIF) and its underlying mechanism.

Methods

First, a surgical model of unilateral ureteral obstruction was established in rats to induce RIF. Then, rats were grouped and treated with PTFS at different concentration. Second, HK‐2 cells underwent an epithelial‐mesenchymal transition (EMT) by the addition of transforming growth factor‐β1 (TGF‐β1). Additionally, HK‐2 cells after inducing for EMT were transfected with microRNA‐21 (miR‐21) mimic or inhibitor. These HK‐2 cells were grouped and treated with PTFS at different concentration. Finally, real‐time polymerase chain reaction and Western blot analysis were performed to detect the expression of possible signaling factor involved in RIF in renal tissues or HK‐2 cells after PTFS treatment.

Results

In vivo and in vitro experiments indicated that PTFS treatment could decrease the expression of α‐smooth muscle actin (α‐SMA; mesenchymal marker) and increase the expression of E‐cadherin (epithelial marker) in both messenger RNA and protein level. Moreover, PTFS also attenuated the expression of TGF‐β1/Smad signaling in both renal tissues and HK‐2 cells that underwent EMT. Overexpression or inhibition of miR‐21 in HK‐2 cells activated or blocked the PI3K/Akt signaling via targeting phosphatase and tension homolog (PTEN), and then promoted or suppressed the progress of TGF‐β1‐induced EMT by regulating the expression of α‐SMA and E‐cadherin. Furthermore, PTFS treatment inhibited TGF‐β1‐induced EMT progress by blocking miR‐21/PTEN/PI3K/Akt signaling.

Conclusion

PTFS has strong anti‐EMT and antifibrosis effects both in vitro and in vivo. The mechanism underlying these effects may be related to inhibition of TGF‐β1/Smad, and their downstream miR‐21/PTEN signaling, leading to blocks of EMT process during RIF.
Ablation alleviates atrial fibrillation by regulating the signaling pathways of endothelial nitric oxide synthase/nitric oxide via miR‐155‐5p and miR‐24‐3p
Authors: Wang Maojing , Sun Libo , Ding Wei , Cai Shanglang , Zhao Qing
Published: October 2018

Background

This study aimed to identify the microRNAs implicated in atrial fibrillation (AF) to investigate the molecular mechanisms underlying the role of microRNAs in ablation‐based AF treatment.

Methods

Real‐time polymerase chain reaction (PCR) and microRNA microarrays were utilized to measure the profiles of microRNA expression in AF to identify differentially expressed microRNAs. Enzyme‐linked immunosorbent assay, real‐time PCR, Western blot analysis, and immunohistochemistry assays were also performed to investigate the regulatory relationships among various factors implicated in AF. Finally, bioinformatic tools and luciferase assays were used to confirm the roles of miR‐155‐5p, miR‐24‐3p, endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) in the pathogenesis of AF.

Results

We demonstrated that the levels of miR‐155‐5p and miR‐24‐3p were greatly reduced in postablation AF patients compared with those AF patients not treated by ablation. Furthermore, the NO level in the AF+ group was much lower than that of the AF− group. Finally, in a swine model of AF, evident upregulation of miR‐155‐5p and miR‐24‐3p was found in AF pigs, whereas the ablation treatment reduced the levels of miR‐155‐5p and miR‐24‐3p in AF pigs. On contrary, as targets of miR‐155‐5p and miR‐24‐3p, the levels of eNOS and NO increased when the expression of miR‐155‐5p and miR‐24‐3p decreased.

Conclusion

MiR‐155‐5p and miR‐24‐3p are involved in the pathogenesis of AF via regulating the expression of eNOS and the production of NO. In addition, ablation treatment helps the recovery from AF by reducing the expression of miR‐155‐5p and miR‐24‐3p.
Regulation of miR‐125a expression by rs12976445 single‐nucleotide polymorphism is associated with radiotherapy‐induced pneumonitis in lung carcinoma patients
Authors: Huang Xuan , Zhang Tianze , Li Guanghua , Guo Xiaona , Liu Xuesong
Published: October 2018

Background

The expression of miR‐125 is regulated by an single‐nucleotide polymorphism (SNP), rs12976445, which may be involved in the risk of pneumonitis among non–small‐cell lung carcinoma patients undergoing the radiotherapy. We investigated this hypothesis via clinical data analysis and in vitro experiments.

Methods

An online microRNA (miRNA) database (www.mirdb.org) and luciferase reporter assays were used to confirm the role of transforming growth factor‐β1 (TGFB1) as a target gene of miR‐125a. Quantification by real‐time PCR and Western blot analysis were used to measure the expression of miRNA‐125a and TGFB1 among different groups (carrying CC, CT, and TT genotypes of rs12976445) or cells transfected with a scramble control, miR‐125a mimics, TGFB1 siRNA, or miR‐125a inhibitors.

Results

We evaluated 699 NSCLC patients and found that the patients carrying the TT or CT genotype of rs12976445 had a higher risk of radiotherapy‐induced pneumonitis. Computational analysis and luciferase assays validated that TGFB1 is a target gene of miR‐125a. The expression level of miR‐125a mRNA was significantly downregulated in the CT and TT groups, while the expression levels of TGFB1 and SMAD2 were significantly upregulated in the CC group. The expression of TGFB1 and SMAD2 was regulated by miR‐125a in A549 cells.

Conclusion

The rs12976445 SNP in miR‐125a is associated with the risk of pneumonitis after in lung cancer patients undergoing the radiotherapy by regulating the expression of miR‐125a and TGFB1.
Identification of surrogate prognostic biomarkers for allergic asthma in nasal epithelial brushing samples by WGCNA
Authors: Liu Zhaoyu , Li Ming , Fang Xiangming , Shen Lu , Yao Wenxia , Fang Zhiyuan , Chen Jitao , Feng Xiao , Hu La , Zeng Zicheng , Lin Chunyi , Weng Jinsheng , Lai Yuxiong , Yi Gao
Published: October 2018

Background

Allergic asthma is a lower respiratory tract disease of Th2 inflammation with multiple molecular mechanisms. The upper and lower airways can be unified by the concept of a united airway and, as such, gene expression studies of upper epithelial cells may provide effective surrogate biomarkers for the prognostic study of allergic asthma.

Objective

To identify surrogate biomarkers in upper airway epithelial cells for the prognostic study of allergic asthma.

Methods

Nasal epithelial cell gene expression in 40 asthmatic and 17 healthy control subjects were analyzed by weighted gene coexpression network analysis (WGCNA) to identify gene network modules and profiles in allergic asthma. Functional enrichment analysis was performed on the coexpression genes in certain highlighted modules.

Results

A total of 13 coexpression modules were constructed by WGCNA from 2804 genes in nasal epithelial brushing samples of the 40 asthmatic and 17 healthy subjects. The number of genes in these modules ranged from 1086 (Turquoise module) to 45 (Salmon). Eight coexpression modules were found to be significantly correlated (P < 0.05) with two clinic traits, namely disease status, and severity. Four modules were positively correlated (
P < 0.05) with the traits and these, therefore, contained genes that are mostly overexpressed in asthma. Contrastingly, the four other modules were found to be negatively correlated with the clinic traits. Functional enrichment analysis of the positively correlated modules showed that one (Magenta) was mainly enriched in mast cell activation and degranulation; another (Pink) was largely involved in immune cell response; the third (Yellow) was predominantly enriched in transmembrane signal pathways; and the last (Blue) was mainly enriched in substructure components of the cells. The hub genes in the modules were
KIT,
KITLG,
GATA2,
CD44,
PTPRC, and
CFTR, and these were confirmed as having significantly higher expression in the nasal epithelial cells. Combining the six hub genes enabled a relatively high capacity for discrimination between asthmatics and healthy subjects with an area under the receiver operating characteristic (ROC) curve of 0.924.

Conclusions

Our findings provide a framework of coexpression gene modules from nasal epithelial brushing samples that could be used for the prognostic study of allergic asthma.
Microporous cellulosic scaffold as a spheroid culture system modulates chemotherapeutic responses and stemness in hepatocellular carcinoma
Authors: Wu Guoyi , Zhan Shanshan , Rui Chen , Sho Eiketsu , Shi Xiaolei , Ding Yitao
Published: October 2018

Hepatocellular carcinoma (HCC) treatments are evaluated by two‐dimensional (2D) in vitro culture systems, despite their limited ability to predict drug efficacy. The three‐dimensional (3D) microporous scaffold provides the possibility of generating more reliable preclinical models to increase the efficacy of cancer treatments. The physical properties of a microporous cellulosic scaffold were evaluated. The cellulosic scaffold was biocompatible and had a highly porous network with appropriate pore size, swelling rate, and stiffness of cancer cell cultures. Cellulosic scaffolds were compared with 2D polystyrene for the culture of HepG2 and Huh7 human HCC cells. Cellulosic scaffolds promoted tumor spheroid formation. Cells cultured on scaffolds were more resistant to chemotherapy drugs and showed upregulation of EpCAM and Oct4. The migration ability of HCC cells cultured on scaffolds was significantly greater than that of cells grown in 2D cultures as evidenced by the downregulation of E‐cadherin. In addition, the proportion of CD44+/CD133+ HCC cancer stem cells (CSCs) was significantly greater in cells cultured on scaffolds than in those grown in 2D cultures. These findings suggest that cellulosic scaffolds effectively mimic the in vivo tumor behavior and may serve as a platform for the study of anticancer therapeutics and liver CSCs.
Platelet‐neutrophil interaction aggravates vascular inﬂammation and promotes the progression of atherosclerosis by activating the TLR4/NF‐κB pathway
Authors: Liang Xiao , Xiu Chunhong , Liu Minghao , Lin Chaolan , Chen Hanchen , Bao Rui , Yang Shusen , Yu Jiangbo
Published: October 2018

Platelet‐neutrophil interaction is well known for its role in inflammatory diseases; however, its biological role in atherosclerosis (AS) progression remains unclear. Human peripheral blood neutrophils were obtained to compare toll‐like receptor 4 (TLR4), tumor necrosis factor α (TNF‐α), interleukin (IL)‐1β and myeloid‐related proteins 8/14 (Mrp8/14) levels in 22 AS patients with those in 18 healthy controls using quantitative real‐time polymerase chain reaction (qRT‐PCR) and enzyme‐linked immunosorbent assay (ELISA). Meanwhile, mouse marrow neutrophils subjected to different treatment were collected for the ELISA assay, cell apoptosis, and Western blot analysis. Normal diet or high‐fat diet ApoE−/− mice with or without administration of Mrp8/14 antagonist paquinimod were used for plasma collection to measure total cholesterol, triglycerides, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol, TNF‐α, IL‐1β, Mrp8/14, TLR4, and nuclear factor (NF)‐κB p65 levels. The results showed that Mrp8/14 and TLR4‐mediated inflammatory pathway was activated in neutrophils of AS patients. In vitro experiments demonstrated that platelet‐neutrophil interaction promoted the Mrp8/14 release and inhibited neutrophil apoptosis via P‐selectin. Furthermore, platelet‐neutrophil interaction upregulated TLR4/myeloid differentiation factor 88/NF‐κB pathway. Conversely, Mrp8/14/TLR4/NF‐κB interference alleviated AS progression. In conclusion, Mrp8/14/TLR4/NF‐κB activated by platelet‐neutrophil interaction is an important inflammatory signaling pathway for AS pathogenesis.
Upregulated lncRNA small nucleolar RNA host gene 1 promotes 1‐methyl‐4‐phenylpyridinium ion‐induced cytotoxicity and reactive oxygen species production through miR‐15b‐5p/GSK3β axis in human dopaminergic SH‐SY5Y cells
Authors: Xie Na , Qi Jinxing , Li Shuang , Deng Jianzhong , Chen Yuan , Lian Yajun
Published: October 2018

Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been demonstrated to be upregulated and play a crucial role in the pathology of Parkinson's disease (PD). However, the exact role of SNHG1 and its underlying mechanisms in PD remains elusive. In this study, we found that SNHG1 and glycogen synthase kinase 3 beta (GSK3β) were upregulated, but miR‐15b‐5p was downregulated in 1‐methyl‐4‐phenylpyridinium ion (MPP+)‐treated SH‐SY5Y cells. The upregulation of SNHG1 enhanced MPP+‐induced cellular toxicity in SH‐SY5Y cells, as shown by decreased cell viability, increased ROS production, and increased number of TdT‐mediated dUTP Nick‐End labeling‐positive cells, accompanied with the upregulation of cleaved caspase 3 and elevation of cytochrome C release. Meanwhile, SNHG1 knockdown presented the converse effects. SNHG1 was demonstrated to interact with miR‐15b‐5p. Moreover, SNHG1 could attenuate the inhibitory effects of miR‐15b‐5p on MPP+‐induced cytotoxicity and production of ROS. Besides, GSK3β was identified as a direct target of miR‐15b‐5p. The inhibitory effects of SNHG1 knockdown or miR‐15b‐5p overexpression on MPP+‐induced cytotoxicity and reactive oxygen species (ROS) production were abrogated by upregulation of GSK3β. Taken together, these results demonstrate that upregulated lncRNA SNHG1 promotes MPP+‐induced cytotoxicity and ROS production through the miR‐15b‐5p/GSK3β axis in human dopaminergic SH‐SY5Y cells, suggesting that SNHG1 may act as a potential therapeutic target for PD treatment in the future.
Exploring the effect of N308D mutation on protein tyrosine phosphatase‐2 cause gain‐of‐function activity by a molecular dynamics study
Authors: Sun Ying‐Zhan , Chen Xiu‐Bo , Wang Rui‐Rui , Li Wei‐Ya , Ma Ying
Published: October 2018

One of the most common protein tyrosine phosphatase‐2 (SHP2) mutations in Noonan syndrome is the N308D mutation, and it increases the activity of the protein. However, the molecular basis of the activation of N308D mutation on SHP2 conformations is poorly understood. Here, molecular dynamic simulations were performed on SHP2 and SHP2‐N308D to explore the effect of N308D mutation on SHP2 cause gain of function activity, respectively. The principal component analysis, dynamic cross‐correlation map, secondary structure analysis, residue interaction networks, and solvent accessible surface area analysis suggested that the N308D mutation distorted the residues interactions network between the allosteric site (residue Gly244‐Gly246) and C‐SH2 domain, including the hydrogen bond formation and the binding energy. Meanwhile, the activity of catalytic site (residue Gly503‐Val505) located in the Q‐loop in mutant increased due to this region's high fluctuations. Therefore, the substrate had more chances to access to the catalytic activity site of the precision time protocol domain of SHP2‐N308D, which was easy to be exposed. In addition, we had speculated that the Lys244 located in the allosteric site was the key residue which lead to the protein conformation changes. Consequently, overall calculations presented in this study ultimately provide a useful understanding of the increased activity of SHP2 caused by the N308D mutation.
Glaucocalyxin B protects against oxygen‐glucose‐deprivation/reperfusion‐induced neuronal injury in PC‐12 cells
Authors: Liu Yuxin , Wu Xianchuang , An Jihong , Lv Weiling , Geng Yanna , Lou Tingting , Zhang Yongzhou
Published: October 2018

Oxidative stress has been implicated in the development of cerebral ischemia/reperfusion (I/R) injury. Glaucocalyxin B (GLB), one of five ent‐kauranoid diterpenoids, was reported to possess neuroprotective activity. However, the effect of GLB on oxygen‐glucose‐deprivation/reperfusion (OGD/R)‐induced cell injury in PC‐12 cells has not been explored. PC‐12 cells was treated with various concentrations of GLB (0, 2.5, 5 and 10 μM), and cell viability was detected using the MTT assay. PC‐12 cells were pretreated with the indicated concentration of GLB (2.5‐10 μM, 2 hours pretreatment), and were maintained under OGD for 3 hours, followed by 24 hours of reoxygenation. Cell viability was assessed using the MTT assay. The levels of superoxide dismutase, malondialdehyde, and glutathione peroxidase were detected using commercially available ELISA Kits. Intracellular reactive oxygen species level was measured using the fluorescent probe 2′,7′‐dichlorofluorescein diacetate. The levels of Bcl‐2, Bax, p‐Akt, Akt, p‐mTOR, mTOR were detected using Western blot. Our results revealed that GLB significantly protected PC12 cells against OGD/R‐induced cell injury. In addition, GLB efficiently inhibited oxidative stress and cell apoptosis in OGD/R‐stimulated PC‐12 cells. Mechanistic studies revealed that pretreatment with GLB could induce the activation of Akt/mTOR signaling pathway resulting in protection of OGD‐treated PC12 cells. In conclusion, our data indicate for the first time that GLB protects against OGD/R‐induced neuronal injury in PC‐12 cells. The mechanism of the protective effect of GLB is partially associated with activation of the Akt/mTOR signaling pathway. Thus, GLB may be a potential agent for protection against cerebral I/R injury.
Detection of exosomal tyrosine receptor kinase B as a potential biomarker in ovarian cancer
Authors: Li Wenqian , Lu Yunhui , Yu Xiaohui , Yong Minjie , Ma Ding , Gao Qinglei
Published: October 2018

Ovarian cancer (OC) is a lethal disease diagnosed at advanced stages due to the lack of specific biomarkers. Tyrosine receptor kinase B (TrkB), which has recently been found to be related to OC progression, represents a promising potential biomarker for OC diagnosis and prognosis. The discovery of circulating exosomes as biomarkers for various diseases led us to explore exosomal TrkB in OC. Our previous study proved that the expression of TrkB was elevated in OC tissues. In this study, we focused on the detection of exosomal TrkB in OC. Exosomes were first gathered from three different OC cell lines’ conditioned medium, serum samples of patients with OC as well as xenograft mice serum by serial centrifugation method. Then, we identified exosomes by transmission electron microscopy, NanoSight analysis, and expression of typical exosomal protein markers. The existence of TrkB in exosomes was measured by Western blot analysis, and the expression was detected by enzyme‐linked immunosorbent assay. In this study, we demonstrated that exosomes could derive from OC cell lines, serum from OC xenograft nude mice, and clinical patients. Our study shows that serum exosomal TrkB may be considered a minimally invasive biomarker for OC.
Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level
Authors: Ryu Soomin , Bazer Fuller W. , Lim Whasun , Song Gwonhwa
Published: October 2018

Chrysin is a natural compound derived from honey, propolis, or passion flowers and has many functional roles, such as antiinflammatory and antiangiogenesis effects. Although endometriosis is a benign gynecological disease, there is a need to identify the pathology and develop a therapy for endometriosis. Elucidating the biological mechanism of chrysin on endometriosis will improve the understanding of endometriosis. In this study, we confirmed the apoptotic effects of chrysin in human endometriotic cells using End1/E6E7 (endocervix‐derived endometriotic cells) and VK2/E6E7 (vaginal mucosa‐derived epithelial endometriotic cells). The results showed that chrysin suppressed the proliferation of endometriosis and induced programmed cell death through changing the cell cycle proportion and increasing the cytosolic calcium level and generation of reactive oxygen species. In addition, chrysin activated endoplasmic reticulum (ER) stress by stimulating the unfolded protein response proteins, especially the 78‐kDa glucose‐regulated protein–PRKR‐like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) pathway in both endometriotic cell lines. Furthermore, chrysin inactivated the intracellular phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway in a dose‐dependent manner. Collectively, the results of this study indicated that chrysin induced programmed cell death by activating the ER stress response and inactivating the PI3K signaling pathways in human endometriotic cells.
Mesenteric ischemia as an unusual cause of Streptococcus bovis bacteremia in the absence of endocarditis or colorectal neoplasm
Authors: Tse Chung Sang , Nguyen Hang Phuong
Published: October 2018

Streptococcus bovis bacteremia is nearly always pathological and has been associated with colorectal cancer and endocarditis. Here, we present the first published case of S. bovis bacteremia secondary to acute mesenteric ischemia. This case illustrates the typical presentation of acute mesenteric ischemia with an atypical consequence of S. bovis bacteremia, as well as the diagnostic evaluations and management options.
3‐Amino‐5‐cyanomethylpyrazole‐4‐carbonitrile: Versatile Reagent for Novel Bis(pyrazolo[1,5‐a]pyridine) Derivatives via a Multicomponent Reaction
Authors: Abdelmoniem Amr M. , Ghozlan Said A. S. , Abdelmoniem Doaa M. , Elwahy Ahmed H. M. , Abdelhamid Ismail A.
Published: October 2018

An efficient synthesis of novel bis(pyrazolo[1,5‐a]pyridine) derivatives through Michael addition reaction of 3‐amino‐5‐cyanomethylpyrazole‐4‐carbonitrile with bis‐arylidenemalononitrile is reported. All new compounds are characterized by different spectral tools.
Sensory restoration of breast reconstruction – The search for the ideal approach continues
Authors: Zhou Anna , Ducic Ivica , Momeni Arash
Published: October 2018

Contemporary reconstructive modalities focus on breast anatomy and attempt to reconstruct breasts that are soft, of adequate shape, size, and symmetry. However, a functional component, i.e. sensation, has largely been ignored. Flap neurotization addresses this shortcoming. While we are still in search of the ideal surgical technique to achieve this goal, a novel approach that limits nerve harvest to the sensory branch only, thus, minimizing abdominal donor‐site morbidity, is presented.
Application of coordination agent in high‐speed counter‐current chromatography for the preparative separation and isolation ginkgolic acids from the sarcotesta of Ginkgo biloba L
Authors: Zhu Heng , Jiang Hailong , Yu Jinqian , Song Xiangyun , Zhao Hengqiang , Li Jingchao , Geng Yanling , Wang Daijie
Published: October 2018

An efficient coordination high‐speed counter‐current chromatography method for the preparative separation of ginkgolic acids from the sarcotesta of Ginkgo biloba L was developed. The type, concentration, and mechanism of the coordination agent were investigated. Following the use of four types of metal salts including silver nitrate, copper chloride, ferric chloride, and aluminium nitrate, n‐heptane/ethyl acetate/methanol/acetic acid 5:4:1:1, v/v with 0.20 mol/L silver nitrate as the coordination agent was chosen as the optimum two‐phase solvent system. Five main ginkgolic acids including C13:0, C15:0, C15:1, C17:1, and C17:2 were successfully separated with purities greater than 98%. The sample loading was 500 mg, the flow‐rate was 2.0 mL/min, rotation speed was 800 rpm and temperature was 20°C. The structures of the separated ginkgolic acids were identified by comparison with standard samples and electrospray ionization mass spectrometry. The introduction of coordination chemistry in high‐speed counter‐current chromatography is novel and effective for the preparative separation and isolation of ginkgolic acids from the sarcotesta of Ginkgo biloba L and could also be applied to separate compounds which form coordination bonds in other complex natural products.
Grazing exclusion—An effective approach for naturally restoring degraded grasslands in Northern China
Authors: Wang Li , Gan Yantai , Wiesmeier Martin , Zhao Guiqin , Zhang Ruiyang , Han Guodong , Siddique Kadambot H.M. , Hou Fujiang
Published: October 2018

Nearly 90% of the 390 million ha of grasslands in northern China are degraded. ‘Grazing exclusion’ has been implemented as a nature‐based solution to rejuvenate degraded grasslands, but the effectiveness of the rejuvenation processes is uncertain. Here, we investigated the effects of grazing exclusion on aboveground plant community traits, soil physiochemical and biological properties, and the mechanisms responsible for enhanced grassland rejuvenation. A meta‐analysis across various studies was used to assess the effectiveness. On average, grazing exclusion improved vegetation coverage by 18.5 percentage points and increased aboveground biomass by 1.13 t ha−1 and root biomass by 1.27 t ha−1, which represent an increase of 84%, 246%, and 31%, respectively, compared with continuous grazing practices. Grazing exclusion reduced soil bulk density by 13.7% and increased soil water content by 68.9%. Grasslands under grazing exclusion increased soil organic carbon (SOC) in the 0‐ to 15‐cm depth by 3.95 (±0.35 Std err) t ha−1 and total soil N, available N, and total soil P in the 0‐ to 40‐cm depth by 2.39 (±0.14), 0.83 (±0.37), and 1.96 (±0.44) t ha−1, respectively, compared with continuous grazing; these values represent an increase of 31%, 25%, 23%, and 14%, respectively. Prolonging the duration (years) of grazing practices enlarged the differences in SOC and soil N content between grazing exclusion and continuous grazing. Grazing exclusion has improved plant community traits and enhanced soil physiochemical and biological properties of degraded grasslands, and thus, this ‘nature‐based’ approach can serve as an effective means to rejuvenate degraded grasslands.
Exploring biogeographic patterns of bacterioplankton communities across global estuaries
Authors: Ghosh Anwesha , Bhadury Punyasloke
Published: October 2018

Estuaries provide an ideal niche to study structure and function of bacterioplankton communities owing to the presence of a multitude of environmental stressors. Bacterioplankton community structures from nine global estuaries were compared to understand their broad‐scale biogeographic patterns. Bacterioplankton community structure from four estuaries of Sundarbans, namely Mooriganga, Thakuran, Matla, and Harinbhanga, was elucidated using Illumina sequencing. Bacterioplankton communities from these estuaries were compared against available bacterioplankton sequence data from Columbia, Delaware, Jiulong, Pearl, and Hangzhou estuaries. All nine estuaries were dominated by Proteobacteria. Other abundant phyla included Bacteroidetes, Firmicutes, Acidobacteria, Actinobacteria, Cyanobacteria, Planctomycetes, and Verrucomicrobia. The abundant bacterial phyla showed a ubiquitous presence across the estuaries. At class level, the overwhelming abundance of Gammaproteobacteria in the estuaries of Sundarbans and Columbia estuary clearly stood out amidst high abundance of Alphaproteobacteria observed in the other estuaries. Abundant bacterial families including Rhodobacteriaceae, Shingomonadaceae, Acidobacteriaceae, Vibrionaceae, and Xanthomondaceae also showed ubiquitous presence in the studied estuaries. However, rare taxa including Chloroflexi, Tenericutes, Nitrospirae, and Deinococcus‐Thermus showed clear site‐specific distribution patterns. Such distribution patterns were also reinstated by nMDS ordination plots. Such clustering patterns could hint toward the potential role of environmental parameters and substrate specificity which could result in distinct bacterioplankton communities at specific sites. The ubiquitous presence of abundant bacterioplankton groups along with their strong correlation with surface water temperature and dissolved nutrient concentrations indicates the role of such environmental parameters in shaping bacterioplankton community structure in estuaries. Overall, studies on biogeographic patters of bacterioplankton communities can provide interesting insights into ecosystem functioning and health of global estuaries.
Harnessing the gatekeepers of glucocorticoids for chemoprevention of non‐melanoma skin cancer
Authors: Mancha‐Ramirez Anna M. , Yang Xiaoyu , Liang Huiyun , Junco Jacob , Lee Kevin P. , Bovio Sarah F. , Espinoza Maricruz , Wool Julia , Slaga Andrew , Glade Daniel C. , Hanes Martha , Malik Gunjan , Kim Dae Joon , DiGiovanni John , Slaga Thomas J.
Published: October 2018

Despite effective surgical methods for non‐melanoma skin cancer (NMSC), patients suffer from tissue damage, scarring, or even disfigurement; thus, there is a need for chemopreventive approaches. Because of the complex interplay between glucocorticoids (GCs), inflammation, and cancer, we sought to determine the role of 11β‐hydroxysteroid dehydrogenase 1 and 2 (11βHSD1 and 2) in regulating GCs during skin cancer development and progression. 11βHSDs modulate the activation of GCs in a tissue‐specific manner and have been reported to play a role in development and progression of other types of cancer, but their role has not yet been reported in NMSC. Here, we found a significant upregulation of 11βHSD2 protein in skin cancer cells when compared to normal skin cells, suggesting a role for this enzyme in the multifactorial process of skin cancer development. In addition, inhibition of 11βHSD2 with siRNA resulted in significant reduction in colony formation in vitro. Finally, our in vivo study elucidated that inhibition of 11βHSD2 with pharmacological inhibitor, Glycyrrhetinic acid (GA) could significantly diminish tumorigenesis in a well‐studied in vivo mouse model of NMSC. Overall, these studies highlight for the first time a potential novel role for 11βHSD2 in NMSC development and may allow for new GC treatment approaches capable of avoiding deactivation by the enzyme. If 11βHSD2 can be inhibited as we have done here, or circumvented using modified GCs, this may lead to more efficacious outcomes for NMSC patients by preventing deactivation of the GC and minimizing resistance.
Catch Efficiency of Groundgears in a Bottom Trawl Fishery: A Case Study of the Barents Sea Haddock
Authors: Larsen Roger B. , Herrmann Bent , Brinkhof Jesse , Grimaldo Eduardo , Sistiaga Manu , Tatone Ivan
Published: October 2018

The catch efficiency of two types of groundgear—a conventional rockhopper and a new type of groundgear called the semicircular spreading gear (SCSG)—was investigated through experimental fishing for Haddock Melanogrammus aeglefinus conducted in the Barents Sea. A retainer bag was attached behind the footrope of the trawl, and the number of fish that were overrun by the trawl was compared with the catch in the trawl cod end. The catch efficiency increased slightly for larger Haddock for both groundgears. The SCSG was found to have a significantly higher catch efficiency than the conventional rockhopper groundgear. The estimated improvement in catch efficiency varied between 4.5% and 12.3%, with an equivalent reduction in escape rate underneath the groundgear of more than 70%. The rockhopper groundgear can have a catch efficiency as low as 76%, corresponding with values reported in previous studies. Average catch efficiency for the rockhopper gear was significantly lower during the night in comparison with the daytime. No such difference was found with the SCSG. The SCSG is more efficient for catching Haddock, and it is lighter than the rockhopper groundgear. Both are important factors in reducing seabed impact and fuel consumption. When compared to results of a similar study on Atlantic Cod Gadus morhua, we found that in general, both groundgears had a greater catch efficiency for Haddock, which accords with differences in behavior between the two species.
Pharmacokinetics of the Meropenem Component of Meropenem‐Vaborbactam in the Treatment of KPC‐Producing Klebsiella pneumoniae Bloodstream Infection in a Pediatric Patient
Authors: Hanretty Alexandra M. , Kaur Ishminder , Evangelista Alan T. , Moore Wayne S. , Enache Adela , Chopra Arun , Cies Jeffrey J.
Published: October 2018

Meropenem‐vaborbactam is a new β‐lactam/β‐lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)‐producing Enterobacteriaceae. Meropenem‐vaborbactam was United States Food and Drug Administration–approved for complicated urinary tract infections in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem‐vaborbactam. In addition, the safety and efficacy of meropenem‐vaborbactam in a pediatric patient have yet to be described in the literature. The authors conducted a retrospective single‐patient chart review for a 4‐year‐old male patient with short bowel syndrome, colostomy and gastrojejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition and hydration management, complicated with multiple central line–associated bloodstream infections (BSIs). The patient was brought to our medical center with fever concerning for a BSI. On day 2, the patient was started on meropenem‐vaborbactam at a dosage of 40 mg/kg every 6 hours infused over 3 hours for KPC‐producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem‐vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 μg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem‐vaborbactam was continued for a total of 14 days. A meropenem‐vaborbactam regimen of 40 mg/kg every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient.
Clinical Utility of Methicillin‐Resistant Staphylococcus aureus Nasal Screening for Antimicrobial Stewardship: A Review of Current Literature
Authors: Carr Amy L. , Daley Mitchell J. , Givens Merkel Kathryn , Rose Dusten T.
Published: October 2018

Significant clinical and financial consequences are associated with both inadequate and unnecessary exposure to broad‐spectrum antibiotics. As such, antimicrobial stewardship programs seek objective, reliable, and cost‐effective tests to identify patients at highest or lowest risk for drug‐resistant organisms to guide empirical antimicrobial selection. Use of methicillin‐resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA in lower respiratory tract infections has led to significant reductions in duration of vancomycin therapy. The clinical utility of MRSA nasal screening in other types of infection remains less clear. This review describes the performance of MRSA nasal screening in predicting MRSA infection, highlights practical considerations for use of MRSA nasal screening, and provides guidance for incorporating MRSA nasal screening into clinical practice. With a high negative predictive value when the prevalence of MRSA is low, MRSA nasal screening is a valuable antimicrobial stewardship tool with potential applications beyond lower respiratory tract infections. In appropriately selected patients, negative MRSA nasal screening can prevent initiation or guide discontinuation of anti‐MRSA therapy. Antimicrobial stewardship programs should develop institutional guidelines to promote proper use of MRSA nasal screening. Pharmacists are well positioned to assist with education, interpretation, and application of MRSA nasal screening results.