bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of the inflammatory species hypochlorous acid on the corrosion and surface damage of Ti‐6Al‐4V and CoCrMo alloys
Authors: Kubacki Gregory W. , Gilbert Jeremy L.
Published: August 2018

Performance of metallic orthopedic alloys is dependent on the local biological conditions within the joint. Inflammation within a joint can lead to severe conditions at the surface of the implant and may represent a driving force of corrosion which is not well understood. In this study, the corrosion response of CoCrMo and Ti‐6Al‐4V alloys was studied in hypochlorous acid (HOCl) saline solutions, which served as a simulated inflammatory environment. Anodic polarization and electrochemical impedance spectroscopy were used to evaluate the electrochemical behavior of these alloys in a range of hypochlorous acid solutions. The open circuit potential of CoCrMo rose to over 600 mV (vs. Ag/AgCl) in 30 mM HOCl solutions while the corresponding corrosion current increased three orders of magnitude over controls. Visual analysis of CoCrMo disks after immersion in 50 mM HOCl for 5 days revealed extensive surface damage. This study shows that HOCl can polarize CoCrMo surfaces above the transpassive potential without an external power source. Ultimately, long‐term exposure to HOCl within an inflamed joint may significantly affect patient outcomes through accelerated generation of corrosion products. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3185–3194, 2018.
Knockdown of A‐kinase anchor protein 4 inhibits hypoxia‐induced epithelial‐to‐mesenchymal transition via suppression of the Wnt/β‐catenin pathway in human gastric cancer cells
Authors: Li Quanying , Tang Hongna , Hu Fangfang , Qin Changjiang
Published: August 2018

Hypoxia induces epithelial‐mesenchymal transition (EMT) in tumorigenesis. A‐kinase anchor protein 4 (AKAP4) is a member of AKAPs family and plays a critical role in tumorigenesis. However, the biological role of AKAP4 in gastric cancer remains unknown. Thus, we investigated the effect of AKAP4 on EMT in human gastric cancer cells under hypoxic conditions. Our results showed that AKAP4 expression was significantly upregulated in human gastric cancer cell lines. In addition, silenced expression of hypoxia‐inducible factor‐1α markedly suppressed AKAP4 expression in gastric cancer cells under hypoxia. Furthermore, knockdown of AKAP4 significantly prevented hypoxia‐induced migration, invasion, and EMT process in gastric cancer cells. Mechanistically, knockdown of AKAP4 prevented the activation of the Wnt/β‐catenin pathway in gastric cancer cells under hypoxia condition. These findings indicate that knockdown of AKAP4 inhibits hypoxia‐induced EMT in human gastric cancer cells, at least in part, via inactivation of the Wnt/β‐catenin signaling pathway. It is, therefore, AKAP4 may be a potential therapeutic target for the treatment of gastric cancer.
Curcumin‐mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p21Cip1 in vitro
Authors: Chatterjee Biji , Ghosh Krishna , Kanade Santosh R.
Published: August 2018

Curcumin, the active component of the spice turmeric, induce global DNA hypomethylation as it has been shown to inhibit DNA methyltransferases. It promotes cell death in cancer cells by arresting in the G1 phase. It was explained to cause increased expression of cell cycle regulator, p21 (WAF1/Cip1); however, the mechanism remains not clear. The p21 promoter harvests a CpG island (CGI) in the proximal region enriched with CG dinucleotide clusters with Kruppel‐like factor 4 (KLF4) transcription factor binding site. We probed the p21 promoter CGI (spanning from −135 to +12, respective to the transcription start site) to detect alterations in cytosine methylation level in response to curcumin exposure in four different human cancer cell lines: A431, A549, MCF7, and HeLa. We observed curcumin (20 µM) treatment significantly increased the expression of p21, and the promoter CGI was demethylated in a dose‐dependent manner. The curcumin significantly raised the level KLF4 and enhanced the p21 promoter occupancy by KLF4. From our results we hypothesize that curcumin‐mediated demethylation of the p21 proximal promoter and increased KLF4 expression as well as its binding to its proximal promoter could serve as a mechanism that could be hypothesized to cause upregulation of p21 in presence of curcumin and thus its therapeutic implications could further be investigated.
Effects of mycoplasma infection on the host organism response via p53/NF‐κB signaling
Authors: Borchsenius Sergey N. , Daks Alexandra , Fedorova Olga , Chernova Olga , Barlev Nickolai A.
Published: August 2018

Mycoplasmas are bacteria lacking the cell wall, which is the major characteristic of this taxonomic class (Mollicutes). Among bacteria, mycoplasmas possess the smallest genome known for free‐living organisms. This feature limits the autonomy of bacteria and makes them increasingly susceptible to changes in the host organism. Many mycoplasmas themselves cause pathological changes in the host organism, often complicated by immune disorders. Infection with certain strains of mycoplasma results in the activation of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells, which is the major mediator of the inflammatory response. Furthermore, mycoplasmas can inhibit p53‐mediated checkpoint control of cell cycle and apoptosis. Collectively, these properties indicate that mycoplasmas might act as cancer‐promoting factors. In this review, we summarize the information known to date on the role of mycoplasmas in the regulation of the host immune response and their functional interactions with p53.
Retracted: Long non‐coding RNA LINC00152 promotes cell growth and invasion of papillary thyroid carcinoma by regulating the miR‐497/BDNF axis
Authors: Sun Zhihui , Guo Xun , Zang Mingcui , Wang Peisong , Xue Shuai , Chen Guang
Published: August 2018

Long intergenic non‐coding RNA 152 (LINC00152) was reported to be tightly linked to tumorigenesis and progression in multiple cancers. However, its biological role and modulatory mechanism in papillary thyroid carcinoma (PTC) has not been elucidated. In this study, we determined the expression levels of LINC00152 in PTC tissues and cell lines by quantitative real time polymerase chain reaction (qRT‐PCR). Cell proliferation, colony formation, migration, and invasion were measured by a Cell Counting Kit‐8 assay, colony formation analysis, wound healing, and transwell invasion assay, respectively. A luciferase reporter assay and qRT‐PCR were used to determine whether LINC00152 interacts with miR‐497 directly. We established a xenograft mouse model to examine the underlying molecular mechanism and effect of LINC00152 on tumor growth in vivo. We found that LINC00152 expression was significantly increased in PTC tissues and derived cell lines. LINC00152 knockdown significantly inhibited proliferation, colony formation, migration, and invasion in vitro, and impaired tumor growth in vivo. We revealed that LINC00152 functioned as a competing endogenous RNA to the miR‐497 sponge, downregulating its downstream target brain‐derived neurotrophic factor (BDNF), which is an oncogene in thyroid cancer. These findings suggest that LINC00152 is responsible for PTC cell proliferation and invasion and exerts its function by regulating the miR‐497/BDNF axis.
Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP
Authors: Gao Jian , Rong Yingxue , Huang Yuxing , Shi Peng , Wang Xitao , Meng Xuan , Dong Jiahong , Wu Congying
Published: August 2018

A majority of hepatocellular carcinomas (HCCs) combine with liver cirrhosis. The cirrhotic liver has been implicated in interfering with the effects of HCC‐targeted drugs, including sorafenib. Alterations in the tumor microenvironment of the cirrhotic liver include both biochemical and biomechanical factors. In this study, we induced sorafenib resistance in HCC cells. We observed changes in cell morphology, cytoskeletal architecture, and cellular stiffness in these sorafenib‐resistant cells, resembling those adapted to stiffer substrates. To examine the contribution of mechanical factors in HCC cell growth and drug resistance, we used an in vitro cell culture system with adjustable stiffness mimicking the normal or cirrhotic liver tissues. We identified that mechanical adaptation conferred HCC cells with increased motility and sorafenib resistance. We further reported the mechanism underlying the involvement of the transcription coactivator YAP. Our results underline the important role of mechanical factors in the interaction between tumor cells and their microenvironment.
Melatonin, a calpain inhibitor in the central nervous system: Current status and future perspectives
Authors: Tamtaji Omid Reza , Mirhosseini Naghmeh , Reiter Russel J. , Azami Abolfazl , Asemi Zatollah
Published: August 2018

Dysregulation of neuronal Ca2+ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free‐radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.
Activation of type 4 metabotropic glutamate receptor promotes cell apoptosis and inhibits proliferation in bladder cancer
Authors: Zhang Zhichao , Liu Yingfei , Wang Ke , Zhu Kun , Zheng Xiaoyan , Wang Li , Luan Yan , Wang Xinyang , Lu Haixia , Wu Kaijie , Chen Xinlin , He Dalin , Liu Yong
Published: August 2018

Bladder cancer, the second most common genitourinary malignancy, severely endangers the human health. Rising evidence suggests that metabotropic glutamate receptors (mGluRs) are involve in tumor progression. In this study, we observed that metabotropic glutamate receptor 4 (mGluR4) was functionally expressed in normal and cancerous bladder cells and its expression was positively correlated with high bladder cancer grading. We further confirmed that the activation of mGluR4 by VU0155041, an mGluR4‐specific agonist, decreased cyclic adenosine monophosphate (cAMP) concentration and cell viability, promoted apoptosis and inhibited proliferation in bladder cancer cells, whereas MSOP (group III mGluR antagonist) or mGluR4 knockdown eliminated the effects of mGluR4 activity. Western blotting revealed the decreased cyclin D1 expression, increased procaspase‐8/9/3 cleavage, and unbalanced Bcl‐2/Bax expression in bladder cancer cell lines after mGluR4 activation, and likewise MSOP and mGluR4 knockdown abrogated the actions of mGluR4 activity. In vivo study showed that mGluR4 activation significantly inhibited tumor growth of bladder cancer via suppressing proliferation and promoting apoptosis. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) and inhibition of Akt phosphorylation were also observed after mGluR4 activation. Similar with VU0155041, the Akt‐specific inhibitor markedly promoted apoptosis and inhibited proliferation. Nevertheless, the PTEN‐specific inhibitor significantly abolished the mGluR4 activation‐induced cell apoptosis and proliferative inhibition in bladder cancer cell lines. These results indicate that mGluR4 can regulate the switch between survival and death via the cAMP/PTEN/AKT signaling pathway in bladder cancer cells. Our findings suggest that mGluR4 has diagnostic and prognostic potential for bladder cancer, and the development of mGluR4 agonist may be a promising strategy for bladder cancer treatment.
Efficacy of different antidiabetic drugs based on metformin in the treatment of type 2 diabetes mellitus: A network meta‐analysis involving eight eligible randomized‐controlled trials
Authors: Peng Yan , Chen Shu‐Hong , Liu Xiao‐Nan , Sun Qing‐Yun
Published: August 2018

Diabetes mellitus is one of the most prevalent metabolic diseases globally and it is increasing in prevalence. It is one of the most expensive diseases with respect to total health care costs per patient as a result of its chronic nature and its severe complications. To provide a more effective treatment of type 2 diabetes mellitus (T2DM), this study aims to compare different efficacies of six kinds of hypoglycemic drugs based on metformin, including glimepiride, pioglitazone, exenatide, glibenclamide, rosiglitazone, and vildagliptin, in T2DM by a network meta‐analysis that were verified by randomized‐controlled trials (RCTs). Eight eligible RCT in consistency with the aforementioned six hypoglycemic drugs for T2DM were included. The results of network meta‐analysis demonstrated that the exenatide + metformin and vildagliptin + metformin regimens presented with better efficacy. Patients with T2DM with unsatisfactory blood glucose control based on diet control, proper exercise, and metformin treatment were included. The original regimen and dose of medication were unchanged, followed by the addition of glimepiride, pioglitazone, exenatide, glibenclamide, rosiglitazone, and vildagliptin. The results of RCTs showed that all these six kinds of drugs reduced the HbA1c level. Compared with other regimens, exenatide + metformin reduced fasting plasma glucose (FPG), fasting plasma insulin (FPI), total cholesterol (TC), and homeostasis model assessment insulin resistance index (HOMA‐IR) levels, but increased the high‐density lipoprotein (HDL) level; vildagliptin + metformin decreased FPI and low‐density lipoprotein (LDL) levels; glibenclamide + metformin decreased the FPG level, but promoted HDL; and glimepiride + metformin decreased the TC level and rosiglitazone + metformin reduced the LDL level. Our findings indicated that exenatide + metformin and vildagliptin + metformin have better efficacy in T2DM since they can improve insulin sensitivity.
MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2
Authors: Jia Yijie , Zheng Zongji , Yang Yanlin , Zou Meina , Li Jimin , Wang Ling , Guan Meiping , Xue Yaoming
Published: August 2018

Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial‐to‐mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR‐4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR‐4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR‐4756 levels in HK‐2 cells. In addition, an miR‐4756 mimic accelerated albumin‐stimulated HK‐2 cell EMT and ER stress, and an miR‐4756 inhibitor suppressed these events. We then found that miR‐4756 targeted the 3′‐untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR‐4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR‐4756 increased ERK1/2 activation and decreased 5′ monophosphate‐activated protein kinase activation. Thus, our study provides evidence that miR‐4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR‐4756 may be a novel strategy for DKD treatment.
In vitro evaluation of effects of metformin on morphine and methadone tolerance through mammalian target of rapamycin signaling pathway
Authors: Shirooie Samira , Sahebgharani Mousa , Esmaeili Jamileh , Dehpour Ahmad Reza
Published: August 2018

The chronic use of opioids leads to tolerance, psychological, and physical dependence that limits their use as an effective long‐term pain control. Several studies have shown that mammalian target of rapamycin (mTOR) plays a crucial role in the development of opioid tolerance. Metformin activates 5′ adenosine monophosphate‐activated protein kinase (AMPK) which directly suppresses the mTOR complex 1 signaling pathway. On the other hand, metformin can also inhibit mTOR directly and in an AMPK‐independent manner. Thus, in the current study, we aimed to investigate the effects of metformin on the development of morphine and/or methadone‐induced tolerance in human glioblastoma (T98G) cell line. We examined the effects of chronic treatment of morphine and/or methadone in the presence or absence of metformin with or without AMPK inhibitor (dorsomorphin hydrochloride) on levels of nitric oxide and cyclic adenosine monophosphate (cAMP), phosphorylated and dephosphorylated ribosomal protein S6 kinase β‐1 (S6K1) and 4E‐binding protein 1 (4E‐BP1) in T98G cells. Pretreatment of cells with metformin (40 µM) with or without AMPK inhibitor (dorsomorphin hydrochloride; 1 µM) before adding of morphine (2.5 µM) or methadone (1 µM) revealed a protective effects on the development of opioid tolerance. Prior administration of metformin reversed the elevation of nitric oxide levels induced by morphine (p < 0.001) and methadone (p < 0.001) and also prevented the raise of cAMP levels induced by morphine in T98G cells (p < 0.05). Contribution of mTOR signaling pathway in metformin‐induced effect was shown by the inhibition of phosphorylation of S6K1 and 4E‐BP1, the downstream targets of mTOR. mTOR activation suppresses opioid‐induced antinociception, and its activity has also been increased during opioid tolerance.
Circular RNA circ‐VANGL1 as a competing endogenous RNA contributes to bladder cancer progression by regulating miR‐605‐3p/VANGL1 pathway
Authors: Zeng Zhihua , Zhou Wanming , Duan Lingxing , Zhang Jian , Lu Xiongbing , Jin Liang , Yu Yi
Published: August 2018

Increasing reports indicate that circular RNAs (circRNAs) are very important regulators in human diseases, including cancers. In bladder cancer (BC), several circRNAs have been reported to be involved in tumor progressions, such as circ‐ITCH and circTCF25. However, the functions of most circRNAs in BC still remains largely unknown. In this study, we identified a novel circRNA termed as circ‐VANGL1 by bioinformatics analysis. We found that circ‐VANGL1 was highly expressed in BC tissues compared with adjacent normal tissues. Furthermore, we showed that circ‐VANGL1 could serve as a prognostic marker for patients with BC. Through functional experiments, we found that circ‐VANGL1 knockdown significantly suppressed BC cell proliferation, cell cycle, migration, and invasion in vitro. Besides, circ‐VANGL1 silence inhibited BC cell propagation in vivo. Mechanistically, we identified circ‐VANGL1 as a sponge of miR‐605‐3p which targeted VANGL1 in BC cells. Through repressing miR‐605‐3p availability, circ‐VANGL1 contributes to VANGL1 expression, consequently leading to BC cell proliferation, migration, and invasion. Taken together, our study demonstrated circ‐VANGL1/miR‐605‐3p/VANGL1 as a novel essential signaling pathway involved in BC progression.
A review of the molecular mechanisms of hyperglycemia‐induced free radical generation leading to oxidative stress
Authors: Yaribeygi Habib , Atkin Stephen L. , Sahebkar Amirhossein
Published: August 2018

The prevalence of diabetes is growing worldwide with an increasing morbidity and mortality associated with the development of diabetes complications. Free radical production is a normal biological process that is strictly controlled and has been shown to be important in normal cellular homeostasis, and in the bodies response to pathogens. However, there are several mechanisms leading to excessive free radical production that overcome the normal protective quenching mechanisms. Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described.
Glabridin inhibits osteosarcoma migration and invasion via blocking the p38‐ and JNK‐mediated CREB–AP1 complexes formation
Authors: Jie Zhiwei , Xie Ziang , Zhao Xiangde , Sun Xuewu , Yu Hejun , Pan Xin , Shen Shuying , Qin An , Fang Xiangqian , Fan Shunwu
Published: August 2018

Osteosarcoma is the most common bone malignancy, and it seriously affects the quality of life of affected children and adolescents. Glabridin (GLA), a major component of licorice root extract, has been reported to exert antitumor effects against a variety of tumor types; however, its effects on osteosarcoma have not been elucidated. In the current study, we investigate the effects and potential antimetastatic mechanisms of GLA on osteosarcoma in vitro and in vivo. Flow cytometry showed that GLA induced G2/M cell cycle phase arrest and promoted cell apoptosis. Transwell and wound‐healing assays showed that GLA significantly decreased the migration and invasion of osteosarcoma cells. Further western blotting and quantitative real‐time polymerase chain reaction showed that the expression of matrix metalloproteinase (MMP)‐2 and MMP‐9 in MG63 and HOS cells were reduced after GLA treatment. Moreover, western blotting demonstrated that GLA downregulated the phosphorylation of p38 mitogen‐activated protein kinases and c‐Jun N‐terminal kinase. A coimmunoprecipitation assay illustrated that formation of cAMP response element‐binding protein (CREB)–activating protein 1 (AP1) complexes and the DNA binding activities of CREB and AP1 in MG63 and HOS cells were impaired following treatment with GLA. Finally, GLA inhibited tumor growth and suppressed osteosarcoma cell metastasis in vivo. Overall, our findings highlight the potential of GLA as a therapeutic agent for the prevention and treatment of tumor metastasis.
Reduced cardiomyocyte Na+ current in the age‐dependent murine Pgc‐1β−/− model of ventricular arrhythmia
Authors: Ahmad Shiraz , Valli Haseeb , Smyth Robert , Jiang Anita Y. , Jeevaratnam Kamalan , Matthews Hugh R. , Huang Christopher L.‐H.
Published: August 2018

Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β−/−) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch‐clamp techniques in intact young and aged, wild‐type (WT) and Pgc‐1β−/−, ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage‐dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two‐way analysis of variance associated Pgc‐1β−/− genotype with independent reductions in maximum peak ventricular Na+ currents from −36.63 ± 2.14 (n = 20) and −35.43 ± 1.96 (n = 18; young and aged WT, respectively), to −29.06 ± 1.65 (n = 23) and −27.93 ± 1.63 (n = 20; young and aged Pgc‐1β−/−, respectively) pA/μm2 (p < 0.0001), without independent effects of, or interactions with age. Voltages at half‐maximal current V*, and steepness factors k in plots of voltage dependences of both Na+ current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K+) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current–voltage properties directly implicate decreases specifically in maximum available Na+ current with unchanged voltage dependences and unaltered K+ current properties, in proarrhythmic reductions in AP conduction velocity in Pgc‐1β−/− ventricles.
A systemic insight into astrocytoma biology across different grades
Authors: Chakraborty Sohini , Ghosh Zhumur
Published: August 2018

Astrocytomas are the most common type of brain tumors, which originate from glial cells, and are classified into specific grades based on their histopathological behavior. To develop precise therapeutic strategies for the disease, it is important to identify the molecular signatures specific to each grade as well as the key factors responsible for the transition from one grade to the next. In this study, we have taken a systems approach to investigate the gene expression profiles of each grades of the disease by mapping shortest paths of gene interaction in each grade and also between one grade and the next. Module core genes govern the topology of these networks and serve as important functional players in each grade as well as help in grade transition events. Shortlisted among these module core genes are well‐characterized players of glioma as well as novel molecules (32 grade‐specific genes and 15 grade transition–specific genes), which influence important prooncogenic functions but have not been linked to glioma biology yet. These module core genes provide interesting insight into the biology of astrocytic tumors and are potential therapeutic targets for astrocytoma.
Asiaticoside, a component of Centella asiatica attenuates RANKL‐induced osteoclastogenesis via NFATc1 and NF‐κB signaling pathways
Authors: He Lilei , Hong Guoju , Zhou Lin , Zhang Jianguo , Fang Jian , He Wei , Tickner Jennifer , Han Xiaorui , Zhao Lilian , Xu Jiake
Published: August 2018

Identification of natural compounds that inhibit osteoclastogenesis will facilitate the development of antiresorptive treatment of osteolytic bone diseases. Asiaticoside is a triterpenoid derivative isolated from Centella asiatica, which exhibits varying biological effects like angiogenesis, anti‐inflammation, wound healing, and osteogenic differentiation. However, its role in osteoclastogenesis remains unknown. Here, we show that Asiaticoside can suppress RANKL‐induced osteoclast formation and bone resorption in a dose‐dependent manner. Asiaticoside attenuated the expression of osteoclast marker genes including Ctsk, Atp6v0d2, Nfatc1, Acp5, and Dc‐stamp. Furthermore, Asiaticoside inhibited RANKL‐mediated NF‐κB and NFATc1 activities, and RANKL‐induced calcium oscillation. Collectively, this study demonstrates that Asiaticoside inhibited osteoclast formation and function through attenuating RANKL‐induced key signaling pathways, which may indicate that Asiaticoside is a potential antiresorptive agent against osteoclast‐related osteolytic bone diseases.
Noncoding RNAs in acute kidney injury
Authors: Ren Gui‐Ling , Zhu Jie , Li Jun , Meng Xiao‐Ming
Published: August 2018

Acute kidney injury (AKI), caused by various stimuli including ischemia reperfusion, nephrotoxic insult, and sepsis, is characterized by abrupt decline of kidney function. Till now, the molecular mechanisms for AKI have not been fully explored and the effective therapies are still lacking. Noncoding RNAs (ncRNAs), a group of biomolecules function at RNA level, are involved in a wide range of physiopathological processes including AKI. MicroRNAs (miRNAs) are the most extensively studied ncRNAs in AKI. Evidence indicated that miRNAs are altered significantly in various types of AKI. Gain‐and‐loss‐of‐function studies demonstrated that miRNAs, such as miR‐24, miR‐126, miR‐494, and miR‐687, may bind to the 3′‐untranslated region of their target genes to regulate inflammation, programmed cell death, and cell cycle in the injury and repair stages of AKI, indicating their therapeutic potential in AKI. In contrast, functions of long noncoding RNAs and circular RNAs in AKI are hot topics but still largely unknown. Additionally, ncRNAs packaged in exosome can be detected in circulation and urine, they may serve as specific biomarkers for AKI. This review summarized the alteration and functional role of ncRNAs and their therapeutic potential in AKI.
Antrodia camphorata inhibits epithelial‐to‐mesenchymal transition by targeting multiple pathways in triple‐negative breast cancers
Authors: Hseu You‐Cheng , Chang Geng‐Ruei , Pan Jian‐You , Rajendran Peramaiyan , Mathew Dony Chacko , Li Mei‐Ling , Liao Jiunn‐Wang , Chen William Tzu‐Liang , Yang Hsin‐Ling
Published: August 2018

Antrodia camphorata (AC) exhibits potential for engendering cell‐cycle arrest as well as prompting apoptosis and metastasis inhibition in triple‐negative breast cancer (TNBC) cells. We performed the current study to explore the anti‐epithelial‐to‐mesenchymal transition (EMT) properties of fermented AC broth in TNBC cells. Our results illustrated that noncytotoxic concentrations of AC (20–60 μg/ml) reversed the morphological changes (fibroblastic‐to‐epithelial phenotype) as well as the EMT by upregulating the observed E‐cadherin expression. Furthermore, we discovered treatment with AC substantially inhibit the Twist expression in human TNBC (MDA‐MB‐231) cells as well as in those that were transfected with Twist. In addition, we determined AC to decrease the observed Wnt/β‐catenin nuclear translocation through a pathway determined to be dependent on GSK3β. Notably, AC treatment consistently inhibited the EMT by downregulating mesenchymal marker proteins like N‐cadherin, vimentin, Snail, ZEB‐1, and fibronectin; at that same time upregulating epithelial marker proteins like occludin and ZO‐1. Bioluminescence imaging that was executed in vivo demonstrated AC substantially suppressed breast cancer metastasis to the lungs. Notably, we found that western blot analysis confirmed that AC decreased lung metastasis as demonstrated by upregulation of E‐cadherin expression in biopsied lung tissue. Together with our results support the anti‐EMT activity of AC, indicating AC as having the potential for acting as an anticancer agent for the treatment of human TNBC treatment.
Transcriptional regulation of CD4+ TH cells that mediate tissue inflammation
Authors: Loo Tiffany T , Gao Yuanyuan , Lazarevic Vanja
Published: August 2018

Acquired and genetic immunodeficiencies have revealed an indispensable role for CD4+ T cells in the induction of protective host immune responses against a myriad of microbial pathogens. Influenced by the cytokines present in the microenvironment, activated CD4+ T cells may differentiate into several highly-specialized helper subsets defined by the production of distinct signature cytokines tailored to combat diverse classes of pathogens. The process of specification and differentiation is controlled by networks of core, master, and accessory transcription factors, which ensure that CD4+ T helper (TH) cell responses mounted against an invading microbe are of the correct specificity and type. However, aberrant activation or inactivation of transcription factors can result in sustained and elevated expression of immune-related genes, leading to chronic activation of CD4+ TH cells and organ-specific autoimmunity. In this review, we provide an overview of the molecular basis of CD4+ TH cell differentiation and examine how combinatorial expression of transcription factors, which promotes genetic plasticity of CD4+ TH cells, can contribute to immunological dysfunction of CD4+ TH responses. We also discuss recent studies which highlight the potential of exploiting the genetic plasticity of CD4+ TH cells in the treatment of autoimmune and other immune-mediated disorders.

Review on how combinatorial expression of transcription factors, which promotes genetic plasticity of CD4+ TH cells, can contribute to immunological dysfunction of CD4+ TH responses.
Prolonged middle ear development in Rhinella horribilis
Authors: Womack Molly C. , Stynoski Jennifer L. , Voyles Meredith K. , Coloma Luis A. , Hoke Kim L.
Published: August 2018

Despite the benefit of the tympanic middle ear to airborne hearing sensitivity, anurans range in how soon they develop functional middle ears after transitioning to life on land. Previous evidence suggested that bufonids had particularly slow middle ear developmental rates, but precise timelines have not yet been published for this family. Here, we provide the first age‐verified middle ear development timeline for a true toad species (family Bufonidae). We find that although middle ear development begins during metamorphosis in Rhinella horribilis, the middle ear remains incomplete 15 weeks after the transition from aquatic tadpole to land‐dwelling toadlet. Using this new middle ear timeline, we discuss commonalities and differences in middle ear development among bufonids, as well as among Anura.
The Impact of Resident and Fellow Participation in Transsphenoidal Pituitary Surgery
Authors: Wong Anni , Filimonov Andrey , Lee Yung‐Jae , Hsueh Wayne D. , Baredes Soly , Liu James K. , Eloy Jean Anderson
Published: August 2018

Objectives/Hypothesis

Postoperative complications is an important marker of healthcare quality. The aim of this study was to analyze the impact of resident and fellow participation on postoperative complications in transsphenoidal pituitary surgery in a multi‐institutional setting.

Study Design

Retrospective analysis of population‐based surgical registry.

Setting

Academic medical center.

Methods

The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was utilized to generate transsphenoidal pituitary surgery patient cohorts. The attending with resident and/or fellow group was compared to the attending alone based on demographics and preoperative and postoperative variables.

Results

A total of 469 cases were included in the analysis, with 315 performed with resident participation and 154 by attendings alone. The attending group had higher rates of diabetics (20.1% vs. 11.7%, P = 0.015) and patients with a history of previous percutaneous coronary intervention (6.0 vs. 1.6%, P = 0.009). Although the attending group demonstrated higher rates of surgical complications, and the resident/fellow group showed increased incidence in medical and overall complication rates, there was no statistical difference between the two groups. Multivariate analysis further demonstrated lack of significance in complication rates between attendings and residents/fellows.

Conclusion

Resident and fellow participation in transsphenoidal surgery is not associated with significant differences in surgical complications, medical complications, mortality, operating time, reoperation rates, or readmission rates when compared to attendings.

Level of Evidence

4 Laryngoscope, 128:2707–2713, 2018
Utility of intraoral ultrasound in managing oral tongue squamous cell carcinoma: Systematic review
Authors: Tarabichi Osama , Bulbul Mustafa G. , Kanumuri Vivek V. , Faquin William C. , Juliano Amy F. , Cunnane Mary E. , Varvares Mark A.
Published: August 2018

Objectives/Hypothesis

Adequate surgical resection of early stage oral tongue cancer provides the best chance at preventing locoregional disease recurrence. Determination of tumor dimensions and margin location is challenging and can lead to inadequate resections with close/positive margins. Ultrasonography has proven its utility in determining the thickness and extent of tongue tumors. Preoperative tumor dimension measurements carry increased significance with the addition of depth of invasion (DOI) to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system. We report the results of a systematic review of the literature pertaining to the use of ultrasound in the diagnosis and management of oral tongue carcinoma.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta‐analysis statement checklist was used to inform the design of this systematic review. All studies that utilized ultrasound in the diagnosis/management of primary carcinoma of the oral tongue were included. PubMed, Embase, and Cochrane were reviewed to identify eligible studies.

Results

Nineteen articles were included in our analysis. Six hundred seventy‐eight patients were studied in the articles included. Ultrasound tumor thickness measurements correlate well with those on histopathology and show promise as a predictor of cervical lymph node metastasis. Ultrasound can be safely used intraoperatively for deep margin assessment.

Conclusions

Ultrasound is useful in the evaluation of oral tongue malignancies. More experience is needed to determine if it is reliable in determining preoperative DOI in light of the role this tumor parameter plays in the eighth edition of the AJCC staging manual. Laryngoscope, 129:662–670, 2019
Permeability and Weibel–Palade Bodies of the Blood Vessels in the Human Vocal Fold Mucosa
Authors: Sato Kiminori , Chitose Shun‐ichi , Sato Kiminobu , Sato Fumihiko , Umeno Hirohito
Published: August 2018

Objectives

Transendothelial exchange and permeability of the capillaries in Reinke space (the superficial layer of the lamina propria) of the vocal fold mucosa affect physiological and pathological conditions of the human vocal fold mucosa. The mechanism of permeability and Weibel–Palade bodies of the blood vessels in the human vocal fold mucosa were investigated using electron microscopy.

Study design

Histologic analysis of the human vocal fold.

Methods

Six normal human vocal folds (three adults and three newborns) obtained from autopsy cases and three human vocal folds with Reinke edema from surgical specimens were investigated under transmission electron microscopy.

Results

There were three possible capillary wall transport systems related to the permeability of the blood vessels in the vocal fold mucosa: 1) Fenestra transport, plasma exuded from the capillaries into surrounding tissue via the fenestration with or without a diaphragm; 2) vesicular transport (transcellular transport via vesicles), the use of vesicles to ferry fluid and solutes across endothelial cells; and 3) junctional transport (intercellular transport), molecules passed through intercellular gaps between endothelial cells.

Weibel–Palade bodies were present in the cytoplasm of endothelial cells both in adults and newborns. They were present in high numbers in the cytoplasm of endothelial cells, with intercellular transport in the vocal folds with Reinke edema.

Conclusion

There were three types of mechanisms for the permeability of the blood vessels in the human vocal fold mucosa. Some physiologically active substances, such as histamine produced by Weibel–Palade bodies, may adversely influence the permeability of the blood vessels.

Level of Evidence

NA. Laryngoscope, 2588–2592, 2018
Adjuvant Chemotherapy Is Associated With Improved Survival for Late‐Stage Salivary Squamous Cell Carcinoma
Authors: Cheraghlou Shayan , Schettino Amy , Zogg Cheryl K. , Otremba Michael D. , Bhatia Aarti , Park Henry S. , Osborn Heather A. , Mehra Saral , Yarbrough Wendell G. , Judson Benjamin L.
Published: August 2018

Objective

Salivary squamous cell carcinomas (SCCs) represent a unique disease entity because many are thought to represent metastases from primary cutaneous malignancies. Nevertheless, they represent a significant proportion of parotid gland cancers and have a notably poor prognosis. Recently, there has been controversy regarding the utility of adjuvant chemotherapy in the treatment of these malignancies, with most studies concluding that there is no survival benefit. We aim to determine the outcomes associated with the use of adjuvant radiotherapy and chemoradiotherapy in the treatment of early‐ and late‐stage salivary SCC.

Methods

A retrospective study of 2,285 of surgically resected adult salivary SCC diagnosed from 2004 to 2014 in the National Cancer Database was conducted. Patients were divided into early‐ (I/II) and late‐stage (III/IV) groups. Demographic, facility, tumor, and survival variables were included in the analyses. Multivariate Cox survival regressions, propensity‐score matched analyses, and univariate Kaplan‐Meier analyses were conducted.

Results

The use of adjuvant chemoradiotherapy for late‐stage patients was associated with improved survival compared to the use of adjuvant radiotherapy alone (hazard ratio [HR] 0.774, P = 0.026). Five‐year survival for late‐stage patients treated with surgery alone, surgery with adjuvant radiotherapy, and surgery with adjuvant chemoradiotherapy was 31.1% (standard error [SE]: 2.5), 45.6% (SE: 2.2), and 58.9% (SE: 3.4). Use of adjuvant therapy (either chemoradiotherapy or radiotherapy alone) was associated with improved survival for early‐stage patients (HR 0.746, P = 0.037).

Conclusion

The addition of chemotherapy to the adjuvant therapy of late‐stage patients with salivary SCC may result in improved long‐term survival. Expanded use of adjuvant therapy for early‐stage disease may also improve patient outcomes.

Level of Evidence

4 Laryngoscope, 129:883–889, 2019
Free Flap Versus Pedicled Flap Reconstruction of Laryngopharyngeal Defects: A 10‐Year National Surgical Quality Improvement Program Analysis
Authors: Haidar Yarah M. , Kuan Edward C. , Verma Sunil P. , Goddard Julie A. , Armstrong William B. , Tjoa Tjoson
Published: August 2018

Objectives/Hypothesis

Large defects after total laryngectomy (TL) and total laryngopharyngectomy (TLP) often benefit from free flap (FF) or pedicled flap (PF) reconstruction to maintain continuity of the aerodigestive tract, protect great vessels, or reinforce pharyngeal closure. Although both techniques are commonly used, no consensus exists as to which results in fewer complications. The goal of this study was to determine if 30‐day morbidity/mortality outcomes differ between PF and FF reconstruction in patients undergoing TL/TLP.

Study Design

Retrospective cohort study.

Methods

Patients were analyzed who underwent TL/TLP with reconstruction using records from the American College of Surgeons National Surgical Quality Improvement Program database (2005–2015).

Results

A total of 347 patients were included; 204 received FF reconstruction, whereas 143 received PF reconstruction. FF reconstruction was more commonly used with TLP defects (P = .001). The total operative time in the FF (590 ± 140 minutes) was longer than the PF (441 ± 125 minutes) group (P < .0001). There was a higher rate of postoperative transfusions in those undergoing FF reconstruction (P = .022). There was no significant difference in complication rates among TLP patients. Among TL patients only, FF reconstruction had a higher association with wound infections than PFs (P = .040). On multivariate analysis, low hematocrit was associated with complications (P = .031). Age (P = .031) and congestive heart failure exacerbation (P < .001) were associated with increased hospital stay. Overall, there were no differences in readmissions, reoperations, or deaths between the groups.

Conclusions

Reported complication rates after TL/TLP remain high, despite widespread usage of vascularized flaps in reconstruction. This comparison reveals no significant difference in postoperative complications between patients who received PF and FF laryngopharyngeal reconstruction.

Level of Evidence

4 Laryngoscope, 129:105–112, 2019
Electrochemical methods for the determination of Pedeferri's diagram of stainless steel in chloride containing environment
Authors: Dastgerdi Arash Azimi , Brenna Andrea , Ormellese Marco , Pedeferri MariaPia , Bolzoni Fabio
Published: August 2018

Stainless steels are prone to localized corrosion (pitting and crevice) in the presence of oxygen and chlorides over a critical threshold. Prediction of the corrosion behavior of stainless steels in chloride containing environment is of great importance; for this reason, Pedeferri's diagram is proposed to define corrosion and passivity (perfect and imperfect conditions) as a function of the potential and chloride content. In this paper, the first effort is carried out to define electrochemical conditions to obtain the diagram. Potentiodynamic and potentiostatic polarization tests are performed on AISI 304L type stainless steel. Localized corrosion potential and critical chloride content found with two different methods are in fair agreement. Pedeferri's diagram is built for type 304L stainless steel at room temperature and pH 6. Corrosion, perfect and imperfect passivity regions are separated by scattering band for localized corrosion and repassivation potentials.
Corrosion behavior of bronze under organic acid‐containing thin electrolyte layer
Authors: Chen Cheng , Cai Lankun , Wang Xiong , Wang Yitian , Zhang Lehua , Zhou Hao , Wu Laiming , Yan Ying
Published: August 2018

The corrosion process and mechanism of three kinds of bronze materials under organic acid‐containing thin electrolyte layer (TEL) are investigated by electrochemical impedance spectroscopy (EIS) and Tafel polarization curves. It can be seen from the results that the corrosion rate of three specimens under TELs is lower than that in bulk solution. For bare bronze, the corrosion rate increases with the thickness of TEL, while for Cu2O patina bronze and CuCl patina bronze, there exists a critical thickness under TELs where the patina bronze have the maximum corrosion rate. In addition, the results show that Cu2O patina could increase the corrosion resistance, while CuCl patina, as a harmful patina, can accelerate the corrosion process. The principal corrosion products identified on the surface of bare bronze and Cu2O patina bronze are CuO, Cu(OH)2, and Cu(COOH)2, while the principal corrosion products identified on the surface of CuCl patina bronze is Cu2Cl(OH)3.
Phantom limb pain: peripheral neuromodulatory and neuroprosthetic approaches to treatment
Authors: Petersen Bailey A. , Nanivadekar Ameya C. , Chandrasekaran Santosh , Fisher Lee E.
Published: August 2018

Post‐amputation phantom limb pain (PLP) is a widespread phenomenon that can have physical, psychological, and functional impacts on amputees who experience the condition. The varying presentations and mechanisms of PLP make it difficult to effectively provide long‐term pain relief. Multiple neuromodulatory approaches to treating PLP have focused on electrical stimulation of the peripheral nervous system, with varying degrees of success. More recently, research has been done to study the effects of neuroprosthetic approaches on PLP. Neuroprosthetics combine the use of a functional prosthetic with stimulation to the peripheral nerves in the residual limb. Although many of the neuroprosthetic studies focus on improving function, several have shown preliminary evidence for the reduction of severity of PLP. In this review we provide an overview of the current understanding of the neurological mechanisms that initiate and sustain PLP, as well as the neuromodulatory and neuroprosthetic approaches under development for treatment of the condition.Muscle Nerve59:154–167, 2019