bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative tract‐based white matter heritability in 1‐ and 2‐year‐old twins
Authors: Lee Seung Jae , Zhang Jingwen , Neale Michael C. , Styner Martin , Zhu Hongtu , Gilmore John H.
Published: October 2018

White matter (WM) microstructure, as determined by diffusion tensor imaging (DTI), is increasingly recognized as an important determinant of cognitive function and is also altered in neuropsychiatric disorders. Little is known about genetic and environmental influences on WM microstructure, especially in early childhood, an important period for cognitive development and risk for psychiatric disorders. We studied the heritability of DTI parameters, fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) along 34 tracts, including 10 bilateral fiber pathways and the respective subdivision, using quantitative tractography in a longitudinal sample of healthy children at 1 year (N = 215) and 2 years (N = 165) of age. We found that heritabilities for whole brain AD, RD, and FA were 0.48, 0.69, and 0.72 at age 1, and 0.59, 0.77, and 0.76 at age 2 and that mean heritabilities of tract‐averaged AD, RD, and FA for individual bundles were moderate (over 0.4). However, the heritability of DTI change between 1 and 2 years of age was not significant for most tracts. We also demonstrated that point‐wise heritability tended to be significant in the central portions of the tracts and was generally spatially consistent at ages 1 and 2 years. These results, especially when compared to heritability patterns in neonates, indicate that the heritability of WM microstructure is dynamic in early childhood and likely reflect heterogeneous maturation of WM tracts and differential genetic and environmental influences on maturation patterns.
Ten‐year recurrence rates for breast cancer subtypes in the Netherlands: A large population‐based study
Authors: van Maaren Marissa C. , de Munck Linda , Strobbe Luc J.A. , Sonke Gabe S. , Westenend Pieter J. , Smidt Marjolein L. , Poortmans Philip M.P. , Siesling Sabine
Published: October 2018

Here we report for the first time the relation between breast cancer subtypes and 10‐year recurrence rates and mortality in the Netherlands. All operated women diagnosed with invasive non‐metastatic breast cancer in 2005 in the Netherlands were included. Patients were classified into breast cancer subtypes according to ER, PR, HER2 status and grade: luminal A, luminal B, HER2 positive and triple negative. Percentages and hazards of recurrence were compared among subtypes. Adjusted 10‐year overall (OS) and recurrence‐free survival (RFS) were calculated using multivariable Cox regression. Of 8,062 patients, 4,482 (56%) were luminal A, 2,090 (26%) luminal B, 504 (6%) HER2 positive and 986 (12%) triple negative. Local recurrences (7.5%) and distant metastases (25.6%) occurred most often in HER2 positive disease and the least often in luminal A (3.7% and 9.5%, respectively). Regional recurrences were most often diagnosed in triple negative disease (5.2%), and the least often in luminal A (1.7%). HER2 positive and triple negative subtypes had the highest recurrence rates in the second year, while luminal A and B showed a more continuous pattern over time, with lobular tumours recurring more often. After adjustment for differences in baseline characteristics, triple negative disease showed worse 10‐year OS and triple negative and HER2 positive disease had the lowest 10‐year RFS. In the Netherlands, breast cancer subtypes are important predictors for 10‐year recurrence rates. Knowledge on recurrence and survival rates according to these different subtypes, in combination with other prognostic factors, can support patient‐tailored treatment and individualised follow‐up.
Phosphonates Meet Metal−Organic Frameworks: Towards CO2 Adsorption
Authors: da Silva Cleiser Thiago P. , Howarth Ashlee J. , Rimoldi Martino , Islamoglu Timur , Rinaldi Andrelson W. , Hupp Joseph T.
Published: October 2018

Here we report a new highly microporous zirconium phosphonate material synthesized under solvothemal conditions. The specific Brunauer‐Emmett‐Teller (BET) surface area of the “unconventional metal−organic framework” (UMOF) is measured to be ∼900 m2/g, after following an appropriate activation protocol. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) shows that the material bears a free −OH functionality on the phosphonate linker that may interact with CO2. CO2 adsorption isotherms were collected and a measured heat of adsorption of 31 kJ/mol was obtained. In addition, adsorption isotherms of CO2, N2, and CH4 at 298 K combined with Ideal Adsorbed Solution Theory (IAST) show that the material can be expected to display high selectivities for uptake of CO2 versus N2 or CH4.
Foreign direct investment with tax holidays and policy uncertainty
Authors: Azevedo Alcino , Pereira Paulo J. , Rodrigues Artur
Published: October 2018

We study foreign direct investment agreements that entitle firms to a lower tax rate during a tax holiday period. Our model considers both finite and uncertain tax holiday period settings. We show that the tax holiday duration may have, for small tax rate reductions, a nonmonotonic effect on the investment timing. For sufficiently high tax reductions, a longer tax holiday speeds up investment. A higher tax reduction during the tax holiday and a lower uncertainty are shown to have a monotonic effect on the threshold, hastening investment. However, in case of a finite tax holiday, for exceptional high salvage values, a higher uncertainty can speed up investment. We show the usefulness of our model to design an optimal incentives package that prompts investment.
Enzalutamide‐induced severe thrombocytopenia complicated by a seizure in a 76‐year‐old man with castration‐resistant prostate cancer
Authors: Murata Masaki , Takizawa Itsuhiro , Maruyama Ryo , Kasahara Takashi , Hara Noboru , Tomita Yoshihiko
Published: October 2018

Introduction

Adverse events with enzalutamide widely used for men with castration‐resistant prostate cancer are of interest.

Case presentation

A 76‐year‐old man developed castration‐resistant prostate cancer. He received 160 mg of enzalutamide daily. On the 13th day after treatment, severe thrombocytopenia was observed (platelet count: 1.9 × 104/μL). Normal coagulation and fibrinolytic systems suggested thrombocytopenia induced by enzalutamide. Enzalutamide was withdrawn immediately, and platelet count uneventfully recovered to 7.0 × 104/μL and 28.8 × 104/μL 9 and 30 days after discontinuation, respectively. He restarted enzalutamide therapy without thrombocytopenia recurrence. However, 81 days after restarting enzalutamide, he experienced a seizure. There were no significant findings from brain computed tomography, which suggested that the seizure was also an enzalutamide‐associated adverse event.

Conclusion

Thrombocytopenia may occur early following enzalutamide therapy, and blood analysis within 2 weeks after treatment may facilitate its management. Enzalutamide‐induced thrombocytopenia, complicated by seizure, has not been reported.
Positive deviance, big data, and development: A systematic literature review
Authors: Albanna Basma , Heeks Richard
Published: October 2018

Positive deviance is a growing approach in international development that identifies those within a population who are outperforming their peers in some way, eg, children in low‐income families who are well nourished when those around them are not. Analysing and then disseminating the behaviours and other factors underpinning positive deviance are demonstrably effective in delivering development results. However, positive deviance faces a number of challenges that are restricting its diffusion. In this paper, using a systematic literature review, we analyse the current state of positive deviance and the potential for big data to address the challenges facing positive deviance. From this, we evaluate the promise of “big data‐based positive deviance”: This would analyse typical sources of big data in developing countries—mobile phone records, social media, remote sensing data, etc—to identify both positive deviants and the factors underpinning their superior performance. While big data cannot solve all the challenges facing positive deviance as a development tool, they could reduce time, cost, and effort; identify positive deviants in new or better ways; and enable positive deviance to break out of its current preoccupation with public health into domains such as agriculture, education, and urban planning. In turn, positive deviance could provide a new and systematic basis for extracting real‐world development impacts from big data.
Critical success factors for m‐Government adoption in Tanzania: A conceptual framework
Authors: Ishengoma Fredrick , Mselle Leonard , Mongi Hector
Published: October 2018

The advancement of wireless and mobile technologies has given rise to the mobile government (m‐Government). A new channel of public service delivery using a mobile phone. In Tanzania, several m‐Government initiatives have been undertaken. Among these, some can be said to have succeeded while others are still struggling. The reasons for these variations are not known. This study aimed to capture the critical success factors (CSFs) for the adoption of m‐Government and propose a framework under the Tanzanian context. The study builds upon an extensive literature review methodology based on six electronic databases from 2003 to 2017. The results show that security, usability, access, cost, infrastructure, and personal initiatives and characteristics have the strongest effect on the adoption of m‐Government services. Based on the findings of the critical review, a conceptual framework is proposed by extending the mobile services acceptance model (MSAM). A further finding is that most of the m‐Government adoption research have not considered the environmental setting. Hence, this study calls for more research on m‐Government adoption with consideration to the environmental setting (mandatory or optional environment). The study culminates by providing both practical, theoretical, and policy implications of the findings.
Noninvasive and sensitive optical assessment of brain death
Authors: Pan Boan , Huang Chong , Fang Xiang , Huang Xiaobo , Li Ting
Published: October 2018

Brain death is an irreversible loss of all brain functions, and the assessment is crucial for organ supply for transplantation. The noninvasive, sensitive, universally available and timely ancillary method to assess brain death has not been established. Here, we attempted to explore a noninvasive way in brain death assessment. Eighteen brain‐dead patients and 20 healthy subjects were measured by near‐infrared spectroscopy (NIRS), with a multiple‐phase protocol at varied fraction of inspired O2 (FIO2). We found that the concentration changes ratios of oxyhemoglobin to deoxyhemoglobin (Δ[HbO2]/Δ[Hb]) in the cerebral cortex of brain‐dead patients were significantly higher than those of healthy subjects. And, the Δ[HbO2]/Δ[Hb] in low‐to‐high FIO2 phase was most sensitive to distinguish brain‐dead patients from healthy subjects, with a recommended threshold ranged in 1.40~1.50. The innovative incorporation of NIRS and a varied FIO2 protocol was shown to be a noninvasive and reliable way in assessing brain death. This successful attempt of NIRS application is a help for fast and accurate evaluation of brain death, promptly offering quality‐assured donor organs and indicate us a protocol‐aided way to expand the use of NIRS.
Improved ex vivo expansion of mesenchymal stem cells on solubilized acellular fetal membranes
Authors: Shakouri‐Motlagh Aida , O'Connor Andrea J. , Kalionis Bill , Heath Daniel E.
Published: October 2018

Coatings produced from extracellular matrixes (ECMs) have emerged as promising surfaces for the improved ex vivo expansion of mesenchymal stem cells (MSCs). However, identifying a readily available source of ECM to generate these coatings is currently the bottleneck of this technology. In this study, we assessed if ECM coatings derived from decellularized fetal membranes were a suitable substrate for MSC expansion. We separated and decellularized the two main components of the fetal membranes, the amnion and the chorion. Characterization of the decellularized membranes revealed that each membrane component has a distinct composition, implying that coatings produced from these materials would have unique biological properties. The membranes were processed further to produce solubilized forms of the decellularized amniotic membrane (s‐dAM) and decellularized chorionic membrane (s‐dCM). On s‐dAM coatings decidual MSCs (DMSC) were more proliferative than those cultured on tissue culture plastic alone or on Matrigel coatings; were smaller in size (a measure of MSC potency); exhibited greater adipogenic differentiation capacity; and improved osteogenic capacity. Additionally, long term culture studies showed late passage DMSCs (passage 8) cultured on s‐dAM showed a decrease in cell diameter over three passages. These data support the use of s‐dAM as a substrate for improved MSC expansion. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 232–242, 2019.
7,8‐Dihydroxy‐3‐(4‐nitrophenyl)coumarin induces cell death via reactive oxygen species–independent S‐phase cell arrest
Authors: Musa Musiliyu A , Gbadebo Akintunde J , Latinwo Lekan M , Badisa Veera LD
Published: October 2018

We herein report the synthesis and in vitro cytotoxicity of 3‐arylcoumarin derivatives (6a‐f and 7a‐f) in human liver (HepG2), prostate (LNCap), and pancreatic (BxPC3) cancer cell lines. Among the tested compounds, 7,8‐dihydroxy‐3‐(4‐nitrophenyl) coumarin (7b) showed the highest cytotoxicity in the HepG2 cell line. The mechanism of cytotoxic action indicated that compound (7b) arrested HepG2 cells at the S phase of the cell cycle progression, induced loss of mitochondrial membrane potential, and caused reactive oxygen species (ROS)‐independent cell death. The cell viability result of pretreated HepG2 cells with antioxidant N‐acetylcysteine followed by compound (7b) treatment and the free radical scavenging activities of compound (7b) confirmed the ROS‐independent cell death. These results demonstrate that compound (7b) could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for hepatocellular carcinoma treatment.
Neuroprotective effect of quercetin against radiation‐induced endoplasmic reticulum stress in neurons
Authors: Chatterjee Jit , Langhnoja Jaldeep , Pillai Prakash P , Mustak Mohammed S
Published: October 2018

The endoplasmic reticulum (ER) plays an important role in the regulation and maintenance of cellular homeostasis. However, unresolved ER stress leads to deleterious effects by inducing the accumulation of unfolded proteins in the cell. Here we have demonstrated the protective aspects of quercetin against radiation‐induced ER stress and against inflammation in primary cultured dorsal root ganglion (DRG) neurons. The mature DRG neurons were pretreated with different concentrations of quercetin (5‐100 μM) for 24 hours before 2 Gy gamma radiation exposure and then subjected to a cytotoxicity assay, quantitative real‐time polymerase chain reaction and Western blot analysis. The results showed that quercetin decreased the expression of BiP and C/EBP‐homologous protein, the ER stress marker genes along with downregulation of tumor necrosis factor‐α, JNK in irradiated DRG neurons. Furthermore, quercetin pretreatment significantly increased the cytoskeletal protein Tuj1 and the neurotrophin brain‐derived neurotrophic factor in the neuron. These results indicate that quercetin plays a neuroprotective role against radiation‐mediated ER stress and inflammatory responses.
Boron ameliorates arsenic‐induced DNA damage, proinflammatory cytokine gene expressions, oxidant/antioxidant status, and biochemical parameters in rats
Authors: Ince Sinan , Kucukkurt Ismail , Acaroz Ulas , Arslan‐Acaroz Damla , Varol Nuray
Published: October 2018

Arsenic, an element found in nature, causes hazardous effects on living organisms. Meanwhile, natural compounds exhibit protective effects against hazardous substances. This study evaluated the effects of boron against arsenic‐induced genotoxicity and altered biochemical parameters in rats. Thirty‐five male Wistar albino rats were equally divided into five groups, and the experimental period lasted 30 days. One group was used as the control, and another group was treated with 100 mg/L arsenic in drinking water. The other groups were orally treated with 5, 10, and 20 mg/kg boron plus arsenic (100 mg/L via drinking water). Arsenic caused changes in biochemical parameters, total oxidant/antioxidant status, and DNA damage in mononuclear leukocytes. Moreover, it increased IFN‐γ, IL‐1β, TNF‐α, and NFκB mRNA expression levels in rat tissue. However, boron treatment improved arsenic‐induced alterations in biochemical parameters and increases in DNA damage and proinflammatory cytokine gene expressions.
Hesperidin promotes lysosomal biogenesis in chronically ethanol‐induced cardiotoxicity in rats: A proposed mechanisms of protection
Authors: Gaballah Hanaa H. , Ghanem Heba B. , Tahoon Nahid M. , Mohamed Darin A. , Ebeid Abla M.
Published: October 2018

Alcohol consumption is a major global risk factor for mortality and morbidity. We aimed to delineate the mechanisms underlying the potential ameliorative effects of hesperidin against chronically ethanol‐induced cardiotoxicity. Sixty male albino rats were divided into normal control group, hesperidin‐treated control group, untreated alcoholic group, and hesperidin‐treated alcoholic group. Transcription factor‐EB (TFEB) expression levels were estimated using real‐time reverse transcription‐polymerase chain reaction. Peroxisome proliferator–activated receptor γ coactivator 1‐α (PGC1‐α), macrophage inflammatory protein‐1 α, poly‐(ADP‐ribose)‐polymerase‐1 (PARP‐1) activity, and tenascin C levels in cardiac tissues were estimated by enzyme‐linked immunosorbent assay; while tissue malondialdehyde and total antioxidant capacity were evaluated spectrophotometrically. Our data portrayed promoting lysosomal biogenesis, as judged by upregulation of TFEB expression and its target PGC1‐α, as well as decreased PARP‐1 activity and offsetting inflammation, oxidative stress, and tissue injury as the principal culprits mediating the cardioprotective effect of hesperidin in alcohol‐induced cardiotoxicity. In conclusion, hesperidin can be used as a cardioprotective agent in chronically ethanol‐induced cardiotoxicity.
Hydrogen sulfide alleviates uranium‐induced rat hepatocyte cytotoxicity via inhibiting Nox4/ROS/p38 MAPK pathway
Authors: Yi Juan , Yuan Yan , Zheng Jifang , Zhao Tingting
Published: October 2018

As a gasotransmitter, hydrogen sulfide (H2S) plays a crucial role in regulating the signaling pathway mediated by oxidative stress. The purpose of this study was to investigate the protective effects of H
2S on uranium‐induced rat hepatocyte cytotoxicity. Primary hepatocytes were isolated and cultured from
Sprague Dawley rat liver tissues. After pretreating with sodium hydrosulfide (an H
2S donor) for 1 hour (or GKT‐136901 for 30 minutes), hepatocytes were treated by uranyl acetate for 24 hours. Cell viability, reactive oxygen species (ROS), malondialdehyde (MDA), NADPH oxidase 4 (Nox4), and p38 mitogen‐activated protein kinase (p38 MAPK) phosphorylation were respectively determined. The effects of direct inhibition of Nox4 expression by GKT‐136901 (a Nox4 inhibitor) on ROS and phospho‐p38 MAPK levels were examined in uranium‐treated hepatocytes. The results implicate that H
2S can afford protection of rat hepatocytes against uranium‐induced adverse effects through attenuating oxidative stress via prohibiting Nox4/ROS/p38 MAPK signaling.
Investigation of the effect of telomerase inhibitor BIBR1532 on breast cancer and breast cancer stem cells
Authors: Doğan Fatma , Özateş Neslihan Pınar , Bağca Bakiye Göker , Abbaszadeh Zeka , Söğütlü Fatma , Gasımlı Röya , Gündüz Cumhur , Biray Avcı Çığır
Published: October 2018

It is emphasized that cancer stem cells (CSCs) forming the subpopulation of tumour cells are responsible for tumour growth, metastasis, and cancer drug resistance. Inadequate response to conventional therapy in breast cancer leads researchers to find new treatment methods and literature surveys that support CSC studies. A selective anticancer agent BIBR1532 inhibits the telomerase enzyme. Many of the chemotherapeutic drugs used in clinical trials have harmful effects, but the advantage of telomerase‐based inhibitors is that they are less toxic to healthy tissues. The phosphoinositide 3‐kinase (PI3K)/serine/threonine kinase (Akt)/mammalian target of rapamycin (mTOR) pathway is common in breast cancer, and the interaction between the mTOR pathway and human telomerase reverse transcriptase (hTERT) is essential for the survival of cancer cells. In our study, we treated MCF‐7, breast cancer stem cell (BCSC) and normal breast epithelial cell MCF10A with the BIBR1532 inhibitor. The IC
50 doses for the 48th hour of BIBR1532 treatment were detected as 34.59 μM in MCF‐7, 29.91 μM in BCSCs, and 29.07 μM in MCF10A. It has been observed that this agent induces apoptosis in the BCSC and MCF‐7 cell lines. According to the results of cell cycle analysis, G
2/M phase accumulation was observed in BCSC and MCF‐7 cell lines. It has also been shown that BIBR1532 suppresses telomerase activity in BCSC and MCF‐7. The effect of BIBR1532 on the mTOR signalling pathway has been investigated for the first time in this study. It is thought that the telomerase inhibitor may bring a new approach to the treatment and it may be useful in the treatment of CSCs.
Involvement of NYD‐SP15 in growth and oxidative‐stress responses of ARPE‐19
Authors: Xu Yidan , Wang Linnong , Cao Liu , Chen Lixun , Liu Qinghuai
Published: October 2018

The aim of this study was to investigate the role of NYD‐SP15 in the growth and oxidative‐stress responses of ARPE‐19 cells. ARPE‐19 cell lines overexpressing wild type or RNA interference against NYD‐SP15 were established via lentivirus transfection. Cell growth and proliferation, migration, apoptosis, and cell cycle progression were monitored using the Cell Counting Kit‐8 assay, the wound scratch assay, and flow cytometry, respectively. Caspase‐3/8/9 activity was examined using the caspase‐3/8/9 assay kit. An hydrogen peroxide (H
2O
2)–induced oxidative‐stress damage model was used to study the effect of NYD‐SP15 knockdown by examining the activity of reactive oxygen species (ROS). Expressions of Kelch‐like ECH‐associated protein 1 (Keap‐1)/heme oxygenase‐1 (HO‐1)/nuclear factor erythroid 2–related factor 2 (Nrf2), mitogen‐activated protein kinase (MAPK), and Akt were detected by Western blot analysis. The mRNA chip of NYD‐SP15 overexpressed ARPE‐19 cells as well as controls were performed by one array plus process. Overexpression (OE) of NYD‐SP15 inhibited the proliferation and migration of ARPE‐19 cells, and led to apoptosis and caspase‐3/9 activation. OE of NYD‐SP15 inhibited MAPKs and Akt signaling. Downregulation of NYD‐SP15 had no effect on the growth of normally cultured ARP19 cells with 10% fetal bovine serum, but promoted the growth of ARP19 cells in the presence of starvation challenge. Gene chip showed that OE of NYD‐SP15 led to downregulation of 254 genes and upregulation of 57 genes. Downregulation of NYD‐SP15 also exerted a protective effect on H
2O
2‐induced cell apoptosis and ROS. NYD‐SP15 downregulation led to increments in the expression of Nrf2, Keap‐1, and HO‐1 in response to 200 μM H
2O
2. NYD‐SP15 might inhibit the growth, proliferation, and migration and promote apoptosis of ARPE‐19 cells via MAPK and Akt signaling. Downregulation of NYD‐SP15 could protect ARPE‐19 cells from H
2O
2‐induced oxidative damage by active Keap‐1/HO‐1/Nrf2, Akt, and MAPK signaling.
Exploring the antidiabetic and anti‐obesity properties of Samanea saman through in vitro and in vivo approaches
Authors: Vinodhini Shanmugam , Rajeswari V. Devi
Published: October 2018

In recent years, diabetes and obesity have become a major problem in global health care because of changes in lifestyle, food habits, and age‐related metabolic disorders. Diabetes mellitus is one of the most common diseases, affecting millions of people worldwide. Currently, herbal drugs are used to control obesity and diabetes. The present study investigates the anti‐obesity, antidiabetic, and antioxidant activities of Samanea saman leaf extract. A methanolic extract of
S. saman leaves was prepared by a maceration method. The
S. saman leaf extract was studied for its inhibitory effect on glucose utilization using specific in vitro procedures to analyze its antioxidant, anti‐obesity, and antidiabetic activities via different assays, such as α‐amylase and α‐glucosidase inhibition assay, glucose uptake by yeast cells, nonenzymatic glycosylation assay followed by glucose diffusion assay. The outcome of the study showed that the methanolic extract strongly inhibited the pancreatic lipase, α‐amylase, and glucosidase activities, compared with the standard drug. The results showed that the extract possessed considerable antioxidant and antidiabetic activities, and further studies are needed to confirm the results using an in vivo model. Thus, it is proposed that
S. saman can be used as a therapeutic agent.
Perilaldehyde activates AMP‐activated protein kinase to suppress the growth of gastric cancer via induction of autophagy
Authors: Zhang Yu , Liu Suosi , Feng Qin , Huang Xiuyun , Wang Xiangyang , Peng Ya , Zhao Zhihong , Liu Zhan
Published: October 2018

Background and Aim: Perillaldehyde (PAH), one of the major oil components in
Perilla frutescens, is very critical to health maintenance, for a wide range of human chronic diseases, including cancers. AMP‐activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. This study was designed to explore whether PAH prevents gastric cancer growth and to investigate the molecular mechanism.

Methods and Results: In cultured mouse gastric cancer cell line MFCs and human gastric cancer cell lines GC9811‐P, PAH activated AMPK by increasing the Thr172 phosphorylation and activity in a time‐/concentration‐dependent manner. Furthermore, incubation of MFCs with PAH also increased autophagy as determined by monodansylcadaverine (MDC) staining, which was reversed by AMPK inhibitor compound C. PAH further decreased MFCs cell survival, which was abolished by compound C or autophagy inhibitor 3‐Methyladenine (3‐MA). In vivo studies indicated that 4‐week administration of PAH (100 mg/kg/day) suppressed the growth of gastric cancer and increased the levels of autophagy‐related proteins, including beclin‐1, LC3‐II, cathepsin, caspase‐3, p53, and cathepsin in tumors isolated from the xenograft model of gastric cancer in mice. Moreover, these anticancer effects produced by PAH were abolished by coadministration of compound C or 3‐MA in vivo.

Conclusions: PAH increases AMPK phosphorylation and activity to induce gastric cancer cell autophagy to inhibit the growth of gastric cancer. In perspective, therapy of PAH should be applied to treat patients with gastric cancer.
Downregulation of antidifferentiation noncoding RNA promotes chondrogenic differentiation and calcification of ligamentum flavum‐derived mesenchymal stem cells
Authors: Zhang Qiang , Wang Shenyu , Sheng Yifei , Zhao Shujie , Jiang Yuqing , Zhou Dong , Yang Huilin
Published: October 2018

Ligamentum flavum (LF)‐derived mesenchymal stem cells (MSCs) have been implicated in the pathogenesis of calcification of the ligamentum flavum (CLF) leading to the increased presence of chondrocyte‐like cells and calcium deposition in CLF; however, the mechanisms of LF‐MSCs in differentiation are not defined. In this study, we investigated the role of antidifferentiation noncoding RNA (ANCR) in the differentiation of LF‐MSCs. We found that ANCR was downregulated in human CLF tissues. In cultured LF‐MSCs, ANCR downregulation led to decreased cell proliferation but enhanced chondrogenic differentiation and calcification. In contract, ANCR overexpression increased cell proliferation but inhibited differentiation and calcification. Mechanistically, we detected a positive correlation between ANCR and enhancer of zeste homolog 2 (EZH2) in human CLF tissues. In cultured LF‐MSCs, ANCR knockdown decreased while ANCR overexpression increased EZH2 expression. In addition, physical association between ANCR and EZH2 was revealed by an RNA pull‐down assay. Functionally, EZH2 overexpression prevented chondrogenic differentiation and calcification enhanced by ANCR knockdown. These findings indicated that ANCR upregulates EZH2 expression and physically binds to EZH2 in LF‐MSCs to suppress chondrogenic differentiation and calcification. Therefore, downregulated ANCR contributes to increasing of chondrocyte‐like cells and calcium deposition in CLF. ANCR may serve as a therapeutic target for CLF.
The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer
Authors: Samavarchi Tehrani Sadra , Mahmoodzadeh Hosseini Hamideh , Yousefi Tooba , Abolghasemi Maryam , Qujeq Durdi , Maniati Mahmood , Amani Jafar
Published: October 2018

DNA damage response (DDR) is a regulatory system responsible for maintaining genome integrity and stability, which can sense and transduce DNA damage signals. The severity of damage appears to determine DDRs, which can include damage repair, cell‐cycle arrest, and apoptosis. Furthermore, defective components in DNA damage and repair machinery are an underlying cause for the development and progression of various types of cancers. Increasing evidence indicates that there is an association between trace elements and DDR/repair mechanisms. In fact, trace elements seem to affect mediators of DDR. Besides, it has been revealed that oxidative stress (OS) and trace elements are associated with cancer development. In this review, we discuss the role of some critical trace elements in the risk of cancer. In addition, we provide a brief introduction on DDR and OS in cancer. Finally, we will further review the interactions between some important trace elements including selenium, zinc, chromium, cadmium, and arsenic, and DDR, and OS in cancer.
Retracted: Daidzin inhibits RANKL‐induced osteoclastogenesis in vitro and prevents LPS‐induced bone loss in vivo
Authors: Wei Gejin , Liang Tihong , Wei Chengming , Nong Xiaolian , Lu Qiteng , Zhao Jinmin
Published: October 2018

Osteoclasts are multinuclear giant cells responsible for bone resorption in bone loss diseases, including rheumatoid arthritis, periodontitis, and the aseptic loosening of orthopedic implants. Because of injurious side effects with currently available drugs, it is necessary to continue research novel bone‐protective therapies. Daidzin, a naturally occurring isoflavone found in leguminous plants, has numerous beneficial pharmacologic effects, including anti‐cancer, anti‐cholesterol, and anti‐angiocardiopathy, promoting osteoblasts differentiation, and even anti‐osteoporosis. However, the effect of daidzin on the regulation of osteoclast activity has not yet been investigated. In this study, our study showed that daidzin significantly inhibited receptor activator of nuclear factor‐kB ligand (RANKL)‐induced osteoclast differentiation of bone marrow macrophages and the hydroxyapatite‐resorbing activity of mature osteoclasts by inhibiting RANKL‐induced NF‐kB signaling pathway. In addition, daidzin could inhibit the expression of osteoclast marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene fos (c‐Fos), tartrate‐resistant acid phosphatase (TRAP), and cathepsin K (CTSK). Consistent with in vitro results, daidzin inhibited lipopolysaccharide‐induced bone loss by suppressing the osteoclast differentiation. Together our data demonstrated that daidzin inhibits RANKL‐induced osteoclastogenesis through suppressing NF‐ĸB signaling pathway and that daidzin is a promising agent in the treatment of osteolytic diseases.
Therapeutic potential of targeting the Wnt/β‐catenin pathway in the treatment of pancreatic cancer
Authors: Javadinia Seyed Alireza , Shahidsales Soodabeh , Fanipakdel Azar , Joudi‐Mashhad Mona , Mehramiz Mehrane , Talebian Sahar , Maftouh Mona , Mardani Ramin , Hassanian Seyed Mahdi , Khazaei Majid , Ferns Gordon A. , Avan Amir
Published: October 2018

The Wnt/β‐catenin pathway is an important, dysregulated pathway in several tumor types, including pancreatic ductal adenocarcinoma. Although the activation of this pathway is an important component of normal development, its aberrant activation resulting from activating or inactivating mutations in the
CTNNB1 gene locus, or in the negative regulators AXIN and APC involving stabilization of β‐catenin, and activation of target genes leads to a more aggressive phenotype, suggesting its potential value as a therapeutic target in the treatment of pancreatic ductal adenocarcinoma. A number of small molecule and biologic agents have now been developed for targeting this pathway. This review summarizes the current knowledge about the therapeutic potential of targeting the Wnt pathway with particular emphasis on preclinical/clinical studies in the treatment of pancreatic ductal adenocarcinoma.
Downregulation of miR‐20b‐5p facilitates Mycobacterium tuberculosis survival in RAW 264.7 macrophages via attenuating the cell apoptosis by Mcl‐1 upregulation
Authors: Zhang Defeng , Yi Zhengjun , Fu Yurong
Published: October 2018

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). The interaction between Mtb and macrophages, which is regulated by microRNAs, determines the development of TB. However, the function of microRNA‐20b‐5p (miR‐20b‐5p) in RAW 264.7 macrophages against Mtb remains unknown. In this study, we analyzed the expression level of miR‐20b‐5p in macrophage responses to Mtb infection and exosomes derived from macrophages after Mtb infection. MiR‐20b‐5p mimics and inhibitor were, respectively, transfected to evaluate the effect of miR‐20b‐5p on Mtb and macrophages. In addition, the targets of miR‐20b‐5p were predicted by a bioinformatics analysis. The macrophages were respectively transfected with miR‐20b‐5p mimics and inhibitor to determine the messenger RNA expression levels of the targets by reverse transcription‐polymerase chain reaction assay. The results revealed that the miR‐20b‐5p expression level was decreased in the infected macrophages at different times. MiR‐20b‐5p was shown in the exosomes released from macrophages infected with Mtb. Upregulation of the miR‐20b‐5p level suppressed the survival of Mtb in macrophages, while downregulation of the miR‐20b‐5p level enhanced the survival of Mtb in macrophages. Overexpression of miR‐20b‐5p decreased the cell viability and induced apoptosis in Mtb‐infected macrophages, while underexpression of miR‐20b‐5p increased the cell vitality and attenuated apoptosis in Mtb‐infected macrophages. The bioinformatics analysis revealed that Mcl‐1 was a target of miR‐20b‐5p. MiR‐20b‐5p negatively regulated the expression of Mcl‐1. Overall, this study is the first to demonstrate the effect of miR‐20b‐5p on Mtb infection and present miR‐20b‐5p and exosomes as the potential therapeutic targets of TB.
Novel association of oral squamous cell carcinoma with GSTP1 Arg187Trp gene polymorphism
Authors: Rajesh Deepa , Balakrishna Sharath , Azeem Mohiyuddin S. M. , Suryanarayana Ravishankar , Kutty A. V. Moideen
Published: October 2018

Aims

Glutathione S‐transferase subtype pi 1 (GSTP1) is an enzyme that is involved in the detoxification of carcinogenic substances. Arg187Trp is a functional polymorphism in the corresponding GSTP1 gene that reduces the enzymatic activity by 45%. We evaluated, for the first time, the association of Arg187Trp with the risk of oral squamous cell carcinoma and compared it with other established
GSTP1 polymorphisms viz, Ile105Val and Ala114Val.

Materials and Methods

We carried out a 1:2 case‐control study by recruiting 100 patients with oral squamous cell carcinoma and 200 age and gender‐matched healthy individuals. Ile105Val, Ala114Val, and Arg187Trp polymorphisms were genotyped by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method and their distribution in the study groups was compared by chi‐squared test (Fisher’s exact).

Results

The minor allele of Ala114Val and Arg187Trp were more common in patients than in controls. In contrast, the distribution of Ile105Val minor allele was similar in the two groups. The differential distribution was also significant at the level of genotypes.

Conclusions

These results indicate that GSTP1 Arg187Trp is associated with the risk of developing oral squamous cell carcinoma. Our study underlines the importance of detoxification pathway in the risk of carcinogenesis.
Heme oxygenase‐1 attenuates the inhibitory effect of bortezomib against the APRIL‐NF‐κB‐CCL3 signaling pathways in multiple myeloma cells: Corelated with bortezomib tolerance in multiple myeloma
Authors: He Zheng C. , Li Xin Y. , Guo Yong L. , Ma Dan , Fang Qin , Ren Ling L. , Zhang Zhao Y. , Wang Weili , Yu Zheng Y. , Zhao Peng , Wang Ji S.
Published: October 2018

Osteoclasts (OCs) play an essential role in bone destruction in patients with multiple myeloma (MM). Bortezomib can ameliorate bone destruction in patients with MM, but advanced MM often resists bortezomib. We studied the molecular mechanisms of bortezomib tolerance in MM. The expression of the MM‐related genes in newly diagnosed patients with MM and normal donors were studied. C‐C motif chemokine ligand 3 (CCL3) is a cytokine involved in the differentiation of OCs, and its expression is closely related to APRIL (a proliferation‐inducing ligand). We found that bortezomib treatment inhibited APRIL and CCL3. But the heme oxygenase‐1 (HO‐1) activator hemin attenuated the inhibitory effects of bortezomib on APRIL and CCL3. We induced mononuclear cells to differentiate into OCs, and the enzyme‐linked immunosorbent assay showed that the more OCs differentiated, the higher the levels CCL3 secretions detected. Animal experiments showed that hemin promoted MM cell infiltration in mice. The weight and survival rate of tumor mice were associated with HO‐1 expression. Immunohistochemical staining showed that HO‐1, APRIL, and CCL3 staining were positively stained in the tumor infiltrating sites. Then, MM cells were transfected with L‐HO‐1/si‐HO‐1 expression vectors and cultured with an nuclear factor (NF)‐kappa B (κB) pathway inhibitor, QNZ. The results showed that HO‐1 was the upstream gene of APRIL, NF‐κB, and CCL3. We showed that HO‐1 could attenuate the inhibitory effect of bortezomib against the APRIL‐NF‐κB‐CCL3 signaling pathways in MM cells, and the tolerance of MM cells to bortezomib and the promotion of bone destruction are related to HO‐1.
Endoplasmic reticulum stress, autophagic and apoptotic cell death, and immune activation by a natural triterpenoid in human prostate cancer cells
Authors: Johnson Benjamin M. , Radwan Faisal F. Y. , Hossain Azim , Doonan Bently P. , Hathaway‐Schrader Jessica D. , God Jason M. , Voelkel‐Johnson Christina V. , Banik Narendra L. , Reddy Sakamuri V. , Haque Azizul
Published: October 2018

Though the current therapies are effective at clearing an early stage prostate cancer, they often fail to treat late‐stage metastatic disease. We aimed to investigate the molecular mechanisms underlying the anticancer effects of a natural triterpenoid, ganoderic acid DM (GA‐DM), on two human prostate cancer cell lines: the androgen‐independent prostate carcinoma (PC‐3), and androgen‐sensitive prostate adenocarcinoma (LNCaP). Cell viability assay showed that GA‐DM was relatively more toxic to LNCaP cells than to PC‐3 cells (IC50s ranged 45‐55 µM for PC‐3, and 20‐25 µM for LNCaP), which may have occurred due to differential expression of p53. Hoechst DNA staining confirmed detectable nuclear fragmentation in both cell lines irrespective of the p53 status. GA‐DM treatment decreased Bcl‐2 proteins while it upregulated apoptotic Bax and autophagic Beclin‐1, Atg5, and LC‐3 molecules, and caused an induction of both early and late events of apoptotic cell death. Biochemical analyses of GA‐DM‐treated prostate cancer cells demonstrated that caspase‐3 cleavage was notable in GA‐DM‐treated PC‐3 cells. Interestingly, GA‐DM treatment altered cell cycle progression in the S phase with a significant growth arrest in the G2 checkpoint and enhanced CD4
+ T cell recognition of prostate tumor cells. Mechanistic study of GA‐DM‐treated prostate cancer cells further demonstrated that calpain activation and endoplasmic reticulum stress contributed to cell death. These findings suggest that GA‐DM is a candidate for future drug design for prostate cancer as it activates multiple pathways of cell death and immune recognition.
PKM2 promotes glucose metabolism through a let‐7a‐5p/Stat3/hnRNP‐A1 regulatory feedback loop in breast cancer cells
Authors: Yao Ao , Xiang Yuan , Si Yu‐Rui , Fan Li‐Juan , Li Jia‐Peng , Li Hui , Guo Wei , He Hui‐Xin , Liang Xing‐Jie , Tan Yao , Bao Le‐Yuan , Liao Xing‐Hua
Published: October 2018

Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let‐7a‐5p/Stat3/hnRNP‐A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)‐A1 expression, hnRNP‐A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let‐7a‐5p, which functionally targets Stat3, whereas hnRNP‐A1 blocks the biogenesis of let‐7a‐5p to counteract its ability to downregulate the Stat3/hnRNP‐A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP‐A1/PKM2 by let‐7a‐5p is verified using a breast cancer. These results suggest that let‐7a‐5p, Stat3, and hnRNP‐A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention.
Management of individuals with chronic hepatitis B virus infection and persistent normal or mildly elevated aminotransferase levels
Authors: Yan Jing‐Ya , Li Zhi‐Qin , Yu Zu‐Jiang , Kan Quan‐Chen
Published: October 2018

No consensus exists with respect to positive hepatitis B virus (HBV) DNA results and persistent normal or mildly elevated alanine aminotransferase (ALT). The aim of this study is to investigate the appropriate management and prognosis of these populations with chronic hepatitis B (CHB). A total of 235 subjects with positive HBV DNA results and persistent normal or mildly elevated ALT were enrolled in this study. Liver biopsy and liver stiffness measurements (LSM) were performed in all participants at baseline. Antiviral therapy was initiated in patients with significant hepatic inflammation (G ≥ 2) and/or fibrosis (S ≥ 2). The patients were divided into entecavir and adefovir groups based on HBV DNA load (>2000 IU/mL vs <2000 IU/mL). The liver biopsies were repeated at 72 weeks for the patients received antiviral therapy. We found that 112 subjects were hepatitis B e antigen (HBeAg) positive, and 123 subjects were negative. The corresponding median ALTs were 46 (39.5‐52.5) and 48 (41.5‐57.0) U/mL, respectively. G ≥ 2 and/or S ≥ 2 diseases were present in 48.8% (82/168) of the HBeAg‐positive and 51.2% (86/168) of HBeAg‐negative patients, respectively. In addition, 96 HBeAg‐positive and 72 HBeAg‐negative patients were divided into entecavir and adefovir groups. Meanwhile, liver biopsies had greater diagnostic accuracy for determining cirrhosis than LSM (0.711 vs 1.0, P < 0.0001). At the end of the study period, undetectable HBV DNA levels and normal ALT levels were observed in CHB‐infected patients. Furthermore, the patients showed histologic improvement at 72 weeks compared with baseline measurements (G, 1.72 ± 1.00 vs 0.73 ± 0.88, P = 0.0002; S, 1.484 ± 0.90 vs 0.99 ± 1.13, P < 0.0001). Collectively, liver biopsy enhanced diagnostic accuracy for CHB‐infected individuals with persistent normal or mildly elevated aminotransferase levels. Moreover, antiviral therapy can improve or regress the hepatic fibrosis and cirrhosis.
Downregulation of miR‐33b promotes non‐small cell lung cancer cell growth through reprogramming glucose metabolism miR‐33b regulates non‐small cell lung cancer cell growth
Authors: Zhai Shengping , Zhao Lingyan , Lin Tiantian , Wang Wei
Published: October 2018

Glucose metabolism is a common target for cancer regulation and microRNAs (miRNAs) are important regulators of this process. Here we aim to investigate a tumor‐suppressing miRNA, miR‐33b, in regulating the glucose metabolism of non‐small cell lung cancer (NSCLC). In our study, quantitative real‐time polymerase chain reaction (qRT‐PCR) showed that miR‐33b was downregulated in NSCLC tissues and cell lines, which was correlated with increased cell proliferation and colony formation. Overexpression of miR‐33b through miR‐33b mimics transfection suppressed NSCLC proliferation, colony formation, and induced cell‐cycle arrest and apoptosis. Meanwhile, miR‐33b overexpression inhibited glucose metabolism in NSCLC cells. Luciferase reporter assay confirmed that miR‐33b directly binds to the 3′‐untranslated region of lactate dehydrogenase A (LDHA). qRT‐PCR and Western blot analysis showed that miR‐33b downregulated the expression of LDHA. Moreover, introducing LDHA mRNA into cells over‐expressing miR‐33b attenuated the inhibitory effect of miR‐33b on the growth and glucose metabolism in NSCLC cells. Taken together, these results confirm that miR‐33b is an anti‐oncogenic miRNA, which inhibits NSCLC cell growth by targeting LDHA through reprogramming glucose metabolism.
Tissue differences revealed by gene expression profiles of various cell lines
Authors: Chen Lei , Pan Xiaoyong , Zhang Yu‐Hang , Kong Xiangyin , Huang Tao , Cai Yu‐Dong
Published: October 2018

Mechanisms through which tissues are formed and maintained remain unknown but are fundamental aspects in biology. Tissue‐specific gene expression is a valuable tool to study such mechanisms. But in many biomedical studies, cell lines, rather than human body tissues, are used to investigate biological mechanisms Whether or not cell lines maintain their tissue‐specific characteristics after they are isolated and cultured outside the human body remains to be explored. In this study, we applied a novel computational method to identify core genes that contribute to the differentiation of cell lines from various tissues. Several advanced computational techniques, such as Monte Carlo feature selection method, incremental feature selection method, and support vector machine (SVM) algorithm, were incorporated in the proposed method, which extensively analyzed the gene expression profiles of cell lines from different tissues. As a result, we extracted a group of functional genes that can indicate the differences of cell lines in different tissues and built an optimal SVM classifier for identifying cell lines in different tissues. In addition, a set of rules for classifying cell lines were also reported, which can give a clearer picture of cell lines in different issues although its performance was not better than the optimal SVM classifier. Finally, we compared such genes with the tissue‐specific genes identified by the Genotype‐tissue Expression project. Results showed that most expression patterns between tissues remained in the derived cell lines despite some uniqueness that some genes show tissue specificity.