bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular inhibitory mechanism study on the potent inhibitor brigatinib against four crizotinib‐resistant ALK mutations
Authors: Tu Jing , Song Li Ting , Liu Rui Rui , Zhai Hong Lin , Wang Juan , Zhang Xiao Yun 
Published: September 2018

AbstractAs a potent and selective drug, brigatinib exhibits high efficacy against wild‐type and mutant anaplastic lymphoma kinase (ALK) proteins to treat non–small cell lung cancer. In this work, the mechanisms of brigatinib binding to wild type and four mutant ALKs were investigated to gain insight into the dynamic energetic and structural information with respect to the design of novel inhibitors. Comparison between ALK‐brigatinib and ALK‐crizotinib suggests that the scaffold of brigatinib is well anchored to the residue Met1199 of hinge region by two hydrogen bonds, and the residue Lys1150 has the strong electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. These ALK mutations have significant influences on the flexibility of P‐loop region and DFG sequences, but do not impair the hydrogen bonds between brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and Asp1203. Together, the detailed explanation of mechanisms of those mutations with brigatinib further provide several guidelines for the development of more effective ALK inhibitors.
Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside
Authors: Dolati Sanam , Yousefi Mehdi , Mahdipour Mahdi , Afrasiabi Rad Abbas , Pishgahi Alireza , Nouri Mohammad , Jodati Ahmad Reza 
Published: September 2018

AbstractTo date, stem cell–based therapies for cardiac diseases have not achieved any significant clinical accomplishment. Globally, numerous patients are currently treated with autologous stem cells. The safety and practicality of this technique have been well‐examined, its disadvantages have been recognized, and many trials have been proposed. Inadequate description of the implemented cell types, a variety of cell‐handling proficiencies, and concerning factors related to autologous stem cells have been known as the central elements restricting the approval of cell‐based therapies. The idea that bone marrow (BM)‐derived cells could be applied to regenerate and cure damage in various organs is the basis for bone marrow mononuclear cell (BMMNC) therapy for heart disease. Mesenchymal stem cells (MSCs) are a part of the BMMNCs; on one hand, they have the capability to differentiate into various tissues, and, on the other, their immunomodulatory effects have been considered and clinically confirmed in different experiments. In this review, we summarize the knowledge obtained by trials in which mesenchymal cell–based therapy has been practiced. Furthermore, we accentuate the developments in the purification and lineage specification of MSCs as well as BMMNCs that have influenced the progress of future stem cell–based therapies with special attention on cardiovascular disease.
Retracted: MicroRNA‐590‐5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial–mesenchymal transition by downregulating the Wnt–β‐catenin signaling pathway
Authors: Gao Jin , Yu Shao‐Rong , Yuan Yuan , Zhang Li‐Li , Lu Jian‐Wei , Feng Ji‐Feng , Hu Sai‐Nan 
Published: September 2018

AbstractBreast cancer remains one of the foremost primary causes of female morbidity and mortality worldwide. During the current study, the effect of miR‐590‐5p and paired‐like homeodomain transcription factor 2 (PITX2) on proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) of human breast cancer via the Wnt–β‐catenin signaling pathway was investigated. Breast cancer–related genes and related signaling pathways were obtained from KEGG database. The PITX2 regulatory microRNA was predicted. To define the contributory role by which miR‐590‐5p influences the progression of breast cancer, the interaction between miR‐590‐5p and PITX2 was explored; the proliferation, invasion, and migration abilities as well as the tumor growth and metastasis in nude mice were detected following the overexpression or silencing of miR‐590‐5p. PITX2 was determined to share a correlation with breast cancer and miR‐590‐5p was selected for further analysis. PITX2, Wnt‐1, β‐catenin, N‐cadherin, and vimentin all displayed higher levels, while miR‐590‐5p and E‐cadherin expression were lower among breast cancer tissues than in the adjacent normal tissue. After overexpression of miR‐590‐5p or si‐PITX2, the expression of E‐cadherin was markedly increased, decreases in the expression of Wnt‐1, β‐catenin, N‐cadherin, and vimentin, as well as inhibited cell proliferation, invasion, migration, metastasis, and EMT were observed. This study provides evidence suggesting that the transfection of overexpressed miR‐590‐5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as EMT by suppressing the expression of PITX2 and activation of the Wnt–β‐catenin pathway.
PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma cell line CNE‐2 by inducing endoplasmic reticulum stress, downregulating STAT3 signaling, and modulating the MAPK pathway
Authors: Tan Gui‐Xiang , Wang Xin‐Ning , Tang Yun‐Yun , Cen Wan‐Jing , Li Zhen‐Hua , Wang Guo‐Cai , Jiang Jian‐Wei , Wang Xi‐Cheng 
Published: September 2018

AbstractParis polyphylla var. yunnanensis, named Chong Lou, is considered an antitumor substance. In this study, we investigated the effect of
PP‐22, a monomer purified from
P. polyphylla var. yunnanensis, on the nasopharyngeal carcinoma cell line CNE‐2 in vitro. The results showed that
PP‐22 could inhibit the proliferation of CNE‐2 cells via the induction of apoptosis, with evidence of the characteristic morphological changes in the apoptosis in the nucleus and an increase in Annexin V‐positive cells. In addition, we found that
PP‐22 could activate the p38 mitogen‐activated protein kinase (MAPK) pathway and that this activation was reversed by SB203580, a specific inhibitor of the p38 MAPK pathway. In contrast,
PP‐22 promoted apoptosis via an intrinsic pathway, including the endoplasmic reticulum stress pathway, in a caspase‐dependent manner. A further study showed that
PP‐22 also induced apoptosis by downregulating the signal transducers and activators of transcription 3 (STAT3) pathway, and the inhibitory effect was also confirmed by STAT3 small interfering RNA. In addition,
PP‐22 could promote autophagy by inhibiting the extracellular regulated protein kinases (ERK) pathway. And autophagy plays a protective role against apoptosis. Together, these data show that
PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma CNE‐2 cell line.
Methylation of CLEC14A is associated with its expression and lung adenocarcinoma progression
Authors: Su Chongyu , Shi Kang , Cheng Xu , Han Yi , Li Yunsong , Yu Daping , Liu Zhidong 
Published: September 2018

AbstractOur main objective is probing the effect of methylation of CLEC14A on its expression and lung adenocarcinoma (LUAD) progression. Microarray analysis was utilized to screen out differentially downregulated genes with hypermethylation in LUAD tissues. The
CLEC14A expression level was measured by western blot analysis and qRT‐PCR. Methylation‐specific‐PCR was performed to evaluate methylation status of
CLEC14A. The 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromid (MTT) assay was used to check the relation between
CLEC14A expression and cell proliferation. Cell cycle, cell apoptosis, migration, and invasion were respectively detected by the flow cytometry assay, wound healing assay, and transwell assay. Tumor xenograft models were established for investigating the effect of
CLEC14A on tumor formation.
CLEC14A expression in LUAD tissues was impaired compared with that in adjacent tissues, and
CLEC14A promoter was highly methylated in LUAD. Overexpressing
CLEC14A or inhibiting the methylation level of
CLEC14A in A549 and LTEP‐a‐2 cells impeded the duplication of LUAD cells, promoted apoptosis, attenuated cell migration, and invasion ability, and arrested cell cycle at the G0/G1 phase. Overexpression of
CLEC14A inhibited tumorigenesis of LUAD cells in nude mice. The promoter of
CLEC14A is methylated in LUAD, leading to downregulation of
CLEC14A in LUAD.
CLEC14A acts as an antitumor role in LUAD by suppressing cell proliferation, migration, invasion, promoting cell apoptosis, and reducing tumorigenicity in nude mice. Thus, the inhibition of CLEC14A methylation is a novel strategy for the clinic treatment of LUAD.
KRT1 gene silencing ameliorates myocardial ischemia–reperfusion injury via the activation of the Notch signaling pathway in mouse models
Authors: Fang Hong‐Cheng , Wu Bao‐Quan , Hao Yun‐Ling , Luo Ying , Zhao Hong‐Lei , Zhang Wen‐Ying , Zhang Zhi‐Ling , Liang Jin‐Jie , Liu Wei , Chen Xie‐Hui 
Published: September 2018

AbstractMyocardial ischemia and reperfusion injury (MIRI) includes major drawbacks, such as excessive formation of free radicals and also overload of calcium, which lead to cell death, tissue scarring, and remodeling. The current study aims to explore whether KRT1 silencing may ameliorate MIRI via the Notch signaling pathway in mouse models. Myocardial tissues were used for the determination of the positive rate of KRT1 protein expression, apoptosis of myocardial cells, creatine kinase (CK) and lactate dehydrogenase (LDH) expression, expression of related biomarkers as well as myocardial infarction area. The transfected myocardial cells were treated with KRT1‐siRNA, Jagged1, and DAPT (inhibitor of Notch‐1 signaling pathway). The expression of KRT1, NICD, Hes1, Bcl‐2, and Bax protein was detected. The MTT assay was applied for cell proliferation and flow cytometry was used for cell apoptosis. Mice with MIRI had a higher positive rate of KRT1 protein expression, apoptosis of myocardial cells, CK and LDH expression, myocardial infarction area, increased expression of MDA, NO, SDH, IL‐1, IL‐6, TNF‐α, CRP, KRT1, Bax protein, CK, and LDH, and decreased expression of SOD, NICD, Hes1, and Bcl‐2. The downregulation of KRT1 led to decreased expression of KRT1 and Bax protein, increased expression of NICD, Hes1, and Bcl‐2, decreased cell apoptosis, and improved cell proliferation. The inhibition of the Notch signaling pathway leads to reduced expression of Bax, increased expression of NICD, Hes1, and Bcl 2, and also decreased cell apoptosis and increased cell proliferation. Our data conclude that KRT1 silencing is able to make MIRI better by activating the Notch signaling pathway in mice.
Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality?
Authors: Marofi Faroogh , Vahedi Ghasem , hasanzadeh Ali , Salarinasab Sadegh , Arzhanga Pishva , Khademi Bahareh , Farshdousti Hagh Majid 
Published: September 2018

AbstractRecently a growing attention in scientific community has been gathered on potential application of mesenchymal stem cells (MSCs) in various fields of medicine. Owing to the fact that they can be easily isolated from different sources, and simply proliferated in large quantities while keeping their original biological characteristics, they can be successfully used as cell‐based therapeutics. Engineering MSCs and other type of stem cells to be carriers of therapeutic agents is a new tactic in the targeted gene and cell therapy of cancers and degenerative diseases. Various useful properties of MSCs including tropism toward tumor/injury site(s), weakly immunogenic, production of anti‐inflammatory molecules, and safety against normal tissues have made them prone for regenerative medicine, targeted therapy and treating injured tissues, and immunological abnormalities. In this review, we introduce latest advances, methods, and applications of MSCs in gene therapy of various malignant organ disorders. Additionally, we will cover the problems and challenges which researchers have faced with when trying to translate their basic experimental findings in MSCs research to clinically applicable therapeutics.
Cell shape alteration during adipogenesis is associated with coordinated matrix cues
Authors: Mor‐Yossef Moldovan Lisa , Lustig Maayan , Naftaly Alex , Mardamshina Mariya , Geiger Tamar , Gefen Amit , Benayahu Dafna 
Published: September 2018

AbstractObesity has become one of the leading pathophysiologic disorders in recent years. Adipose tissue is the main tissue related to obesity and is known to play a role in various physiological complications, including type 2 diabetes. To better understand how the fat tissue develops, we used an in vitro live cell imaging system to quantify the adipogenesis by means of nondestructive digital imaging to monitor the accumulation of intracellular lipid droplets (LDs), a hallmark of adipogenesis, from the macro‐ to the micro‐scale. Analyzing the cells’ shape at the single‐cell level allows to quantify the cells’ shape change from a fibroblast to spherical morphology, indicating the start of adipogenesis. To reveal the molecular alterations, we applied a proteomic approach using high‐resolution mass spectrometry of the proliferation, confluent fibroblasts and of adipocytes. During this process, we noted the reorganization of the cells’ extracellular matrix (ECM) network microenvironment from fibrillary collagen types I, III and V to collagens IV and VI, which affected the cells niche. The changes in ECM are translated for cytoskeleton remodeling according to cell fate‐determining mechanisms. We quantified the cytoskeleton rearrangement of long oriented actin fibers or short cortical and disorganized fibers, associated with LDs accumulation in adipocytes. Developing in vitro models and analytical methods enable us to study differentiation into adipocytes that will advance our understanding regarding the niche conditions that affect adipogenesis. Consequently, this will enable the development of new modalities to prevent obesity and its deleterious outcomes and to develop potential treatments to battle pathophysiology‐related diseases.
Clinicopathological and prognostic value of lncRNA PANDAR expression in solid tumors: Evidence from a systematic review and meta‐analysis
Authors: Mehrad‐Majd Hassan , Akhtari Javad , Haerian Monir‐Sadat , Ravanshad Yalda 
Published: September 2018

AbstractPANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76–3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25–6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11–2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17–3.44 and pooled HR 2.62; 95% CI, 1.98–3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.
The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases
Authors: Ranjbar Reza , Shafiee Mojtaba , Hesari AmirReza , Ferns Gordon A. , Ghasemi Faezeh , Avan Amir 
Published: September 2018

AbstractInflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti‐inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT1) receptor, and direct renin inhibitors, angiotensin‐converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti‐inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.
Comparative study of interruption of signaling pathways in lung epithelial cell by two different Mycobacterium tuberculosis lineages
Authors: Hadifar Shima , Behrouzi Ava , Fateh Abolfazl , Khatami Shohreh , Rahimi Jamnani Fatemeh , Siadat Seyed Davar , Vaziri Farzam 
Published: September 2018

AbstractAlveolar epithelial cell (AEC) provides a replication niche for Mycobacterium tuberculosis. Based on the role of AEC in
M. tuberculosis pathogenesis and existence of genetic diversity within this bacterium, we investigated interactions between AEC II and two different
M. tuberculosis lineages. We have compared the transcriptome and cytokines/chemokines levels of A549 infected by
M. tuberculosis lineage three and four using qRT‐PCR and ELISA arrays, respectively. We showed different
M.
tuberculosis strains induced changes in different effectors that involved in TLRs and NF‐κB signaling pathways. We observed different reaction of the studied lineages specifically in pathogenesis, immune evasion mechanism, IL‐12/IFN‐γ axis, and autophagy. Similar behavior was detected in regarding to apoptosis, necroptosis, anti‐inflammatory responses, and canonical inflammasome. Our findings contribute to elucidate more details in pathogenesis, immune evasion strategies, novel target and druggable pathway for therapeutic intervention, and host directed therapy in tuberculosis infection. Also, different
M.
tuberculosis lineages‐dependent host–pathogen interactions suggested using only one strain for this kind of research will be controversial.
Dose‐Finding Studies Among Orphan Drugs Approved in the EU: A Retrospective Analysis
Authors: Schuller Yvonne , Gispen‐de Wied Christine , Hollak Carla E. M. , Leufkens Hubertus G. M. , Stoyanova‐Beninska Violeta 
Published: September 2018

AbstractIn the development process for new drugs, dose‐finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose‐finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose‐finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose‐finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose‐related major objections were raised for 9 orphan drugs. Postmarketing dose‐finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose‐finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose‐finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose‐finding studies both pre‐ and postmarketing.
Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data
Authors: Ounissi Marwa , Rodrigues Christelle , Bienayme Hugues , Duhamel Paul , Pons Gérard , Dulac Olivier , Nabbout Rima , Chiron Catherine , Jullien Vincent 
Published: September 2018

AbstractVigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure‐related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36‐mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose‐ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4‐5.7 years) for the active S(+)‐enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one‐compartment model with zero‐order absorption and first‐order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36‐mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms.