bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trastuzumab‐monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2‐positive human breast cancer
Authors: Abdollahpour‐Alitappeh Meghdad , Lotfinia Majid , Bagheri Nader , Sineh Sepehr Koushan , Habibi‐Anbouhi Mahdi , Kobarfard Farzad , Balalaie Saeed , Foroumadi Alireza , Abbaszadeh‐Goudarzi Ghasem , Abbaszadeh‐Goudarzi Kazem , Abolhassani Mohsen 
Published: September 2018

AbstractTargeted therapy using specific monoclonal antibodies (mAbs) conjugated to chemotherapeutic agents or toxins has become one of the top priorities in cancer therapy. Antibody–drug conjugates (ADCs) are emerging as a promising strategy for cancer‐targeted therapy. In this study, trastuzumab, a humanized monoclonal anti‐HER2 antibody, was reduced by dithiothreitol and conjugated to the microtubule‐disrupting agent monomethyl auristatin E (MMAE) through a valine‐citrulline peptide linker (trastuzumab‐MC‐Val‐Cit‐PABC‐MMAE [trastuzumab‐vcMMAE]). After conjugation, ADCs were characterized by using UV–vis, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE), and flow cytometry. The antitumor activity of the ADC was evaluated in breast cancer cells in vitro. In addition, ADCs were further characterized using purification by the protein A chromatography, followed by assessment using apoptosis and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide) assays. Hydrophobic interaction chromatography was used to determine drug‐to‐antibody ratio species of ADCs produced. Our finding showed that approximately 5.12 drug molecules were conjugated to each mAb. H2L2, H2L, HL, H2, H, and L forms of ADCs were detected in nonreducing SDS‐PAGE. The binding of trastuzumab‐vcMMAE to HER2‐positive cells was comparable with that of the parental mAb. The MTT assay showed that our ADCs induced significant cell death in HER2‐positive cells, but not in HER2‐negative cells. The ADCs produced was a mixture of species, unconjugated trastuzumab (14.147%), as well as trastuzumab conjugated with two (44.868%), four (16.886%), six (13.238%), and eight (10.861%) molecules of MMAE. These results indicated that MMAE‐conjugated trastuzumab significantly increases the cytotoxic activity of trastuzumab, demonstrating high affinity, specificity, and antitumor activity in vitro. Trastuzumab‐vcMMAE is an effective and selective agent for the treatment of HER2‐positive breast tumors.
HDAC8 regulates canonical Wnt pathway to promote differentiation in skeletal muscles
Authors: Ferrari Luca , Bragato Cinzia , Brioschi Loredana , Spreafico Marco , Esposito Simona , Pezzotta Alex , Pizzetti Fabrizio , Moreno‐Fortuny Artal , Bellipanni Gianfranco , Giordano Antonio , Riva Paola , Frabetti Flavia , Viani Paola , Cossu Giulio , Mora Marina , Marozzi Anna , Pistocchi Anna 
Published: September 2018

AbstractHistone deacetylase 8 (HDAC8) is a class 1 histone deacetylase and a member of the cohesin complex. HDAC8 is expressed in smooth muscles, but its expression in skeletal muscle has not been described. We have shown for the first time that HDAC8 is expressed in human and zebrafish skeletal muscles. Using RD/12 and RD/18 rhabdomyosarcoma cells with low and high differentiation potency, respectively, we highlighted a specific correlation with
HDAC8 expression and an advanced stage of muscle differentiation. We inhibited HDAC8 activity through a specific PCI‐34051 inhibitor in murine C2C12 myoblasts and zebrafish embryos, and we observed skeletal muscles differentiation impairment. We also found a positive regulation of the canonical Wnt signaling by HDAC8 that might explain muscle differentiation defects. These findings suggest a novel mechanism through which HDAC8 expression, in a specific time window of skeletal muscle development, positively regulates canonical Wnt pathway that is necessary for muscle differentiation.
Distinct Tie2 tyrosine phosphorylation sites dictate phenotypic switching in endothelial progenitor cells
Authors: Siavashi Vahid , Nassiri Seyed Mahdi , Rahbarghazi Reza , Mohseni Zahra , Sharifi Ali Mohammad 
Published: September 2018

AbstractAngiogenesis is a regulated process involving the proliferation, migration, and remodeling of different cell types particularly mature endothelial and their progenitor cells, nominated as endothelial progenitor cells (EPCs). Tie2/Tek is a tyrosine kinase receptor expressed by endothelial cells that induces signal transduction pathways involved in endothelial biology. To address the potential importance of the various tyrosine residues of Tie2 in EPC development, we generated a series of Tie2 tyrosine mutated (Y1106F, Y1100F, and Y1111F) EPCs and then assess the biological features of these cells. Clonogenic, tubulogenic, proliferative, migratory, and functional properties of these cells were analyzed. Next, GFP‐positive EPCs containing Tie2 tyrosine mutations were systemically transplanted into sublethaly irradiated mice to analyze the potency of these cells for marrow reconstitution. We found that mutation in the Tie2 tyrosine 1106 residue directed EPCs toward a mature endothelial phenotype, which was associated with augmented tubulogenic and migratory properties, and increased phosphorylation of the active site (tyrosine 992) as well as increased vascular perfusion in the in vivo Matrigel plug assay. Moreover, transplantation of 1106 Tie2 mutant EPCs failed to reconstitute the bone marrow after myeloablation, whereas transplantation of EPCs with the 1100 or 1111 Tie2 tyrosine mutation resulted in bone marrow engraftment, leading to improved survival of recipient mice. Our findings demonstrate that the tyrosine 1106 residue in Tie2 plays a key role to maintain the stemness features of EPCs.
Gene expression of TWIST1 and ZBTB16 is regulated by methylation modifications during the osteoblastic differentiation of mesenchymal stem cells
Authors: Marofi Faroogh , Vahedi Ghasem , Solali Saeed , Alivand Mohammadreza , Salarinasab Sadegh , Zadi Heydarabad Milad , Farshdousti Hagh Majid 
Published: September 2018

AbstractBackgroundOsteoblastic differentiation of mesenchymal stem cells (MSCs) is the principal stage during the restoration and regeneration of bone tissue. Epigenetic modifications such as DNA methylation play a key role in the differentiation process of stem cells. In this study, the methylation status of the promoter region of ZBTB16 and Twist1 genes and their role in controlling osteoblastic differentiation in MSCs was investigated during the osteoblastic differentiation of MSCs.MethodsThe MSCs were cultured under standard conditions and differentiated into the osteoblasts. We had three treatment groups including 5‐azacytidine (methylation inhibitor), metformin (Twist‐inhibitor), and procaine (Wnt/β‐catenin inhibitor) and a non‐treated group (control). Methylation level of DNA in the promoter regions was monitored by methylation specific‐quantitative polymerase chain reaction (PCR). Also, the mRNA levels of key genes in osteoblastic differentiation were measured using real‐time PCR.ResultsZBTB16 gene expression was upregulated, and promoter methylation was decreased. For Twist1 messenger RNA (mRNA) level decreased and promoter methylation increased during osteoblastic differentiation of MSCs. 5‐Azacytidine caused a significant reduction in methylation and increased the mRNA expression of ZBTB16 and Twist1. Metformin repressed the Twist1 expression, and therefore osteoblastic differentiation was increased. On the opposite side, procaine could block the WNT/β‐catenin signaling pathway, as a consequence the gene expression of key genes involved in osteoblastic differentiation was declined.ConclusionWe found that methylation of DNA in the promoter region of ZBTB16 and Twist1 genes might be one of the main mechanisms that controlling the gene expression during osteoblastic differentiation of MSCs. Also, we could find an association between regulation of Twist1 and ZBTB16 genes and osteoblastic differentiation in MSCs by showing the relation between their expression and some key genes involved in osteoblastic differentiation. In addition, we found a connection between the Twist1 expression level and osteoblastic differentiation by using a Twist‐inhibitor (metformin).
TGF‐β1‐PML SUMOylation‐peptidyl‐prolyl cis–trans isomerase NIMA‐interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis
Authors: Wu Di , Huang Di , Li Liang‐Liang , Ni Ping , Li Xiu‐Xian , Wang Bing , Han Yan‐Na , Shao Xiao‐Qi , Zhao Dan , Chu Wen‐Feng , Li Bai‐Yan 
Published: September 2018

AbstractTransforming growth factor‐β (TGF‐β) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF‐β1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF‐β1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac ﬁbroblasts (NMCFs), we found that exogenous TGF‐β1 induced the upregulation of TGF‐β1 itself in a time‐ and dose‐dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML‐NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF‐β signal or Pin1 with LY364947 (3 μM) or Juglone (3 μM), the TGF‐β1‐induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF‐β1 and Pin1. To verify the cellular function of PML by means of gain‐ or loss‐of‐function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF‐β‐Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF‐β1/PML SUMOylation/Pin1 leading to myocardial fibrosis.
Curcumin induces concentration‐dependent alterations in mitochondrial function through ROS in C2C12 mouse myoblasts
Authors: Yu Tianzheng , Dohl Jacob , Elenberg Falicia , Chen Yifan , Deuster Patricia 
Published: September 2018

AbstractCurcumin exhibits antioxidant properties in normal cells where the uptake is low, unlike in tumor cells where uptake is high and curcumin increases reactive oxygen species (ROS) production and cell death. Mitochondria are the main source and primary target of cellular ROS. We hypothesized that curcumin would regulate cellular redox status and mitochondrial function, depending on cell sensitivity and/or curcumin concentration in normal cells. We examined the differences between low and high concentrations of curcumin, with specific attention focused on ROS levels, mitochondrial function, and cell viability in mouse C2C12 myoblast under normal and simulated conditions of diabetes. Cells incubated with high concentrations of curcumin (10–50 μM) resulted in decreased cell viability and sustained robust increases in ROS levels. Mechanistic studies showed that increased ROS levels in cells incubated with 20 μM curcumin induced opening of mitochondrial permeability transition pores and subsequent release of cytochrome c, activation of caspases 9 and 3/7, and apoptotic cell death. Low concentrations of curcumin (1–5 μM) did not affect cell viability, but induced a mild increase in ROS levels, which peaked at 2 hr after the treatment. Incubation with 5 μM curcumin also induced ROS‐dependent increases in mitochondrial mass and membrane potential. Finally, pretreatment with 5 μM curcumin prevented high glucose‐induced oxidative cell injury. Our study suggests that mitochondria respond differentially depending on curcumin concentration‐dependent induction of ROS. The end result is either cell protection or death. Curcumin may be an effective therapeutic target for diabetes and other mitochondrial diseases when used in low concentrations.
Dynamics changes in the transcription factors during early human embryonic development
Authors: Godini Rasoul , Fallahi Hossein 
Published: September 2018

AbstractDevelopment of an embryo from a single cell, zygote, to multicellular morulae requires activation of hundreds of genes that were mostly inactivated before fertilization. Inevitably, transcription factors (TFs) would be involved in modulating the drastic changes in gene expression pattern observed at all preimplantation stages. Despite many ongoing efforts to uncover the role of TFs at the early stages of embryogenesis, still many unanswered questions remained that need to be explored. This could be done by studying the expression pattern of multiple genes obtained by high‐throughput techniques. In the current study, we have identified a set of TFs that are involved in the progression of the zygote to blastocyst. Global gene expression patterns of consecutive stages were compared and differences documented. Expectedly, at the early stages of development, only a few sets of TFs differentially expressed while at the later stages hundreds of TFs appear to be upregulated. Interestingly, the expression levels of many TFs show an oscillation pattern during development indicating a need for their precise expression. A significant shift in gene expression was observed during the transition from four‐ to eight‐cell stages, an indication of zygote genome activation. Additionally, we have found 11 TFs that were common in all stages including ATF3, EN1, IFI16, IKZF3, KLF3, NPAS3, NR2F2, RUNX1, SOX2, ZBTB20, and ZSCAN4. However, their expression patterns did not follow similar trends in the steps studied. Besides, our findings showed that both upregulation and active downregulation of the TFs expression is required for successful embryogenesis. Furthermore, our detailed network analysis identified the hub TFs for each transition. We found that HNF4A, FOXA2, and EP300 are the three most important elements for the first division of zygote.
Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: A study based on The Cancer Genome Atlas
Authors: Gao Chundi , Zhuang Jing , Zhou Chao , Ma Ke , Zhao Minzhang , Liu Cun , Liu Lijuan , Li Huayao , Feng Fubin , Sun Changgang 
Published: September 2018

AbstractCurrently, research on genome‐scale epigenetic modifications for studying the pathogenesis of lung cancer is lacking. Aberrant DNA methylation, as the most common and important modification in epigenetics, is an important means of regulating genomic function and can be used as a biomarker for the diagnosis and prognosis of lung squamous cell carcinoma (LUSC). In this paper, methylation information and gene expression data from patients with LUSC were extracted from the TCGA database. Univariate and multivariate COX analyses were used to screen abnormally methylated genes related to the prognosis of LUSC. The relationship between key DNA methylation sites and the transcriptional expression of LUSC‐related genes was explored. A prognostic risk model constructed by four abnormally methylated genes (VAX1, CH25H, AdCyAP1, and Irx1) was used to predict the prognosis of LUSC patients. Also, the methylation levels of the key gene IRX1 are significantly correlated with the prognosis and correlated with the methylation of the site cg09232937 and cg10530883. This study is based on high‐throughput data mining and provides an effective bioinformatics basis for further understanding the pathogenesis and prognosis of LUSC, which has important theoretical significance for follow‐up studies on LUSC.
Raloxifene attenuates oxidative stress and preserves mitochondrial function in astrocytic cells upon glucose deprivation
Authors: Vesga‐Jiménez Diego J. , Hidalgo‐Lanussa Oscar , Baez‐Jurado Eliana , Echeverria Valentina , Ashraf Ghulam Md , Sahebkar Amirhossein , Barreto George E. 
Published: September 2018

AbstractOxidative stress and mitochondrial dysfunction induced by metabolic insults are both hallmarks of various neurological disorders, whereby neuronal cells are severely affected by decreased glucose supply to the brain. Likely injured, astrocytes are important for neuronal homeostasis and therapeutic strategies should be directed towards improving astrocytic functions to improve brain's outcome. In the present study, we aimed to assess the actions of raloxifene, a selective estrogen receptor modulator in astrocytic cells under glucose deprivation. Our findings indicated that pretreatment with 1 µM raloxifene results in an increase in cell viability and attenuated nuclei fragmentation. Raloxifene's actions also rely on the reduction of oxidative stress and preservation of mitochondrial function in glucose‐deprived astrocytic cells, suggesting the possible direct effects of this compound on mitochondria. In conclusion, our results demonstrate that raloxifene's protective actions might be mediated in part by astrocytes in the setting of a metabolic insult.
The Path to Perfect Pediatric Posology — Drug Development in Pediatrics
Authors: Korth‐Bradley Joan M. 
Published: September 2018

AbstractReluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States). These plans are extensive, outlining planned studies, subjects to be enrolled, dose and dosage form justification, planned observations, and statistical analysis as well as planned modeling, simulation, and extrapolation analyses. The extent to which efficacy information in adults can be extrapolated to children depends on how similar the disease is in adults and each of the 5 pediatric age groups. Extrapolation may not be possible for conditions that do not occur in adults, requiring a complete development plan in adults, or extrapolation may be complete because of similar pathology and response to treatment. Pharmacokinetic and safety information cannot be extrapolated and must be collected in children of all ages, unless a waiver is granted. Physiologically based pharmacokinetic modeling, optimal design, population pharmacokinetics, and scavenged samples are all examples of new methodologies being used to study pediatric therapeutics. Clinicaltrials.gov and EU Clinical Trials registry are good sources of results of pediatric trials, although sponsors are also working toward prompt publication of study results in peer‐reviewed journals.
Potassium recovery from centrate: taking advantage of autotrophic nitrogen removal for multi‐nutrient recovery
Authors: Johansson Sara , Ruscalleda Maël , Saerens Bart , Colprim Jesús 
Published: September 2018

AbstractBACKGROUNDPotassium is a key macronutrient, but little attention has been paid to its recovery from waste streams. This study investigates simultaneous recovery of phosphorus and potassium in the form of potassium struvite (MgKPO4·6H2O) from centrate after nitrogen removal by partial nitritation–anammox (PNA). Lab‐scale batch experiments to assess the influence of pH, Mg:P ratio and temperature on nutrient removal were conducted on effluent from two PNA reactors fed with centrate from municipal wastewater treatment plants.RESULTSpH had a strong impact on potassium removal, which increased up to pH 11. At this pH, a product containing 11.4% P, 3.51% N and 4.34% K was obtained. X‐ray diffraction confirmed the presence of potassium struvite together with ammonium struvite (MgNH4PO4.6H2O). PNA reduced the alkalinity by 90%, which surpasses the performance of conventional CO2 stripping by aeration.CONCLUSIONCoupling PNA with struvite precipitation allows for the recovery of N, P and K in a multi‐nutrient product and may drastically reduce the need for alkali dosing for pH control. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Cell therapy products: focus on issues with manufacturing and quality control of chimeric antigen receptor T‐cell therapies
Authors: Eyles Jim E , Vessillier Sandrine , Jones Anika , Stacey Glyn , Schneider Christian K , Price Jack 
Published: September 2018

AbstractRecent accelerated approvals of Chimeric Antigen Receptor T‐cell (CAR‐T) therapies targeting refractory haematological malignancies underscore the potential for this novel technology platform to provide new therapeutic options for oncology areas with high unmet medical needs. However, these powerful ‘living drugs’ are markedly different to conventional small molecule and biologic therapies on several levels. The highly complex nature and varied composition of CAR‐T based products still requires considerable investigation to resolve the best approaches to ensure reproducible and cost‐effective manufacture, clinical development, and application. This review will focus on key issues for manufacturing and quality control of these exciting new therapeutic modalities, preceded by a brief description of CAR principals and clinical development considerations. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Polynomial relations between matrices of graphs
Authors: Spiro Sam 
Published: September 2018

AbstractWe derive a correspondence between the eigenvalues of the adjacency matrix and the signless Laplacian matrix of a graph when is ‐biregular by using the relation . This motivates asking when it is possible to have for a polynomial, , and matrices associated to a graph . It turns out that, essentially, this can only happen if is either regular or biregular.
Triangle‐free planar graphs with the smallest independence number
Authors: Dvořák Zdeněk , Masařík Tomáš , Musílek Jan , Pangrác Ondřej 
Published: September 2018

AbstractSteinberg and Tovey proved that every ‐vertex planar triangle‐free graph has an independent set of size at least , and described an infinite class of tight examples. We show that all ‐vertex planar triangle‐free graphs except for this one infinite class have independent sets of size at least .
Efficient Green Synthesis and Computational Chemical Study of Some Interesting Heterocyclic Derivatives as Insecticidal Agents
Authors: Fahmy A. F. M. , Rizk S. A. , Hemdan M. M. , El‐Sayed A. A. , Hassaballah A. I. 
Published: September 2018

A series of 5,5‐diarylhydantoin (Dilantin) 3, 4, and 7, imidazole 1, 2, 5, 6, 8, and 9, thiazole 10–12, triazinthione 13, 15, 16, and 17, and thiadiazine 14 derivatives, containing diverse hydrophobic groups, were green synthesized through one‐pot stepwise reaction of aromatic aldehydes, vitamin B1, and nitrogen nucleophiles, for example, urea, thiourea, and thiosemicarbazide using grinding technique as well as conventional thermal methods. Such synthesized compounds have potent insecticidal activities; for example, compounds 4, 6, and 17 exhibited the highest insecticidal activity against both Plutella xylostella and Helicoverpa armigera with minimum inhibitory concentration values at 500 μg/mL and LD50 activities at 50 μg/mL. The density functional theory was then applied to explore the structural and electronic characteristics of these compounds. All the synthesized compounds have been characterized based on their elemental analyses and spectral data.