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The presence of "ill-posed samples" specifically in low-volume datasets leads to accuracy decrement in the learning procedure and the generalization of neural networks. Such samples can be caused by various reasons such as noise contamination, corrupted sensors, or even, the complex distribution of physical properties governing the problem. The peak ground acceleration (PGA) datasets are definitely among the last mentioned. Focusing on speed and accuracy, a method for calculating earthquake magnitude based on the PGA data recorded at a single station along with hypocentral information has been presented in this research. Here, after training a deep neural network, the regression errors of the training data samples are clustered into two groups, namely well and ill posed using the grey wolf optimization algorithm. Instead of being removed, the data samples with low learning rates are then modified using samples selected from the other cluster in a fusional form. Then, two separate models are used and trained independently for the clusters. Next, in addition to the routine procedure of network generalization, every new sample is first checked whether is more likely to belong to which group of the clustered data, and after processing, the corresponding trained model is used. The results of the experiments show that using the proposed method results in magnitude calculation with an error order of less than 0.212 units of moment magnitude with a probability of more than 99.7%, which is superior to the conventional methods some of which were reviewed in this research. [ABSTRACT FROM AUTHOR]

Background: The study aimed at evaluating steroid biomarker genes (ERα, PGR, ERβ) and determining the expression level of estrogen-regulated genes (SCUB2 and BCL2) and growth factors receptors (HER2 and IGFR1) in cancer tissue samples obtained from Iranian patients with breast cancer. Moreover, relationships with clinicopathologic aspects of tumor and response to treatment were studied. Methods: The current study was conducted on 246 breast tissue samples. The expression levels of these genes and their relationships with clinicopathologic aspects and treatment response were evaluated. Results: Based on immunohistochemistry (IHC) results, 12% of the ER negative patients expressed ERα. Comparing the effects of ERα and coexpression of BCL2 and SCUBE2 on the survival of the patients demonstrated remarkably poorer survival in ERα positive, SCUBE2, and BCL2 negative groups in comparison with other patients, which was statistically significant in the logrank analysis (P = 0.01). Evaluation of the effects of coexpression of HER2 and IGFR1 on patients' survival demonstrated a worse survival rate in patients with positive expression of both receptors, which was insignificant. Conclusion: Many studies suggest that PGR alone is not enough for the functional evaluation of ERα. Evaluation of the progesterone receptor expression as well as other genes such as BLC2, SCUBE2, and IGFR1, seems necessary to evaluate functionality. [ABSTRACT FROM AUTHOR]

Mutations in the Additional Sex Combs Like 1 (ASXL1) gene were first reported in myelodysplastic syndromes. Recent studies have clarified the relationship between ASXL1 mutations and the development of cancers. This study aims to review the roles of ASXL1 and ASXL1 CircRNAs, such as epigenetic regulation, chromatin modification, and transcription factor function in malignancies. This study is a review of articles related to the role of ASXL1 and ASXL1 CircRNAs in malignancies, retrieved from PubMed and Scopus. ASXL1 plays a role in malignancies and is also related to poor overall survival and cancer metastasis. ASXL1 encodes conserved and abundant Circular RNAs (circRNAs) that act as post-transcriptional regulators, regulating tumorigenesis and progression in cancer. ASXL1 circRNA was identified in the top 10% of differentially expressed circRNAs in clinically relevant tissues. Additionally, the role of ASXL1 gene circRNAs in cancer development is reviewed in this study. ASXL1 and ASXL1circRNA have dual functions in combination with different proteins, being involved in both transcriptional activation and repression in a context-dependent manner. Moreover, studies indicate these genes play an important role in epithelial-mesenchymal transition (EMT) and metastasis. Ongoing research is aimed at determining this gene family's function in biological events. [ABSTRACT FROM AUTHOR]

Background: CD44 encoded by a single gene is a cell surface transmembrane glycoprotein. Exon 2 is one of the important exons to bind CD44 protein to hyaluronan. Experimental evidences show that hyaluronan-CD44 interaction intensifies the proliferation, migration, and invasion of breast cancer cells. Therefore, the current study aimed at investigating the association between specific polymorphisms in exon 2 and its flanking region of CD44 with predisposition to breast cancer. Methods: In the current study, 175 Iranian female patients with breast cancer and 175 age-matched healthy controls were recruited in biobank, Breast Cancer Research Center, Tehran, Iran. Single nucleotide polymorphisms of CD44 exon 2 and its flanking were analyzed via polymerase chain reaction and gene sequencing techniques. Association between the observed variation with breast cancer risk and clinico-pathological characteristics were studied. Subsequently, bioinformatics analysis was conducted to predict potential exonic splicing enhancer (ESE) motifs changed as the result of a mutation. Results: A unique polymorphism of the gene encoding CD44 was identified at position 14 nucleotide upstream of exon 2 (A37692→G) by the sequencing method. The A > G polymorphism exhibited a significant association with higher-grades of breast cancer, although no significant relation was found between this polymorphism and breast cancer risk. Finally, computational analysis revealed that the intronic mutation generated a new consensus-binding motif for the splicing factor, SC35, within intron 1. Conclusions: The current study results indicated that A > G polymorphism was associated with breast cancer development; in addition, in silico analysis with ESE finder prediction software showed that the change created a new SC35 binding site. [ABSTRACT FROM AUTHOR]

A series of 4-amino-5-cinnamoylthiazoles 3a-p were designed and synthesized as chalcone-like anticancer agents. The synthesized derivatives 3a-p were evaluated for their in vitro antiproliferative activities against three different human cancer cell lines including MCF-7, HepG2 and SW480. Most of compounds could significantly prevent proliferation of tested cell lines. In particular, the pyrrolidine derivative 3e namely ( E )-1-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one showed promising activity, especially against HepG2 cells (IC 50  = 10.6 μg/ml). Flow cytometric analyses revealed that the prototype compound 3e can prevent the proliferation of HepG2 cells by blockade of the cell cycle at the G2 phase and induction of apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: Bone marrow-derived mesenchymal stem cells (MSCs) have the potential ability to differentiate into bone, muscle, fat, and cartilage lineage cells. Furthermore, MSCs are known to migrate into tumor-associated stroma of cancer. This tumor microenvironment consists of a dynamic network of growth factors, immune cells, fibroblasts, extracellular matrix, and MSCs. MSCs as nonhematopoietic stem cells affect tumor, epithelial cells by alteration proliferative capacity, morphology, and aggregation pattern of tumor cells. Materials and Methods: This research aimed to further elucidate the MSCs effects in the progress of proliferation, cell cycle, and apoptosis in breast cancer by gene expression analysis in human breast cancer cell lines exposed to MSCs conditioned media (CM). Expression pattern of two genes, including survivin (Birc5) as anti-apoptotic gene and serine threonine kinase 15 as proliferative gene, were studied. Results: Anti-apoptotic and proliferative genes were up-regulated in co-cultured breast tumor cells with MSCs-CM that correlate with tumor progression and poor prognosis. Conclusion: Our results and other findings indicate the interaction of breast tumor cells with MSCs through paracrine factors. Also, the applications of MSCs as therapeutic tools are facing controversial concerns. [ABSTRACT FROM AUTHOR]

Background: Different cells and mediators in the tumor microenvironment play important roles in the progression of breast cancer. The aim of this study was to determine the composition of the microenvironment during tumor progression in order to discover new related biomarkers and potentials for targeted therapy. Methods: In this study, breast cancer biopsies from four different stages, and control breast biopsies were collected. Then, the mRNA expression of several markers related to different CD4+ T cell subsets including regulatory T cells (Treg), T helper (Th) type 1, 2 and 17 were determined. In addition, we investigated the expression of two inflammatory cytokines (TNF-α and IL-6) and inflammatory mediators including FASL, IDO, SOCS1, VEGF, and CCR7. Results: The results showed that the expression of Th1 and Th17 genes was decreased in tumor tissues compared to control tissues. In addition, we found that the gene expression related to these two cell subsets decreased during cancer progression. Moreover, the expression level of TNF-α increased with tumor progression. Conclusion: We conclude that the expression of genes related to immune response and inflammation is different between tumor tissues and control tissues. In addition, this difference was perpetuated through the different stages of cancer. [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen (CEA) family members play important roles in malignancies and are introduced as biomarkers in different types of cancers. Among them CEACAM19 (CEAL1) gene, a new member of the CEA family, remains to be fully elucidated. The aim of this study was investigating the mRNA expression level of CEACAM19 in tumor samples of breast cancer patients compared to breast tissue of normal individuals. We evaluated the expression level of this gene in 75 breast tumors by using real-time quantitative PCR. Also, we studied the correlation between CEACAM19 expression and clinicopathological features and hormone receptors status, including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 of patients. Out of the enrolled patients, six of them (7.9%) showed low expression, ten (13.2%) showed normal expression and 59 (77.6%) showed high expression of CEACAM19. There was a significant correlation between high expression of CEACAM19 gene in tumor samples compared to normal tissues ( P = 0.039). No significant correlation was seen between clinicopathological factors and disease-free survival with mRNA levels of CEACAM19 in tumor samples, while the difference between the expression of CEACAM19 in ER/PR-positive and ER/PR-negative breast cancer patients was statistically significant ( P = 0.046). In conclusion, CEACAM19 showed high expression in tumor samples compared to normal mammary tissue. In addition, CEACAM19 may represent as a novel therapeutic target in certain subgroups of breast cancer patients such as ER/PR-negative. Critical roles of CEA proteins in tumor progression may nominate them as robust potential targets for therapeutic intervention in near future. [ABSTRACT FROM AUTHOR]

Background: Biomedical researchers have long looked for ways to diagnose and treat cancer patients at the early stages through biomarkers. Although conventional techniques are routinely applied in the detection of biomarkers, attitudes towards using Real-Time PCR techniques in detection of many biomarkers are increasing. Normalization of quantitative Real-Time PCR is necessary to validate non-biological alteration occurring during the steps of RNA quantification. Selection of variably expressed housekeeping genes (HKs) will affect the validity of the data. The aim of the present study was to identify uniformly expressed housekeeping genes in order to use in the breast cancer gene expression studies. Urokinase Plasminogen Activator was used as a gene of interest. Findings: The expression of six HKs (TFRC, GUSB, GAPDH, ACTB, HPRT1 and RPLP0) was investigated using geNorm and NormFinder softwares in forty breast tumor, four normal and eight adjacent tissues. RPLP0 and GAPDH revealed maximum M value, while TFRC demonstrated lowest M value. Conclusions: In the present study the most and the least stable genes were TFRC and RPLP0 respectively. TFRC and ACTB were verified as the best combination of two genes for breast cancer quantification. The result of this study shows that in each gene expression analysis HKs selection should be done based on experiment conditions. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis delta virus (HDV) is an RNA virus that can lead to severe acute, and chronic forms of liver disease using the helper function of the hepatitis B virus. HDV strains are categorized into three genotypes and eight clades, which distribute geographically. The prevalence rate of HDV infection varies from 2.4 to 10 percent in blood donors for chronic liver disease in Iran. The aim was to find out the phylogenetic background of samples isolated in Tehran. Methods: A molecular phylogenetic analysis in some samples has been conducted in Iran previously. However, the number of cases did not cover the whole country. In addition, based on the restriction in the number of cases, we studied 26 samples. Results: In this study, a phylogenetic distribution of 26 Iranian isolates was determined using a neighbor-joining method. The revealed that all isolates belonged to Genotype I (Clade 1). Conclusions: It is shown that our finding is in concordance with previous studies in Iran. It can be concluded that the strain of HDV being spread in Iran belongs to Genotype 1. This study is in concordance with previous studies in Iran. [ABSTRACT FROM AUTHOR]

Background: Luminal subtype is the most common subgroup of breast cancer (BC), accounting for more than 70% of this cancer. Long non-coding RNAs (lncRNAs) are a group of RNAs which play critical roles in diverse cellular processes. It is proved that dysregulation of them can contribute to the development of various cancers, including BC. LINC00961 was reported to be downregulated in several cancers, however, its expression level in BC remains largely unknown. The purpose of the present study was to investigate the possible role of LINC00961 in luminal A and B subtypes of BC. Methods: To obtain novel lncRNAs associated with different cancers and differentially expressed lncRNAs (DElncRNAs) between BC tumor and normal tissues, Lnc2Cancer and GDC databases were used, respectively. After performing literature review, the expression level of the selected lncRNA (LINC00961) was evaluated in 79 luminal A and B BC specimens and adjacent non-cancerous tissues by Quantitative Reverse Transcription PCR (qRT-PCR). LINC00961 expression was also evaluated in two luminal A BC cell lines, compared to a normal breast cell line. The comparison of the differences between tumor and adjacent non-tumor samples was performed by paired sample t-test. Moreover, correlation analysis between LINC00961 expression and clinicopathological features was performed using the chi-square, fisher exact, and independent t-test. In order to investigate the possible roles of LINC00961 in luminal A and B BC, different bioinformatics analyses such as functional annotation of the LINC00961 co-expressed genes and protein–protein interaction (PPI) networks construction were also performed. Results: LINC00961 was selected as a significant DElncRNA which had not been studied in BC. According to q-RT PCR assay, LINC00961 was downregulated in luminal BC tissues and cell lines. Its expression was correlated with smoking status and the age of menarche in luminal BC patients. Also, the results of the bioinformatics analysis were consistent with the data obtained from q-RT PCR assay. The final results indicated that LINC00961 might be involved in multiple cancer-associated pathways such as chemokine, Ras and PI3K–Akt signaling pathways, GPCR ligand binding, and signal transduction in luminal subtypes of BC. CDH5, GNG11, GNG8, SELL, S1PR1, CCL19, FYN, ACAN, CD3E, ACVRL1, CAV1, and PPARGC1A were identified as the top hub genes of the PPI networks across luminal subgroup. Conclusion: Our findings suggested that LINC00961 was significantly downregulated in luminal A and B subtypes of BC. Moreover, bioinformatics analysis provided a basis for better identification of the potential role of LINC00961 in luminal subtype of BC. [ABSTRACT FROM AUTHOR]

The critical regulatory mechanisms in numerous cellular pathways including cell survival and DNA damage response mostly depend on phosphorylation and dephosphorylation of proteins. The serine/threonine phosphatase wild-type p53-induced phosphatase 1 (Wip1) is a growth-promoting phosphatase and its numerous downstream targets are important tumor suppressors. Here, we review the Wip1 activity and its relevance to cancer as an oncoprotein. Consecutive investigations about Wip1 and its relation to cancer is critical, as these studies ultimately contribute to the etiology of cancer. A number of innovative studies have recently investigated the importance of Wip1 as a new candidate for cancer diagnosis and prognosis. Accordingly, we discuss the present challenges of using Wip1 as a target for cancer treatment. [ABSTRACT FROM AUTHOR]

Pregnancy‐associated breast cancer (PABC) is a poor prognosis in women, and the mortality rate is higher in this subgroup of patients than in non‐PABC. This study aims to assess clinicopathological and ultrasound features of patients with PABC. Of 75 patients with breast cancer, 31 cases were in lactating, or pregnancy phase and 44 patients had no recent history of pregnancy/lactation at the time of cancer detection. The available pathological characteristics and ultrasound findings of the PABC and non‐PABC groups were compared. The analysis of ultrasound findings demonstrated that the percentages of antiparallel orientation (p = 0.04) and heterogeneous internal echo pattern (p = 0.002) were higher in the PABC group. The final Breast Imaging Reporting and Data System (BI‐RADS) assessment in the two groups was significantly different (p = 0.008). In this study, most PABCs were BI‐RADS 4c or 5; compared with age‐matched non‐PABC cases. There were significant differences in ER (p = 0.03), receptor groups (p = 0.007), and tumor grade (p = 0.02) in PABC compared to non‐PABC group. To conclude, radiologists should be careful about ultrasound findings of PABC and recommend core needle biopsy in suspected cases. [ABSTRACT FROM AUTHOR]

The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC50 values between 2.81–29.6 μg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four out of five examined cell lines and was 14 times more selective against MRC5. The flow cytometric analysis confirmed the induction of apoptotic cell death by this compound against HUVEC and MCF-7 cells. In addition, 11n caused sub-G1 phase arrest in the cell cycle arrest. Besides, this compound induced anti-angiogenesis in CAM assay and increased the level of caspase-3 by 5.2 fold. The western-blot analysis of the most active compound, 11n, revealed the inhibition of VEGFR-2 phosphorylation. Molecular docking study also showed the important interactions for compound 11n. [ABSTRACT FROM AUTHOR]

Background: Luminal breast cancer (BC) is the most frequent subtype accounting for more than 70% of BC. LncRNAs, a class of non-coding RNAs with more than 200 nucleotides, are involved in a variety of cellular processes and biological functions. Abberant expression is related to the development of various cancers, such as breast cancer. LINC01133, ZEB1-AS1, and ABHD11-AS1 were reported to be dysregulated in different cancers. However, their expression level in luminal BC remains poorly known. The aim of the present study was to evaluate the potential roles of these lncRNAs in BC, especially in luminal subtypes.Methods: A comprehensive analysis was performed using the Lnc2Cancer database to identify novel cancer-associated lncRNA candidates. After conducting a literature review, three novel lncRNAs named LINC01133, ZEB1-AS1, and ABHD11-AS1 were chosen as target genes of the present study. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression level of the mentioned lncRNAs in both luminal BC tissues and cell lines. Then, the correlation of the three mentioned lncRNAs expression with clinicopathological characteristics of the patients was studied. Moreover, several datasets were used to discover the potential roles and functions of LINC01133, ZEB1-AS1 and ABHD11-AS1 in luminal subtype of BC.Results: According to the qRT-PCR assay, the expression levels of LINC01133 and ZEB1-AS1 were decreased in luminal BC tissues and cell lines. On the other hand, ABHD11-AS1 was upregulated in the above-mentioned samples. The expression levels of LINC01133, ZEB1-AS1, and ABHD11-AS1 were not associated with any of the clinical features. Also, the results obtained from the bioinformatics analyses were consistent with qRT-PCR data. Functional annotation of the co-expressed genes with the target lncRNAs, protein-protein interactions and significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways across luminal BC were also obtained using bioinformatics analysis.Conclusions: Taken together, our findings disclosed the dysregulation of LINC01133, ZEB1-AS1, and ABHD11-AS1 in luminal BC. It was revealed that LINC01133 and ZEB1-AS1 expression was significantly downregulated in luminal BC tissues and cell lines, while ABHD11-AS1 was upregulated considerably in the mentioned tissues and cell lines. Also, bioinformatics and systems biology analyses have helped to identify the possible role of these lncRNAs in luminal BC. However, further analysis is needed to confirm the current findings. [ABSTRACT FROM AUTHOR]

The present study aimed to improve the understanding of non-uterine leiomyosarcoma (NULMS) prognostic genes through system biology approaches. This cancer is heterogeneous and rare. Moreover, gene interaction networks have not been reported in NULMS yet. The datasets were obtained from the public gene expression databases. Seven co-expression modules were identified from 5000 most connected genes; using weighted gene co-expression network analysis. Using Cox regression, the modules showed favorable (HR = 0.6, 95% CI = 0.4–0.89, P = 0.0125), (HR = 0.65, 95% CI = 0.44–0.98, P = 0.04) and poor (HR = 1.55, 95% CI = 1.06–2.27, P = 0.025) prognosis to the overall survival (OS) (time = 3740 days). The first one was significant in multivariate HR estimates (HR = 0.4, 95% CI = 0.28–0.69, P = 0.0004). Enriched genes through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) revealed significant immune-related pathways; suggesting immune cell infiltration as a favorable prognostic factor. The most significant protective genes were ICAM3, NCR3, KLRB1, and IL18RAP, which were in one of the significant modules. Moreover, genes related to angiogenesis, cell–cell adhesion, protein glycosylation, and protein transport such as PYCR1, SRM, and MDFI negatively affected the OS and were found in the other related module. In conclusion, our analysis suggests that NULMS might be a good candidate for immunotherapy. Moreover, the genes found in this study might be potential candidates for targeted therapy. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) were recently discovered as a looped subset of competing endogenous RNAs, with an ability to regulate gene expression by microRNA sponging. There are several studies on their potential roles in cancer development, such as colorectal cancer and basal cell carcinoma. However, there is still a significant gap in the knowledge about circRNA functions in breast cancer (BC) progression. The current study systematically reviewed circRNA biogenesis and their potential roles as a novel biomarker in BC on published studies of the MEDLINE®/PubMed, Cochrane®, and Scopus® databases. The obtained results showed a general dysregulation of circRNAs expression in BC cells with a cell‐type and stage‐specific manner. The potential connection between circRNAs and BC cell proliferation, apoptosis, metastasis, and chemotherapy sensitivity and resistance were discussed. [ABSTRACT FROM AUTHOR]

Abstract Sarcomas are known as a heterogeneous class of cancers arisen in the connective tissues and demonstrated various histological subtypes including both soft tissue and bone origin. Chondrosarcoma is one of the main types of bone sarcoma that shows a considerable deficiency in response to chemotherapy and radiotherapy. While conventional treatment based on surgery, chemo-and radiotherapy are used in this tumor, high rate of death especially among children and adolescents are reported. Due to high resistance to current conventional therapies in chondrosarcoma, there is an urgent requirement to recognize factors causing resistance and discover new strategies for optimal treatment. In the past decade, dysregulation of genes associated with tumor development and therapy resistance has been studied to find potential therapeutic targets to overcome resistance. In this review, clinical aspects of chondrosarcoma are summarized. Moreover, it gives a summary of gene dysregulation, mutation, histone modifications and non-coding RNAs associated with tumor development and therapeutic response modulation. Finally, the probable role of tumor microenvironment in chondrosarcoma drug resistance and targeted therapies as a promising molecular therapeutic approach are summarized. [ABSTRACT FROM AUTHOR]

A series of new coumarin-containing compounds 3a-l and 4a-c was designed and synthesized based on the chalcone-type 4-amino-5-cinnamoylthiazole scaffold 2 , and screened for their in vitro anticancer and antioxidant activities. Representatively, the 2-thiomorpholinothiazole derivative 3k with IC 50 values of 7.5–16.9 μg/ml demonstrated good cytotoxic effects against tested cell lines MCF-7, HepG2 and SW480. Further investigation by flow cytometric analysis confirmed that this compound induces apoptotic cell death in MCF-7 cells and cause G1-phase arrest in the cell cycle. Moreover, most of compounds had intrinsic potential for radical scavenging activity and ferric-reducing power as investigated by DPPH and FRAP assays. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of imidazoquinazoline-based compounds were designed and synthesized. • Two compounds named 18a and 18o showed noticeable IC 50 values against PC3 and HeLa cell lines. • 18a and 18o demonstrated inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). • Western blot analysis of 18a and 18o revealed EGFR and ERK1/2 phosphorylation inhibition. • Computational studies including electrostatic potential map analysis, molecular docking, and non-covalent interaction studies were performed to complete this investigation. Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2- a ]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o , in particular) had great anti-proliferative activities with IC 50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure–activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations. [ABSTRACT FROM AUTHOR]

Menthol in its L -isomer is a key flavoring additive mainly due to its cold-mimicking characteristics. Production of menthol in preferred L -isoform has been studied in different ways through cell-based or multiple-step biocatalyst processes. Herein, we introduce a single-step, cell-free reaction for (-)-menthol production. In this study, recombinant MMR (Menthone Menthol Reductase) was codon-optimized and expressed in Escherichia coli (E. coli) BL21 (DE3). The His-tagged protein was purified with ~ 90% efficiency using Ni-NTA affinity chromatography. The identity of the recombinant MMR was confirmed using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-TOF MS) through in-gel digestion process and analyzing the extracted peptides in NCBIprot database. The reductase activity of recombinant MMR in the presence of NADPH (as a cofactor) was examined through monitoring the UV-Vis absorption by NADPH at 340 nm during NADP+/ NADPH oxidation-reduction reaction. The stereospecific activity of recombinant MMR was analyzed through its interaction with (-)-menthone substrate using Chiral GC and GC-MS techniques. We observed the expected chirality (minus) in resulted menthol with 68% yield. [Display omitted] • Codon optimized sequence of MMR was designed by Vector- NTI software. • MMR was expressed in E. coli BL21 (DE3) and purified using Ni- NTA Chromatography. • Recombinant enzyme identification was explored by MALDI- TOF MS. • Enantioselective MMR activity was analyzed by GC- MS and Chiral GC. [ABSTRACT FROM AUTHOR]

Aim: Breast cancer is the most common cancer among women worldwide. Science has already proved that some breast cancer genes are inherited from parents. It is generally believed that the probability of cancer diagnosis in carriers of those genes is considerably higher than the normal population. It is in the same direction that modern medicine has introduced prophylactic mastectomy - one of the key preventive methods which is the focus of the present research. Nevertheless, whether women that have been diagnosed with breast cancer would take this approach depends on their local culture and their set of beliefs. In this regard, the present research was meant to evaluate the acceptability rate of prophylactic mastectomy among women in Iran after they are informed of the positive genetic test results.Methods: Six hundred and five healthy women, who had no history of breast cancer, were selected by nonprobability sampling method. A predesigned questionnaire was filled out by the interviewer.Results: Results showed that about 15% of respondents were willing to pick the prophylactic mastectomy in case they are identified as carriers of breast cancer genes. Twenty-two percent of participants with positive family history was agreed with prophylactic mastectomy while in the negative family history group it was about 14%.Conclusion: Preventive mastectomy has a higher rate of acceptability among women who have had a family history of breast cancer. Therefore, it may be concluded that raising public awareness about the advantages of prophylactic mastectomy could help better address breast cancer in Iran. [ABSTRACT FROM AUTHOR]

In recent years, recombinant monoclonal antibodies and their derivatives have emerged as important targeted therapy agents. Monoclonal antibodies are extremely difficult to produce. So, the cost of production is very high and many people cannot afford these drugs. In this regard, choosing inexpensive and easy ways to manipulate production systems such as bacterial hosts to reduce the cost of manufacturing these critical components are considered as vital step for developmental issues in recombinant expression systems. We, therefore, attempted to generate a polycistronic construct of anti HER-2 F(ab')2 fragment antibody for insertion in an expression bacterial plasmid. Also some modifications were made in the hinge region to express antibody F(ab')2 fragment in its authentic form preventing from multiple varieties of disulfide bond formation. Finally, synthesized construct was cloned in pET-32 Ek/LIC vector without using restriction enzyme digestion or ligation reactions. The results of this study showed that modified F(ab')2 fragment was simply and successfully inserted in Escherichia coli (E.coli) using the Ligation Independent Cloning technology. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of the current study is to evaluate the effect of silibinin on human hepatocellular carcinoma HepG-2 cells. Microculture tetrazolium test (MTT assay), Lactate dehydrogenase (LDH) release, Gelatin zymography, Griess reaction, Cell-based the extracelluar signal-regulated kinase (ERK) 1/2 phosphorylation assay and quantitative real-time RT-PCR were employed to appraise the effect of silibinin on cell proliferation, cytotoxicity, metastatic potential, nitric oxide (NO) production, ERK 1/2 phosphorylation and activation in HepG-2 cells. Silibinin inhibited cell proliferation, matrix metalloproteinase 2 enzymatic activity, NO production and ERK 1/2 phosphorylation in a dose-dependent manner without exerting any cytotoxicity effect. In addition, an expressive increase in mRNA levels of Raf kinase inhibitor protein (RKIP), sprouty-related protein 1 with EVH-1 domain (Spred-1), sprouty-related protein with EVH-1 domain 2 (Spred-2) coupled with a significant reduction in transcriptional levels of highly expressed in cancer (Hec1) and MMP-2 were observed. Altogether, these issues show for the first time that silibinin treatment could inhibit cell proliferation and invasive potential of HepG-2 cells through inhibition of ERK 1/2 cascade both directly (through suppression of ERK 1/2 phosphorylation) and indirectly (through up-regulation of RKIP, Spred-1 and Spred-2). In addition, cell growth and proliferation may be inhibited by silibinin through down-regulation of Hec1. [Copyright &y& Elsevier]

• 26 new quinazolin based antiproliferative and antiangiogenic agents are synthesized. • The proliferation rate of PC3 cells was reduced by 9f (IC 50 = 17.7 μ M) vs sorafenib (17.3 μ M). • CAM assay revealed that the growth of blood vessels was inhibited by 9f moderately. • Western blot analysis of 9f revealed the inhibition of VEGFR-2 phosphorylation. A series of quinazolin-4(3 H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC 50 = 17.7 μ M) which was comparable with sorafenib (IC 50 = 17.3 μ M). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC 50 = 6.1 μ M). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f , they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y. [ABSTRACT FROM AUTHOR]

In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC 50 > 200 µM) and excellent cytotoxic activity against A549 cell line with IC 50 value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC 50 = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC 50 = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV–Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in cancer therapy. [ABSTRACT FROM AUTHOR]

Inhibition of angiogenesis is a promising strategy for the treatment of cancer. Herein, we describe the design and synthesis of thieno[2,3- d pyrimidine-1,3,4-thiadiazole-aryl urea derivatives 11a-m to evaluate their efficacy in the chick chorioallantoic membrane (CAM) assay. Among target agents, 11i had a considerable activity against prostate cancer cell line, PC3 (IC 50 = 3.6 μ M). Moreover, induction of apoptosis, good inhibitory activity against the growth of capillary blood vessels, and inhibition of VEGFR-2 phosphorylation were noticeable parameters which convinced us that 11i could be considered as a promising candidate for the discovery of novel drugs to treat tumors, particularly prostate cancer. Image 1 • Thienopyrimidine-based compounds bearing the diaryl urea functionality were designed and synthesized. • 11i could inhibit the proliferation of PC3 cells by nearly 4-fold, respectively compared to sorafenib. • CAM assay revealed that the growth of blood vessels was inhibited by 11i tremendously. • Western blot analysis of 11i revealed the inhibition of VEGFR-2 phosphorylation. [ABSTRACT FROM AUTHOR]

A biocompatible fluorogenic chemosensor (N -(3-carboxy acryloyl)) rhodamine B (RHA) comprising a furan-2,5-dione receptor and a rhodamine fluorophore via an iminohydrazine crosslinker has been prepared for more scrutinizing optical properties and utilization in molecular imaging of living cells. The consequences indicated that RHA not only is a good pH indicator in acidic media but also can be used as a great sensitive fluoroionophore with high selectivity. The fluorescence emission of the molecule RHA is quite stable in the presence of 15 diverse cations, 18 anions (especially H 2 PO 4 −, S2, and F−), and 5 amino acids with the different functional group as a model, except Cu2+ ions with observable emission intensity changing. The Cu2+ probe has a dual functional effect, an "on-off" mechanism in solvent media, and an "off-on" mechanism in Phosphate Buffered Saline (PBS) in acidic pH conditions. The detection limits for Cu2+ in acetone-water media was 0.69 μM and 0.18 μM in pH = 5.0. Moreover, RHA can fluorescently and colorimetrically image Cu2+ ions in acidic and neutral pH with low cytotoxicity in living cells. Unlabelled Image • The rhodamine-based chemosensor (RHA) has distinct fluorescent properties. • The fluorophore selectively targeted at Cu2+ ions among 15 different cations, 18 anions (specially F-, S2- and H 2 PO 4 -), and 5 amino acids. • The unique fluoroionophore probe has a dual property in Cu2+ fluorescence responsiveness, which immediately responded to Cu2+ ions in natural pH based on the CHEQ mechanism and acidic pH through fluorescence enhancement. • This probe exhibits excellent membrane-permeable, low cytotoxicity, and good performance in the detection of Cu2+ in the MCF7 cell line. [ABSTRACT FROM AUTHOR]

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3- d ]pyrimidine and thieno[3,2- d ] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N -(4-((3,5-dichlorophenyl)amino)thieno[2,3- d ]pyrimidin-6-yl)cinnamamide 8e and (E)- N -(4-((3,4-dichlorophenyl)amino)thieno[2,3- d ]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC 50 values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds. Image 1 • Two series of thienopyrimidine-based compounds were designed and synthesized. • 8e was the most potent compound with nanomolar IC 50 value on HeLa cell line. • 8e was 720 times more selective on lung cancer cell than normal lung cell. • Western blot analysis of 8e revealed EGFR and ERK1/2 phosphorylation inhibition. [ABSTRACT FROM AUTHOR]

In this study, a simple and facile strategy was developed for the synthesis of novel hydroxyapatite (HA)/nanostructured monticellite ceramic composites by mechanical method. X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive x-ray spectroscopy (EDS) were used to peruse the phase structure, and morphology of soaked ceramic composites in simulated body fluid (SBF). The in vitro bioactivity of HA-based ceramic composites with nanostructured monticellite ranging from 0 to 50 wt% was evaluated via investigating the formation ability of bone-like calcium phosphates in SBF and the effect of obtained extracts from composites dissolution on osteoblast-like G-292 cell line. Moreover, In vitro cytocompatibility of the HA/monticellite ceramic composites was investigated by MTT, cell growth & adhesion and alkaline phosphatase (ALP) activity assays, and quantitative real-time PCR analysis. The results showed that HA/nanostructured monticellite ceramic composites could induce apatite formation in SBF. The cell proliferation and growth exposed to ceramic composites extracts were significantly stimulated and promoted at a certain concentration range compared to control for various time periods of cell culture. The optimized composite extract enhanced considerably gene expression of G-292 type X collagen (COLX) at different days. Also, G-292 cells were spread and adhered well on the ceramic composite disc. Furthermore, ALP activity of G-292 cells exposed to ceramic composites extracts was dramatically enhanced in comparison with pure HA extract (as control) at different concentrations for various time periods of cell culture. The results suggest that the optimized HA/nanostructured monticellite composite is promising biomaterial for clinical applications such as orthopedic and dentistry. Hydroxyapatite-based biomaterials with appropriate biocompatibility are promising for applications in orthopedic surgery and dentistry. However, there are still many efforts to enhance the biological responses of this biomaterial by further addition of other components. This study describes the biological effects of adding nanostructured monticellite bioceramic to hydroxyapatite. Unlabelled Image • A facile synthesis method was used for the novel composites of HA/monticellite. • The apatite forming ability enhanced with adding nanostructured monticellite to HA. • The biological effects of adding nanostructured monticellite to HA were investigated. • The COLX gene expression of G292 on optimized CC1 sample extract was performed. • The CC1 sample containing 10% monticellite showed the highest cytocompatibility. [ABSTRACT FROM AUTHOR]