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1.
Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. 总被引:10,自引:0,他引:10
Cherie-Ann O Nathan Nazanin Amirghahari Fleurette Abreo Xiaohua Rong Gloria Caldito M Lamar Jones Huijuan Zhou Melanie Smith Donnellan Kimberly Jonathan Glass 《Clinical cancer research》2004,10(17):5820-5827
PURPOSE: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway EXPERIMENTAL DESIGN: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. RESULTS: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (beta, gamma, and delta) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated alpha isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05). CONCLUSIONS: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins. 相似文献
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Danny E. Miller Kevin R. Cook Nazanin Yeganeh Kazemi Clarissa B. Smith Alexandria J. Cockrell R. Scott Hawley Casey M. Bergman 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(10):E1352-E1361
Multiply inverted balancer chromosomes that suppress exchange with their homologs are an essential part of the Drosophila melanogaster genetic toolkit. Despite their widespread use, the organization of balancer chromosomes has not been characterized at the molecular level, and the degree of sequence variation among copies of balancer chromosomes is unknown. To map inversion breakpoints and study potential diversity in descendants of a structurally identical balancer chromosome, we sequenced a panel of laboratory stocks containing the most widely used X chromosome balancer, First
Multiple 7 (FM7). We mapped the locations of FM7 breakpoints to precise euchromatic coordinates and identified the flanking sequence of breakpoints in heterochromatic regions. Analysis of SNP variation revealed megabase-scale blocks of sequence divergence among currently used FM7 stocks. We present evidence that this divergence arose through rare double-crossover events that replaced a female-sterile allele of the singed gene (snX2) on FM7c with a sequence from balanced chromosomes. We propose that although double-crossover events are rare in individual crosses, many FM7c chromosomes in the Bloomington Drosophila Stock Center have lost snX2 by this mechanism on a historical timescale. Finally, we characterize the original allele of the Bar gene (B1) that is carried on FM7, and validate the hypothesis that the origin and subsequent reversion of the B1 duplication are mediated by unequal exchange. Our results reject a simple nonrecombining, clonal mode for the laboratory evolution of balancer chromosomes and have implications for how balancer chromosomes should be used in the design and interpretation of genetic experiments in Drosophila.Balancer chromosomes are genetically engineered chromosomes that suppress crossing over with their homologs and are used for many purposes in genetics, including construction of complex genotypes, maintenance of stocks, and estimation of mutation rates. Balancers typically carry multiple inversions that suppress genetic exchange or result in the formation of abnormal meiotic products if crossing over does occur (Fig. 1A); for example, single crossovers inside the inverted segment create acentric or dicentric chromosomes that will fail to segregate properly during meiosis or large deletions or duplications that will likely result in inviable gametes (1, 2). Balancers also often carry recessive lethal or sterile mutations to prevent their propagation as homozygotes as well as dominant markers for easy identification. First developed for use in Drosophila melanogaster, balancer chromosomes remain some of the most powerful tools for genetic analysis in this species (3).Open in a separate windowFig. 1.Consequences of a single or double crossover between a WT X chromosome and an X chromosome carrying a single inversion, In(1)dl-49. Euchromatin is shown in blue, heterochromatin is shown in gray, and centromeres are depicted as circles. Thin white lines mark locations of inversion breakpoints, and yellow crosses/thin lines mark locations of crossover events. (A) A single crossover event within the inverted segment results in the formation of chromosomes with deletions and zero (acentric) centromeres or duplications and two (dicentric) centromeres, neither of which will segregate properly during meiosis. (B) A double crossover within an inverted segment results in intact chromosomes with one centromere that will segregate properly during meiosis.Despite their widespread use, very little is known about the organization of Drosophila balancer chromosomes at the molecular level. Since their original syntheses decades ago, balancers have undergone many manipulations, including the addition or removal of genetic markers. Moreover, rare recombination events can cause spontaneous loss of deleterious alleles on chromosomes kept over balancers in stock, as well as loss of marker alleles on balancer chromosomes themselves (3). Likewise, recent evidence has shown that sequence variants can be exchanged between balancer chromosomes and their wild type (WT) homologs via gene conversion during stock construction or maintenance (4, 5). Thus, substantial variation may exist among structurally identical balancer chromosomes owing to various types of sequence exchange.To gain insight into the structure and evolution of balancer chromosomes, we have undertaken a genomic analysis of the most commonly used X chromosome balancer in D. melanogaster, First Multiple 7 (FM7). We have focused on FM7 because this X chromosome balancer series lacks lethal mutations and thus can be easily sequenced in a hemizygous or homozygous state. In addition, the FM7 chromosome has been shown to pair normally along most of its axis with a standard X chromosome, providing a structural basis for possible exchange events (6). Moreover, although details of how early balancers in D. melanogaster were created are not fully recorded, the synthesis and cytology of the FM7 series is reasonably well documented (3).The earliest chromosome in the FM7 series, FM7a, was constructed using two progenitor X chromosome balancers, FM1 and FM6, to create a chromosome carrying three inversions—In(1)sc8, In(1)dl-49, and In(1)FM6—relative to the WT configuration (7, 8) (Fig. 2A). Subsequently, a female-sterile allele of singed (snX2) was introduced onto FM7a to create FM7c, which prevents the loss of balanced chromosomes carrying recessive lethal or female-sterile mutations (9). More recently, versions of FM7a and FM7c have been generated that carry transgene insertions that allow the determination of balancer genotypes in embryonic or pupal stages (10–14).Open in a separate windowFig. 2.Structure of the FM7 balancer chromosome. Euchromatin is shown in blue, and heterochromatin is shown in gray. (A) Schematic view of the organization of WT and FM7 X chromosomes. FM7 contains three inversions—In(1)sc8, In(1)dl-49, and In(1)FM6—relative to WT. The six breakpoint junctions for the three inversions are numbered 1–6 and are shown in detail in B. (B) Location and organization of inversion breakpoints in FM7. Each inversion has two breakpoints that can be represented as A/B and C/D in the standard WT arrangement and as A/C and B/D in the inverted FM7 arrangement, where A, B, C, and D represent the sequences on either side of the breakpoints. Locations of euchromatic breakpoints are on Release 5 genome coordinates, and the identity of the best BLAST match in FlyBase is shown for heterochromatic sequences. Primers used for PCR amplification are shown above each breakpoint; details are provided in Methods and Datasets S2 and S3. Forward and reverse primers are named with respect to the orientation of the assembled breakpoint contigs, not the orientation of the WT or FM7 X chromosome.To identify the inversion breakpoints in FM7 balancers and to study patterns of sequence variation that may have arisen since the origin of the FM7 series, we sequenced genomes of eight D. melanogaster stocks carrying the FM7 chromosome (four FM7a and four FM7c). We discovered several megabase-scale regions in which FM7c chromosomes differ from one another, which presumably arose via double-crossover (DCO) events from balanced chromosomes (Fig. 1B). These DCOs eliminate the female-sterile snX2 allele in the centrally located In(1)dl-49 inversion and are expected to confer a fitness advantage to sn+ chromosomes, either by allowing propagation of sn+
FM7 as homozygotes in females or by sn+
FM7 males outcompeting snX2
FM7 males in culture. We found that loss of the snX2 allele is common in FM7c chromosomes by screening other FM7c-carrying stocks at the Bloomington Drosophila Stock Center. We also identified the breakpoints of the B1 duplication carried on FM7, and found direct molecular evidence for the role of unequal exchange in the origin and reversion of the B1 allele (15–19). Our results provide clear evidence that the common assumption that balancers are fully nonrecombining chromosomes is incorrect on a historical timescale, and that substantial sequence variation exists among balancer chromosomes in circulation today. 相似文献
6.
Mehdi Esfandyari-Manesh Seyed Hossein Mostafavi Reza Faridi Majidi Mona Noori Koopaei Nazanin Shabani Ravari Mohsen Amini Behrad Darvishi Seyed Nasser Ostad Fatemeh Atyabi Rassoul Dinarvand 《Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences》2015,23(1)
Background
Nanoparticles (NPs) play an important role in anticancer delivery systems. Surface modified NPs with hydrophilic polymers such as human serum albumin (HSA) have long half-life in the blood circulation system.Methods
The method of modified nanoprecipitation was utilized for encapsulation of paclitaxel (PTX) in poly (lactic-co-glycolic acid) (PLGA). Para-maleimide benzoic hydrazide was conjugated to PLGA for the surface modifications of PLGA NPs, and then HSA was attached on the surface of prepared NPs by maleimide attachment to thiol groups (cysteines) of albumin. The application of HSA provides for the longer blood circulation of stealth NPs due to their escape from reticuloendothelial system (RES). Then the physicochemical properties of NPs like surface morphology, size, zeta potential, and in-vitro drug release were analyzed.Results
The particle size of NPs ranged from 170 to 190 nm and increased about 20–30 nm after HSA conjugation. The zeta potential was about -6 mV and it decreased further after HSA conjugation. The HSA conjugation in prepared NPs was proved by Fourier transform infrared (FT-IR) spectroscopy, faster degradation of HSA in Differential scanning calorimetry (DSC) characterization, and other evidences such as the increasing in size and the decreasing in zeta potential. The PTX released in a biphasic mode for all colloidal suspensions. A sustained release profile for approximately 33 days was detected after a burst effect of the loaded drug. The in vitro cytotoxicity evaluation also indicated that the HSA NPs are more cytotoxic than plain NPs.Conclusions
HSA decoration of PLGA NPs may be a suitable method for longer blood circulation of NPs. 相似文献7.
Nazanin Zand Babur Z. Chowdhry Lucie V. Pollard Frank S. Pullen Martin J. Snowden Francis B. Zotor 《Maternal & child nutrition》2015,11(2):202-214
Quantitative analyses of the macronutrient content of eight popular commercial ‘ready‐to‐feed’ baby meals for 6–9‐month old infants in the UK market have been undertaken in order to ascertain their nutritional suitability in relation to the total daily dietary intake as well as nutritional profiling of the products. The chemical analyses conducted included Kjeldhal for protein, acid hydrolysis and extraction for fat, phenol sulphuric acid for carbohydrate and Association of Official Analytical Chemists 985.29 for fibre. The only difference found between different varieties (meat‐ and vegetable‐based) was with respect to the protein content (P = 0.04) per 100 g of food. The experimentally determined concentrations of macronutrients (g/100 kcal) were compared with the declared values provided by the manufacturers on the product labels and, despite some variations, the values obtained comply with regulatory requirements (Commission Directive 2006/125/EC). The total daily intake of fat (27.0 g per day) – based on the menu composed from commercial complementary food – is suggested to exceed the daily recommended values for fat (31%), if the intake of snacks and desserts are incorporated. These findings imply that the formulation of recipes, based on a standard commercial menu, is an important consideration in relation to the nutritional quality of the diet of infants. 相似文献
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Asvadi Nazanin Hajarol Afshari Mirak Sohrab Mohammadian Bajgiran Amirhossein Khoshnoodi Pooria Wibulpolprasert Pornphan Margolis Daniel Sisk Anthony Reiter Robert E. Raman Steven S. 《Abdominal imaging》2018,43(11):3117-3124
Abdominal Radiology - To evaluate 3T mpMRI characteristics of transition zone and peripheral zone index prostate cancer lesions stratified by Gleason Score and PI-RADSv2 with whole mount... 相似文献
9.
Nazanin Navabi Malin E. V. Johansson Sukanya Raghavan Sara K. Lindén 《Infection and immunity》2013,81(3):829-837
To protect the surface of the stomach, the epithelial cells secrete a mucus layer, which is mainly comprised of the MUC5AC mucin. Further protection is provided by a thick glycocalyx on the apical surface of the epithelial cell, with the cell surface mucin MUC1 as a major component. Here, we investigate the production rate and turnover of newly synthesized mucin in mice and analyze the effects of early colonization and chronic infection with H. pylori. Metabolic incorporation of an azido GalNAc analog (GalNAz) was used as a nonradioactive method to perform pulse experiments in the whole animal. First, the subcellular movement of newly synthesized mucin and mucin turnover was determined in uninfected mice. Based on the time line for mucin transport and dissemination, 2, 6, and 12 h after GalNAz injection was selected to collect the stomachs from mice infected with H. pylori strain SS1 during early colonization (7 days) and chronic infection (90 days). The results demonstrated that the speed from the start of glycosylation to the final destination is faster for the membrane-bound mucin to reach the glycocalyx (2 h) than for the secretory mucins to become secreted into the mucus layer (5 h). Furthermore, infection with H. pylori reduces the rate of mucin turnover and decreases the levels of Muc1. Since H. pylori colonizes this mucus niche, the decreased turnover rate indicates that H. pylori creates a more stable and favorable environment for itself by impairing the defense mechanism for clearing the mucosal surface of pathogens by mucus flow. 相似文献
10.
Nazanin Zounemat Kermani Mansoor Saqi Paul Agapow Stelios Pavlidis Chihhsi Kuo Kai Sen Tan Sharon Mumby Kai Sun Matthew Loza Frederic Baribaud Ana R. Sousa John Riley Asa M. Wheelock Craig E. Wheelock Bertrand De Meulder Jim Schofield Stephany Sánchez-Ovando Jodie Louise Simpson Katherine Joanne Baines Peter A. Wark Charles Auffray Sven-Erik Dahlen Peter J. Sterk Ratko Djukanovic Ian M. Adcock Yi-ke Guo Kian Fan Chung U-BIOPRED Project Team 《Allergy》2021,76(1):380-383