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Sample records for molecular target size

  1. A low molecular weight artificial RNA of unique size with multiple probe target regions

    NASA Technical Reports Server (NTRS)

    Pitulle, C.; Dsouza, L.; Fox, G. E.

    1997-01-01

    Artificial RNAs (aRNAs) containing novel sequence segments embedded in a deletion mutant of Vibrio proteolyticus 5S rRNA have previously been shown to be expressed from a plasmid borne growth rate regulated promoter in E. coli. These aRNAs accumulate to high levels and their detection is a promising tool for studies in molecular microbial ecology and in environmental monitoring. Herein a new construct is described which illustrates the versatility of detection that is possible with aRNAs. This 3xPen aRNA construct carries a 72 nucleotide insert with three copies of a unique 17 base probe target sequence. This aRNA is 160 nucleotides in length and again accumulates to high levels in the E. coli cytoplasm without incorporating into ribosomes. The 3xPen aRNA illustrates two improvements in detection. First, by appropriate selection of insert size, we obtained an aRNA which provides a unique and hence, easily quantifiable peak, on a high resolution gel profile of low molecular weight RNAs. Second, the existence of multiple probe targets results in a nearly commensurate increase in signal when detection is by hybridization. These aRNAs are naturally amplified and carry sequence segments that are not found in known rRNA sequences. It thus may be possible to detect them directly. An experimental step involving RT-PCR or PCR amplification of the gene could therefore be avoided.

  2. A low molecular weight artificial RNA of unique size with multiple probe target regions

    NASA Technical Reports Server (NTRS)

    Pitulle, C.; Dsouza, L.; Fox, G. E.

    1997-01-01

    Artificial RNAs (aRNAs) containing novel sequence segments embedded in a deletion mutant of Vibrio proteolyticus 5S rRNA have previously been shown to be expressed from a plasmid borne growth rate regulated promoter in E. coli. These aRNAs accumulate to high levels and their detection is a promising tool for studies in molecular microbial ecology and in environmental monitoring. Herein a new construct is described which illustrates the versatility of detection that is possible with aRNAs. This 3xPen aRNA construct carries a 72 nucleotide insert with three copies of a unique 17 base probe target sequence. This aRNA is 160 nucleotides in length and again accumulates to high levels in the E. coli cytoplasm without incorporating into ribosomes. The 3xPen aRNA illustrates two improvements in detection. First, by appropriate selection of insert size, we obtained an aRNA which provides a unique and hence, easily quantifiable peak, on a high resolution gel profile of low molecular weight RNAs. Second, the existence of multiple probe targets results in a nearly commensurate increase in signal when detection is by hybridization. These aRNAs are naturally amplified and carry sequence segments that are not found in known rRNA sequences. It thus may be possible to detect them directly. An experimental step involving RT-PCR or PCR amplification of the gene could therefore be avoided.

  3. Molecular target size of the vanilloid (capsaicin) receptor in pig dorsal root ganglia

    SciTech Connect

    Szallasi, A.; Blumberg, P.M. )

    1991-01-01

    The size of the vanilloid receptor was examined by high-energy radiation inactivation analysis of the binding of ({sup 3}H)resiniferatoxin to pig dorsal root ganglion membranes; it was found to be 270 {plus minus} 25 kDa. This value most likely represents the size of a receptor complex rather than of an individual subunit. Other ligand-gated cation channel complexes have reported molecular weights in this range, e.g. 300 kDa for the acetylcholine receptor.

  4. Small Molecular-Sized Artesunate Attenuates Ocular Neovascularization via VEGFR2, PKCα, and PDGFR Targets

    PubMed Central

    Zong, Yao; Yuan, Yongguang; Qian, Xiaobing; Huang, Zhen; Yang, Wei; Lin, Leilei; Zheng, Qishan; Li, Yujie; He, Huining; Gao, Qianying

    2016-01-01

    Ocular neovascularization (NV) is the primary cause of blindness in many ocular diseases. Large molecular weight anti- vascular endothelial growth factor (VEGF) protein drugs, such as Avastin and Lucentis, have saved the vision of millions. However, approximately 20–30% of patients respond poorly to anti-VEGF treatment. We found that artesunate (ART), a small molecular derivative of artemisinin, had a significant inhibitory effect on ocular NV by downregulating the expression of VEGFR2, PKCα, and PDGFR. ART significantly inhibited retinal NV in rabbits and macular edema in monkeys with greater anterior chamber penetrability and more durable efficacy than Avastin. Our pilot study showed that intravitreal injection of 80 μg ART significantly inhibited iris and corneal NV in a severe retinal detachment case. Our results suggest that ART might be a potential persistent small-molecule drug to manage ocular NV via multi-targets. PMID:27480521

  5. Molecular Targeting of CEACAM6 Using Antibody Probes of Different Sizes

    PubMed Central

    Niu, Gang; Murad, Yanal M.; Gao, Haokao; Hu, Shuo; Guo, Ning; Jacobson, Orit; Nguyen, Thanh-Dung; Zhang, Jianbing; Chen, Xiaoyuan

    2012-01-01

    Carcinocinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is overexpressed in a number of human malignancies, especially in pancreatic cancer. It has been demonstrated that CEACAM6 is a potential target for monoclonal antibody (mAb) therapy with a safe therapeutic index. Here, we labeled three anti-CEACAM6 antibodies of different sizes, including a single-domain antibody 2A3 (16 kDa), a heavy chain antibody 2A3-mFc (80 kDa) and a full length antibody 9A6 (150 kDa), with 64Cu to image CEACAM6 expression in a xenografted pancreatic tumor model. For positron emission tomography (PET) imaging, the tumor mice were intravenously injected with 64Cu-DOTA-antibodies and static scans were obtained at 5 min, 0.5, 1, 2, 4, 8 and 24 h post-injection (p.i.). All three antibodies showed strong CEACAM6 binding. Ex vivo immunostaining on tumor sections at 24 h after Ab injection demonstrated specific tumor targeting of both 2A3-mFc and 9A6. 64Cu-DOTA-2A3 showed fast BxPC3 tumor uptake and rapid whole-body clearance. At 24 h p.i., the tumor uptakes were 98.2 ± 6.12 %ID/g for 64Cu-DOTA-2A3-mFc and 57.8 ± 3.73 %ID/g for 64Cu-DOTA-9A6, respectively. Compared with the full length antibody 9A6, the heavy chain antibody 2A3-mFc showed higher tumor uptake, lower liver uptake and shorter circulation half-life. All the data supported that the heavy chain antibody 2A3-mFc is superior to the single domain antibody and the full-length antibody with regard to tumor detection and pharmacokinetics, which has great potential to be developed for CEACAM6-targeted pancreatic cancer imaging and therapy. PMID:22568933

  6. Radiation inactivation (target size analysis) of the gonadotropin-releasing hormone receptor: evidence for a high molecular weight complex

    SciTech Connect

    Conn, P.M.; Venter, J.C.

    1985-04-01

    In the present study we used radiation inactivation (target size analysis) to measure the functional mol wt of the GnRH receptor while it is still a component of the plasma membrane. This technique is based on the observation that an inverse relationship exists between the dose-dependent inactivation of a macromolecule by ionizing radiation and the size of that macromolecule. This method demonstrates a mol wt of 136,346 +/- 8120 for the GnRH receptor. This estimate is approximately twice that obtained (60,000) by photoaffinity labeling with a radioactive GnRH analog followed by electrophoresis under denaturing conditions and, accordingly, presents the possibility that the functional receptor consists of a high mol wt complex in its native state. The present studies indicate that the GnRH receptor is either a single weight class of protein or several closely related weight classes, such as might occur due to protein glycosylation.

  7. Molecular dynamics simulations to explore the effect of projectile size on the ejection of organic targets from metal surfaces

    NASA Astrophysics Data System (ADS)

    Zaric, Radomir; Pearson, Brenda; Krantzman, Kristin D.; Garrison, Barbara J.

    1998-03-01

    Experiments have shown that cluster projectiles as compared to atomic projectiles enhance the secondary ion emission of organic molecules. The yield depends nonlinearly on the number of constituent atoms in the primary ion cluster. In this paper, we describe molecular dynamic simulations aimed at determining the fundamental mechanisms responsible for the enhancement in emission yield. Our model system, a biphenyl adsorbate on a Cu(001) surface, is chosen as a prototype of the experimental systems of interest. Cu atoms and Cun clusters with n = 2-4 and kinetic energies from 0.050 to 0.100 keV per atom are brought in at 45[degree sign] incidence. The emission yield of the biphenyl molecule increases nonlinearly with the number of atoms in the cluster. Several parts of the biphenyl molecule must be hit in order for it to be ejected intact. A monatomic projectile initially strikes one atom in the top surface layer, while a polyatomic projectile initially strikes two or more atoms. Therefore, with the cluster projectile, there will be a greater probability of two or more collision cascades that are adjacent in time and space and can collaborate to eject the molecule from the surface.

  8. Molecular Size and Raoult's Law.

    ERIC Educational Resources Information Center

    Kovac, Jeffrey

    1985-01-01

    The concept of an ideal solution is ordinarily introduced in freshman chemistry by means of Raoult's Law, which states that the vapor pressure of a volatile component of a solution is proportional to its mole fraction. The relationship of this law to molecular size is discussed. (JN)

  9. Molecular-sized fluorescent nanodiamonds

    NASA Astrophysics Data System (ADS)

    Vlasov, Igor I.; Shiryaev, Andrey A.; Rendler, Torsten; Steinert, Steffen; Lee, Sang-Yun; Antonov, Denis; Vörös, Márton; Jelezko, Fedor; Fisenko, Anatolii V.; Semjonova, Lubov F.; Biskupek, Johannes; Kaiser, Ute; Lebedev, Oleg I.; Sildos, Ilmo; Hemmer, Philip. R.; Konov, Vitaly I.; Gali, Adam; Wrachtrup, Jörg

    2014-01-01

    Doping of carbon nanoparticles with impurity atoms is central to their application. However, doping has proven elusive for very small carbon nanoparticles because of their limited availability and a lack of fundamental understanding of impurity stability in such nanostructures. Here, we show that isolated diamond nanoparticles as small as 1.6 nm, comprising only ~400 carbon atoms, are capable of housing stable photoluminescent colour centres, namely the silicon vacancy (SiV). Surprisingly, fluorescence from SiVs is stable over time, and few or only single colour centres are found per nanocrystal. We also observe size-dependent SiV emission supported by quantum-chemical simulation of SiV energy levels in small nanodiamonds. Our work opens the way to investigating the physics and chemistry of molecular-sized cubic carbon clusters and promises the application of ultrasmall non-perturbative fluorescent nanoparticles as markers in microscopy and sensing.

  10. [Molecular targets in colon cancer].

    PubMed

    Borner, M M

    2006-04-01

    Colorectal cancer is the second leading cause of cancer death in Switzerland. The nihilism that dominated the treatment of these patients for decades has been replaced by a measure of enthusiasm, given recent therapeutic advances. New anticancer drugs such as irinotecan and oxaliplatin have changed the standard chemotherapy treatment of metastatic colorectal cancer. However, the real hype has come from molecular targeted therapy. Identification of cellular processes characteristic of colon cancer has permitted therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients has therapeutic potential. Angiogenesis, especially the vascular endothelial growth factor pathway, has been proven to be another highly successful molecular target. In this article, we will review molecular targets, which are under active clinical investigation in colon cancer.

  11. Cardiotoxicity of Molecularly Targeted Agents

    PubMed Central

    Hedhli, Nadia; Russell, Kerry S

    2011-01-01

    Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics. PMID:22758623

  12. Spatiotopic buildup of saccade target representation depends on target size.

    PubMed

    Zimmermann, Eckart

    2016-12-01

    How we maintain spatial stability across saccade eye movements is an open question in visual neuroscience. A phenomenon that has received much attention in the field is our seemingly poor ability to discriminate the direction of transsaccadic target displacements. We have recently shown that discrimination performance increases the longer the saccade target has been previewed before saccade execution (Zimmermann, Morrone, & Burr, 2013). We have argued that the spatial representation of briefly presented stimuli is weak but that a strong representation is needed for transsaccadic, i.e., spatiotopic localization. Another factor that modulates the representation of saccade targets is stimulus size. The representation of spatially extended targets is more noisy than that of point-like targets. Here, I show that the increase in transsaccadic displacement discrimination as a function of saccade target preview duration depends on target size. This effect was found for spatially extended targets-thus replicating the results of Zimmermann et al. (2013)-but not for point-like targets. An analysis of saccade parameters revealed that the constant error for reaching the saccade target was bigger for spatially extended than for point-like targets, consistent with weaker representation of bigger targets. These results show that transsaccadic displacement discrimination becomes accurate when saccade targets are spatially extended and presented longer, thus resembling closer stimuli in real-world environments.

  13. Targeted Molecular Therapies for SBMA.

    PubMed

    Rinaldi, Carlo; Malik, Bilal; Greensmith, Linda

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset neuromuscular disease caused by a polyglutamine expansion in the androgen receptor gene which results in progressive spinal and bulbar motor neuron degeneration, and muscle atrophy. Although the causative genetic defect is known, until recently, the molecular pathogenesis of the disease was unclear, resulting in few, if any, targets for therapy development. However, over the past decade, our understanding of the pathomechanisms that play a role in SBMA has increased dramatically, and several of these pathways and mechanisms have now been investigated as possible therapeutic targets. In this review, we discuss some of the key pathomechanisms implicated in SBMA and describe some of the therapeutic strategies that have been tested in SBMA to date, which fall into four main categories: (i) gene silencing; (ii) protein quality control and/or increased protein degradation; (iii) androgen deprivation; and (iv) modulation of AR function. Finally, it is also now clear that in addition to a greater understanding of the molecular mechanisms that underlie disease, the development of an effective disease modifying therapy for SBMA will require the coordinated, collaborative effort of research teams with diverse areas of expertise, clinicians, pharmaceutical companies as well as patient groups.

  14. Molecular structure of rat brain apamin receptor: differential photoaffinity labeling of putative K/sup +/ channel subunits and target size analysis

    SciTech Connect

    Seagar, M.J.; Labbe-Jullie, C.; Granier, C.; Goll, A.; Glossmann, H.; Rietschoten, J.V.; Couraud, F.

    1986-07-01

    Two photoreactive apamin derivatives were prepared with an aryl azide group coupled at different positions on the neurotoxin molecule. These ligands were used to identify membrane components in the environment of the neuronal binding site that is associated with a Ca/sup 2 +/-activated K/sup +/ channel. /sup 125/I-(..cap alpha..-ANPAA-Cys/sub 1/)apamin labeled a single M/sub r/ 86,000 chain in cultured neurons whereas two bands corresponding to M/sub r/ 86,000 and 59,000 were detected in synaptic membrane preparations, suggesting that the M/sub r/ 59,000 polypeptide may be a degradation product. Randomly modified /sup 125/I-ANPAA-apamin gave a cross-linking profile equivalent to the sum of those obtained with the two defined derivatives. The apamin binding site seems to be located at the frontier between three or more putative K/sup +/ channel subunits which are only accessible from limited regions of the receptor-associated photoprobe. Irradiation of frozen rat brain membranes with high-energy electrons led to a reduction in /sup 125/I-apamin receptor capacity, yielding a target size for the functional binding unit of M/sub r/ 84,000-115,000, which could be constituted by the M/sub r/ 86,000 subunit alone or by the M/sub r/ 86,000 subunit in conjunction with one of the two smaller subunits.

  15. Tamoxifen Resistance: Emerging Molecular Targets

    PubMed Central

    Rondón-Lagos, Milena; Villegas, Victoria E.; Rangel, Nelson; Sánchez, Magda Carolina; Zaphiropoulos, Peter G.

    2016-01-01

    17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer. PMID:27548161

  16. Tamoxifen Resistance: Emerging Molecular Targets.

    PubMed

    Rondón-Lagos, Milena; Villegas, Victoria E; Rangel, Nelson; Sánchez, Magda Carolina; Zaphiropoulos, Peter G

    2016-08-19

    17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM's biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein-coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer.

  17. Molecular size of aquatic humic substances

    USGS Publications Warehouse

    Thurman, E.M.; Wershaw, R. L.; Malcolm, R.L.; Pinckney, D.J.

    1982-01-01

    Aquatic humic substances, which account for 30 to 50% of the organic carbon in water, are a principal component of aquatic organic matter. The molecular size of aquatic humic substances, determined by small-angle X-ray scattering, varies from 4.7 to 33 A?? in their radius of gyration, corresponding to a molecular weight range of 500 to greater than 10,000. The aquatic fulvic acid fraction contains substances with molecular weights ranging from 500 to 2000 and is monodisperse, whereas the aquatic humic acid fraction contains substances with molecular weights ranging from 1000 to greater than 10,000 and is generally polydisperse. ?? 1982.

  18. Ion channels: molecular targets of neuroactive insecticides.

    PubMed

    Raymond-Delpech, Valérie; Matsuda, Kazuhiko; Sattelle, Benedict M; Rauh, James J; Sattelle, David B

    2005-11-01

    Many of the insecticides in current use act on molecular targets in the insect nervous system. Recently, our understanding of these targets has improved as a result of the complete sequencing of an insect genome, i.e., Drosophila melanogaster. Here we examine the recent work, drawing on genetics, genomics and physiology, which has provided evidence that specific receptors and ion channels are targeted by distinct chemical classes of insect control agents. The examples discussed include, sodium channels (pyrethroids, p,p'-dichlorodiphenyl-trichloroethane (DDT), dihydropyrazoles and oxadiazines); nicotinic acetylcholine receptors (cartap, spinosad, imidacloprid and related nitromethylenes/nitroguanidines); gamma-aminobutyric acid (GABA) receptors (cyclodienes, gamma-BHC and fipronil) and L-glutamate receptors (avermectins). Finally, we have examined the molecular basis of resistance to these molecules, which in some cases involves mutations in the molecular target, and we also consider the future impact of molecular genetic technologies in our understanding of the actions of neuroactive insecticides.

  19. Molecularly Targeted Therapies for Malignant Gliomas

    PubMed Central

    Argyriou, Andreas A; Kalofonos, Haralabos P

    2009-01-01

    This review critically evaluates current knowledge of molecularly targeted therapies of malignant gliomas. Various molecularly targeted single-agent therapies, including targeted therapies of growth and survival, have been evaluated in clinical trials but have failed to demonstrate a significant survival benefit compared with standard treatment regimens. The efficacy of multi-targeted kinase inhibitors or combinations of single-targeted kinase inhibitors is a promising strategy, but requires additional clinical evaluation before definitive conclusions can be made. Important areas for further research include the assessment of serum or tissue biomarkers, the elucidation of prognostic molecular markers, and the determination of whether the mechanism of action of a drug is appropriate to the genetic alterations observed within individual tumors. PMID:19148300

  20. Molecularly targeted therapies for recurrent glioblastoma: current and future targets

    PubMed Central

    Lau, Darryl; Magill, Stephen T.; Aghi, Manish K.

    2016-01-01

    Object Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma. Methods A systematic search was performed with the phrase “(name of particular agent) and glioblastoma” as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies. Results A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10–15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%–20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%–20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied

  1. Conotoxins: Molecular and Therapeutic Targets

    NASA Astrophysics Data System (ADS)

    Lewis, Richard J.

    Marine molluscs known as cone snails produce beautiful shells and a complex array of over 50,000 venom peptides evolved for prey capture and defence. Many of these peptides selectively modulate ion channels and transporters, making them a valuable source of new ligands for studying the role these targets play in normal and disease physiology. A number of conopeptides reduce pain in animal models, and several are now in pre-clinical and clinical development for the treatment of severe pain often associated with diseases such as cancer. Less than 1% of cone snail venom peptides are pharmacologically characterised.

  2. [Molecular targeted therapy in lymphoid leukemias].

    PubMed

    Kojima, Kensuke; Ando, Toshihiko; Kimura, Shinya

    2014-06-01

    Recent advances in the treatment of lymphoid leukemias have incorporated molecular targeted drugs (CD20-targeting rituximab and BCR-ABL tyrosine kinase inhibitors) into the traditional chemotherapeutic agents. This article reviews novel molecular targeted therapies for patients with lymphoid leukemias including acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairly cell leukemia and HTLV-I-related adult T-cell leukemia. Investigational agents that will be discussed in this review include inotuzumab, blinatumomab, alemtuzumab, ofatumumab, ibrutinib, idelalisib, bafetinib, lenalidomide, ABT-199 and mogamulizumab. Novel approaches warrant continued research to improve outcomes for patients with lymphoid leukemias.

  3. Molecular targeting for malignant gliomas (Review).

    PubMed

    Kondo, Yasuko; Hollingsworth, Emporia F; Kondo, Seiji

    2004-05-01

    With tendency to invade rapidly in the brain, malignant gliomas are very resistant to conventional therapies including radiation and chemotherapy. Recent advances in genetic and molecular techniques have made it possible to define characteristic molecular profiles of malignant gliomas. Based on the list of the molecules closely related to glioblastoma tissues, we reviewed strategies targeting them. Target molecules extensively studied include EGFR, PTEN, telomerase and signal pathway modulators for Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Therapies targeting specific molecules may result in killing tumor cells effectively while keeping normal cells intact.

  4. Molecular tweezers targeting transthyretin amyloidosis.

    PubMed

    Ferreira, Nelson; Pereira-Henriques, Alda; Attar, Aida; Klärner, Frank-Gerrit; Schrader, Thomas; Bitan, Gal; Gales, Luís; Saraiva, Maria João; Almeida, Maria Rosário

    2014-04-01

    Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.

  5. Molecular Targets of Cannabidiol in Neurological Disorders.

    PubMed

    Ibeas Bih, Clementino; Chen, Tong; Nunn, Alistair V W; Bazelot, Michaël; Dallas, Mark; Whalley, Benjamin J

    2015-10-01

    Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases

  6. The molecular targets of resveratrol.

    PubMed

    Kulkarni, Sameer S; Cantó, Carles

    2015-06-01

    Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratrol treatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrol exerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

  7. A Targeting Microbubble for Ultrasound Molecular Imaging

    PubMed Central

    Yeh, James Shue-Min; Sennoga, Charles A.; McConnell, Ellen; Eckersley, Robert; Tang, Meng-Xing; Nourshargh, Sussan; Seddon, John M.; Haskard, Dorian O.; Nihoyannopoulos, Petros

    2015-01-01

    Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described

  8. Class-Size Limits Targeted for Cuts

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2010-01-01

    At a time when policymakers are demanding budget cuts and more innovative approaches to schooling, pressure is building for loosening up constraints on class sizes. After dropping for decades, average class sizes in American schools may be growing again as schools cope with budget shortfalls. Although some educators see the rising numbers as a…

  9. Influence of molecular size on tissue distribution of antibody fragments

    PubMed Central

    Li, Zhe; Krippendorff, Ben-Fillippo; Sharma, Sharad; Walz, Antje C.; Lavé, Thierry; Shah, Dhaval K.

    2016-01-01

    Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues. PMID:26496429

  10. Influence of molecular size on tissue distribution of antibody fragments.

    PubMed

    Li, Zhe; Krippendorff, Ben-Fillippo; Sharma, Sharad; Walz, Antje C; Lavé, Thierry; Shah, Dhaval K

    2016-01-01

    Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.

  11. [Non oncologic applications of molecular targeted therapies].

    PubMed

    Khaled, Wassef; de la Motte Rouge, Thibault; Amirault, Jean-Christophe; Vignot, Stéphane

    2012-10-01

    Significant improvements in the knowledge of cancer biology have permitted the development of new molecular targeted therapies. Meanwhile, a better understanding of the physiology of various non-cancerous diseases has allowed developing these agents in other areas. This review intends to illustrate these perspectives through examples corresponding to different strategies of molecular-targeted therapies : use of a monoclonal antibody binding a receptor (rituximab and rheumatoid arthritis) or a ligand (bevacizumab and age-related macular degeneration), tyrosine kinase inhibitor (imatinib and systemic sclerosis) or inhibitor of cytoplasmic signal transduction pathways (immunosuppressive and antiproliferative effects of mammalian target of rapamycin [mTOR] inhibitors). Clinical results can draw today what could become molecular medicine of tomorrow.

  12. Molecularly targeted therapies for acute myeloid leukemia.

    PubMed

    Stein, Eytan M

    2015-01-01

    The past 15 years have seen major leaps in our understanding of the molecular genetic mutations that act as drivers of acute myeloid leukemia (AML). Clinical trials of agents against specific mutant proteins, such as FLT3-internal tandem duplications (ITDs) and isocitrate dehydrogenase mutations (IDHs) are ongoing. This review discusses agents in clinical trials that target specific gene mutations and/or epigenetic targets. © 2015 by The American Society of Hematology. All rights reserved.

  13. Experience with block targets of small size

    SciTech Connect

    van den Brandt, B.; Konter, J.A.; Mango, S.; Webler, M. )

    1989-05-05

    The polarized proton and deuteron targets using alcohols doped with porphyrexide are made. This fabrication takes place in a He-3 refrigerator, representing an attractive alternative to the standard beads. A single measurement of the polarization gave the preliminary result of 55%.(AIP)

  14. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  15. [Anti-angiogenesis and molecular targeted therapies].

    PubMed

    Miyanaga, Akihiko; Gemma, Akihiko

    2015-08-01

    Tumor angiogenesis contributes to the development of tumor progression. Several vascular endothelial growth factor(VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. In particular, bevacizumab is a humanized monoclonal antibody that specifically targets VEGF, inhibiting angiogenesis, thereby impeding tumor growth and survival. It is also possible that combined VEGF and the epidermal growth factor (EGFR) pathway blockade could further enhance antitumor efficacy and help prevent resistance to therapy. Preclinical and clinical studies have shown new various molecular targets and the functional characteristics of tumor angiogenesis, which may provide strategies for improving the therapeutic benefit.

  16. Promising molecular targeted therapies in breast cancer

    PubMed Central

    Munagala, Radha; Aqil, Farrukh; Gupta, Ramesh C.

    2011-01-01

    In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials. PMID:21713084

  17. Promising molecular targeted therapies in breast cancer.

    PubMed

    Munagala, Radha; Aqil, Farrukh; Gupta, Ramesh C

    2011-05-01

    In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.

  18. Size-varying small target detection for infrared image processing

    NASA Astrophysics Data System (ADS)

    Li, Miao; Zhu, Ran; Long, Yunli; An, Wei; Zhou, Yiyu

    2015-10-01

    IRST (Infrared Search and Track) has been applied to many military or civil fields such as precise guidance, aerospace, early warning. As a key technique, small target detection based on infrared image plays an important role. However, infrared targets have their own characteristics, such as target size variation, which make the detection work quite difficult. In practical application, the target size may vary due to many reasons, such as optic angle of sensors, imaging distance, environment and so on. For conventional detection methods, it is difficult to detect such size-varying targets, especially when the backgrounds have strong clutters. This paper presents a novel method to detect size-varying infrared targets in a cluttered background. It is easy to find that the target region is salient in infrared images. It means that target region have a signature of discontinuity with its neighboring regions and concentrates in a relatively small region, which can be considered as a homogeneous compact region, and the background is consistent with its neighboring regions. Motivated by the saliency feature and gradient feature, we introduce minimum target intensity (MTI) to measure the dissimilarity between different scales, and use mean gradient to restrict the target scale in a reasonable range. They are integrated to be multiscale MTI filter. The proposed detection method is designed based on multiscale MTI filter. Firstly, salient region is got by morphological low-pass filtering, where the potential target exists in. Secondly, the candidate target regions are extracted by multiscale minimum target intensity filter, which can effectively give the optimal target size. At last, signal-to-clutter ratio (SCR) is used to segment targets, which is computed based on optimal scale of candidate targets. The experimental results indicate that the proposed method can achieve both higher detection precision and robustness in complex background.

  19. Molecular Targeted Intervention for Pancreatic Cancer

    PubMed Central

    Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

    2015-01-01

    Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

  20. Liposarcoma: molecular targets and therapeutic implications.

    PubMed

    Bill, Kate Lynn J; Casadei, Lucia; Prudner, Bethany C; Iwenofu, Hans; Strohecker, Anne M; Pollock, Raphael E

    2016-10-01

    Liposarcoma (LPS) is the most common soft tissue sarcoma and accounts for approximately 20 % of all adult sarcomas. Current treatment modalities (surgery, chemotherapy, and radiotherapy) all have limitations; therefore, molecularly driven studies are needed to improve the identification and increased understanding of genetic and epigenetic deregulations in LPS if we are to successfully target specific tumorigenic drivers. It can be anticipated that such biology-driven therapeutics will improve treatments by selectively deleting cancer cells while sparing normal tissues. This review will focus on several therapeutically actionable molecular markers identified in well-differentiated LPS and dedifferentiated LPS, highlighting their potential clinical applicability.

  1. New molecularly targeted therapies for lung cancer.

    PubMed

    Sun, Sophie; Schiller, Joan H; Spinola, Monica; Minna, John D

    2007-10-01

    Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development.

  2. New molecularly targeted therapies for lung cancer

    PubMed Central

    Sun, Sophie; Schiller, Joan H.; Spinola, Monica; Minna, John D.

    2007-01-01

    Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development. PMID:17909619

  3. Molecular imaging with targeted contrast ultrasound.

    PubMed

    Piedra, Mark; Allroggen, Achim; Lindner, Jonathan R

    2009-01-01

    Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation.

  4. High efficiency diffusion molecular retention tumor targeting.

    PubMed

    Guo, Yanyan; Yuan, Hushan; Cho, Hoonsung; Kuruppu, Darshini; Jokivarsi, Kimmo; Agarwal, Aayush; Shah, Khalid; Josephson, Lee

    2013-01-01

    Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In(3+)), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or i.v. methods was assessed by surface fluorescence, biodistribution of [(111)In] RGD and [(111)In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111)In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by i.v.). The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.

  5. Molecular Pathophysiology of Priapism: Emerging Targets

    PubMed Central

    Anele, Uzoma A.; Morrison, Belinda F.; Burnett, Arthur L.

    2015-01-01

    Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies. PMID:25392014

  6. Is size misperception of targets simply justification for poor performance?

    PubMed

    Wesp, Richard; Gasper, John

    2012-01-01

    Recent studies show that those who perform poorly on sporting activities involving targets recall the target as smaller than do better performers. Some have attributed the effect to action-specific perception, suggesting perception is influenced directly by how one interacts with an object. We proposed that underestimation of target size may instead serve as a justification for poor performance. We found that inaccurate dart throwers, given an excuse that the darts were of poor quality, were less likely to recall the target as smaller. The findings extend research indicating that perception is influenced by motivational factors, and provide further evidence that size estimates can be distorted by memory errors.

  7. Molecular size and molecular size distribution affecting traditional balsamic vinegar aging.

    PubMed

    Falcone, Pasquale Massimiliano; Giudici, Paolo

    2008-08-27

    A first attempt at a semiquantitative study of molecular weight (MW) and molecular weight distribution (MWD) in cooked grape must and traditional balsamic vinegar (TBV) with increasing well-defined age was performed by high-performance liquid size exclusion chromatography (SEC) using dual detection, that is, differential refractive index (DRI) and absorbance (UV-vis) based detectors. With this aim, MW and MWD, including number- and weight-average MW and polydispersity, were determined with respect to a secondary standard and then analyzed. All investigated vinegar samples were recognized as compositionally and structurally heterogeneous blends of copolymers (melanoidins) spreading over a wide range of molecular sizes: the relative MW ranged from 2 to >2000 kDa. The extent of the polymerization reactions was in agreement with the TBV browning kinetics. MWD parameters varied asymptotically toward either upper or lower limits during aging, reflecting a nonequilibrium status of the balance between polymerization and depolymerization reactions in TBV. MWD parameters were proposed as potential aging markers of TBV.

  8. Molecular Composition Analysis of Distant Targets

    NASA Technical Reports Server (NTRS)

    Hughes, Gary B.; Lubin, Philip

    2017-01-01

    This document is the Final Report for NASA Innovative Advanced Concepts (NIAC) Phase I Grant 15-NIAC16A-0145, titled Molecular Composition Analysis of Distant Targets. The research was focused on developing a system concept for probing the molecular composition of cold solar system targets, such as Asteroids, Comets, Planets and Moons from a distant vantage, for example from a spacecraft that is orbiting the target (Hughes et al., 2015). The orbiting spacecraft is equipped with a high-power laser, which is run by electricity from photovoltaic panels. The laser is directed at a spot on the target. Materials on the surface of the target are heated by the laser beam, and begin to melt and then evaporate, forming a plume of asteroid molecules in front of the heated spot. The heated spot glows, producing blackbody illumination that is visible from the spacecraft, via a path through the evaporated plume. As the blackbody radiation from the heated spot passes through the plume of evaporated material, molecules in the plume absorb radiation in a manner that is specific to the rotational and vibrational characteristics of the specific molecules. A spectrometer aboard the spacecraft is used to observe absorption lines in the blackbody signal. The pattern of absorption can be used to estimate the molecular composition of materials in the plume, which originated on the target. Focusing on a single spot produces a borehole, and shallow subsurface profiling of the targets bulk composition is possible. At the beginning of the Phase I research, the estimated Technology Readiness Level (TRL) of the system was TRL-1. During the Phase I research, an end-to-end theoretical model of the sensor system was developed from first principles. The model includes laser energy and optical propagation, target heating, melting and evaporation of target material, plume density, thermal radiation from the heated spot, molecular cross section of likely asteroid materials, and estimation of the

  9. New molecular targets in bone metastases.

    PubMed

    Santini, D; Galluzzo, S; Zoccoli, A; Pantano, F; Fratto, M E; Vincenzi, B; Lombardi, L; Gucciardino, C; Silvestris, N; Riva, E; Rizzo, S; Russo, A; Maiello, E; Colucci, G; Tonini, G

    2010-11-01

    Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. The biological mechanisms leading to bone metastasis establishment have been referred as "vicious circle," a complex network between cancer cells and the bone microenvironment. This review is aimed to underline the new molecular targets in bone metastases management other than bisphosphonates. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1, Src have recently emerged as potential targets and nowadays preclinical and clinical trials are underway. The results from those in the advanced clinical phases are encouraging and underlined the need to design large randomised clinical trials to validate these results in the next future. Targeting the bone by preventing skeletal related events (SREs) and bone metastases has major clinical impact in improving survival in bone metastatic patients and in preventing disease relapse in adjuvant setting.

  10. Molecularly Targeted Therapies in Multiple Myeloma

    PubMed Central

    Azab, Feda

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted. PMID:24829804

  11. Molecularly targeted therapies in multiple myeloma.

    PubMed

    de la Puente, Pilar; Muz, Barbara; Azab, Feda; Luderer, Micah; Azab, Abdel Kareem

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

  12. Molecular Imaging of Immunotherapy Targets in Cancer

    PubMed Central

    Ehlerding, Emily B.; England, Christopher G.; McNeel, Douglas G.

    2016-01-01

    Immunotherapy has emerged as a promising alternative in the arsenal against cancer by harnessing the power of the immune system to specifically target malignant tissues. As the field of immunotherapy continues to expand, researchers will require newer methods for studying the interactions between the immune system, tumor cells, and immunotherapy agents. Recently, several noninvasive imaging strategies have been used to map the biodistribution of immune checkpoint molecules, monitor the efficacy and potential toxicities of the treatments, and identify patients who are likely to benefit from immunotherapies. In this review, we outline the current applications of noninvasive techniques for the preclinical imaging of immunotherapy targets and suggest future pathways for molecular imaging to contribute to this developing field. PMID:27469363

  13. Lymphangioleiomyomatosis (LAM): Molecular insights lead to targeted therapies

    PubMed Central

    Glasgow, Connie G.; Steagall, Wendy K.; Taveira-DaSilva, Angelo; Pacheco-Rodriguez, Gustavo; Cai, Xiong; El-Chemaly, Souheil; Moses, Marsha; Darling, Thomas; Moss, Joel

    2011-01-01

    Summary LAM is a rare lung disease, found primarily in women of childbearing age, characterized by cystic lung destruction and abdominal tumors (e.g., renal angiomyolipoma, lymphangioleiomyoma). The disease results from proliferation of a neoplastic cell, termed the LAM cell, which has mutations in either of the tuberous sclerosis complex (TSC) 1 or TSC2 genes. Molecular phenotyping of LAM patients resulted in the identification of therapeutic targets for drug trials. Loss of TSC gene function leads to activation of mammalian target of rapamycin (mTOR), and thereby, effects on cell size and number. The involvement of mTOR in LAM pathogenesis is the basis for initiation of therapeutic trials of mTOR inhibitors (e.g., sirolimus). Occurrence of LAM essentially entirely in women is consistent with the hypothesis that anti-estrogen agents might prevent disease progression (e.g., gonadotropin-releasing hormone analogues). Levels of urinary matrix metalloproteinases (MMPs) were elevated in LAM patients, and MMPs were found in LAM lung nodules. In part because of these observations, effects of doxycycline, an anti-MMP, and anti-angiogenic agent, are under investigation. The metastatic properties of LAM cells offer additional potential for targets. Thus, insights into the molecular and biological properties of LAM cells and molecular phenotyping of patients with LAM have led to clinical trials of targeted therapies. Funded by the Intramural Research Program, NIH/NHLBI PMID:20630348

  14. Selective follicular targeting by modification of the particle sizes.

    PubMed

    Patzelt, Alexa; Richter, Heike; Knorr, Fanny; Schäfer, Ulrich; Lehr, Claus-Michael; Dähne, Lars; Sterry, Wolfram; Lademann, Juergen

    2011-02-28

    Hair follicles represent interesting target sites for topically applied substances such as topical vaccinations or agents used in the field of regenerative medicine. In recent years, it could be shown that particles penetrate very effectively into the hair follicles. In the present study, the influence of particle size on the follicular penetration depths was examined. The penetration depths of two different types of particles sized 122 to 1000 nm were determined in vitro on porcine skin. The results revealed that the particles of medium size (643 and 646 nm, respectively) penetrated deeper into the porcine hair follicles than smaller or larger particles. It was concluded that by varying the particle size, different sites within the porcine hair follicle can be targeted selectively. For the human terminal hair follicle, the situation can be expected to be similar due to a similar size ratio of the hair follicles.

  15. Molecularly targeted agents in oculoplastic surgery.

    PubMed

    Allen, Richard C

    2017-09-01

    Significant advances have been made in oncology and rheumatology with the introduction of molecularly targeted agents (MTAs). MTAs consist of monoclonal antibodies and small molecule inhibitors. The purpose of this manuscript is to review the recent applications of MTAs to orbital, lacrimal, and eyelid disease. The use of monoclonal antibodies has been described in the treatment of orbital vascular lesions, lymphoma, and squamous cell carcinoma. Inflammatory conditions treated with monoclonal antibodies include thyroid eye disease, IgG4 disease, and granulomatosis with polyangiitis. Immunotherapy with checkpoint inhibitors has also found applications to orbital disease. Use of small molecule inhibitors has been described in the treatment of basal cell carcinoma, squamous cell carcinoma, and Erdheim-Chester disease. There are many orbital, lacrimal, and eyelid side effects of MTAs with which the oculoplastic surgeon should be familiar, including hypertrichosis, edema, and orbital and eyelid inflammation. MTAs represent the future of treatment of oncologic and inflammatory conditions. Application of these agents to orbital, lacrimal, and eyelid disease will continue to expand. Elucidating the molecular mechanisms of oculoplastic disorders will facilitate additional potential pathways that could be targeted for therapy.

  16. Novel molecular targets for antimalarial chemotherapy.

    PubMed

    Jana, Snehasis; Paliwal, Jyoti

    2007-07-01

    The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a significant problem for effective control. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets. It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.

  17. Vascular targeting of nanoparticles for molecular imaging of diseased endothelium.

    PubMed

    Atukorale, Prabhani U; Covarrubias, Gil; Bauer, Lisa; Karathanasis, Efstathios

    2016-09-15

    This review seeks to highlight the enormous potential of targeted nanoparticles for molecular imaging applications. Being the closest point-of-contact, circulating nanoparticles can gain direct access to targetable molecular markers of disease that appear on the endothelium. Further, nanoparticles are ideally suitable to vascular targeting due to geometrically enhanced multivalent attachment on the vascular target. This natural synergy between nanoparticles, vascular targeting and molecular imaging can provide new avenues for diagnosis and prognosis of disease with quantitative precision. In addition to the obvious applications of targeting molecular signatures of vascular diseases (e.g., atherosclerosis), deep-tissue diseases often manifest themselves by continuously altering and remodeling their neighboring blood vessels (e.g., cancer). Thus, the remodeled endothelium provides a wide range of targets for nanoparticles and molecular imaging. To demonstrate the potential of molecular imaging, we present a variety of nanoparticles designed for molecular imaging of cancer or atherosclerosis using different imaging modalities.

  18. Protein-targeted corona phase molecular recognition.

    PubMed

    Bisker, Gili; Dong, Juyao; Park, Hoyoung D; Iverson, Nicole M; Ahn, Jiyoung; Nelson, Justin T; Landry, Markita P; Kruss, Sebastian; Strano, Michael S

    2016-01-08

    Corona phase molecular recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromolecular analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single-walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at saturation. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clinically relevant fibrinogen concentrations in the human blood. These results open new avenues for synthetic, non-biological antibody analogues that recognize biological macromolecules, and hold great promise for medical and clinical applications.

  19. Protein-targeted corona phase molecular recognition

    NASA Astrophysics Data System (ADS)

    Bisker, Gili; Dong, Juyao; Park, Hoyoung D.; Iverson, Nicole M.; Ahn, Jiyoung; Nelson, Justin T.; Landry, Markita P.; Kruss, Sebastian; Strano, Michael S.

    2016-01-01

    Corona phase molecular recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromolecular analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single-walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at saturation. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clinically relevant fibrinogen concentrations in the human blood. These results open new avenues for synthetic, non-biological antibody analogues that recognize biological macromolecules, and hold great promise for medical and clinical applications.

  20. Protein-targeted corona phase molecular recognition

    PubMed Central

    Bisker, Gili; Dong, Juyao; Park, Hoyoung D.; Iverson, Nicole M.; Ahn, Jiyoung; Nelson, Justin T.; Landry, Markita P.; Kruss, Sebastian; Strano, Michael S.

    2016-01-01

    Corona phase molecular recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromolecular analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single-walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at saturation. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clinically relevant fibrinogen concentrations in the human blood. These results open new avenues for synthetic, non-biological antibody analogues that recognize biological macromolecules, and hold great promise for medical and clinical applications. PMID:26742890

  1. Apoptosis and Molecular Targeting Therapy in Cancer

    PubMed Central

    Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

    2014-01-01

    Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

  2. Molecular-Targeted Antitumor Agents 19

    PubMed Central

    Liu, Yang; Liu, Rui; Mao, Shui-Chun; Morgan, J. Brian; Jekabsons, Mika B.; Zhou, Yu-Dong; Nagle, Dale G.

    2009-01-01

    A natural product chemistry-based approach was employed to discover small molecule inhibitors of the important tumor-selective molecular target hypoxia-inducible factor-1 (HIF-1). Bioassay-guided isolation of an active lipid extract of a Saipan collection of the marine sponge Lendenfeldia sp. afforded the terpene-derived furanolipid furospongolide as the primary inhibitor of hypoxia-induced HIF-1 activation (IC50 2.9 μM, T47D breast tumor cells). The active component of the extract also contained one new cytotoxic scalarane sesterterpene and two previously reported scalaranes. Furospongolide blocked the induction of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF) and was shown to suppress HIF-1 activation by inhibiting the hypoxic induction of HIF-1α protein. Mechanistic studies indicate that furospongolide inhibits HIF-1 activity primarily by suppressing tumor cell respiration via the blockade of NADH-ubiquinone oxidoreductase (complex I)-mediated mitochondrial electron transfer. PMID:18989978

  3. Size controlled protein nanoemulsions for active targeting of folate receptor positive cells.

    PubMed

    Loureiro, Ana; Nogueira, Eugénia; Azoia, Nuno G; Sárria, Marisa P; Abreu, Ana S; Shimanovich, Ulyana; Rollett, Alexandra; Härmark, Johan; Hebert, Hans; Guebitz, Georg; Bernardes, Gonçalo J L; Preto, Ana; Gomes, Andreia C; Cavaco-Paulo, Artur

    2015-11-01

    Bovine serum albumin (BSA) nanoemulsions were produced by high pressure homogenization with a tri-block copolymer (Poloxamer 407), which presents a central hydrophobic chain of polyoxypropylene (PPO) and two identical lateral hydrophilic chains of polyethylene glycol (PEG). We observed a linear correlation between tri-block copolymer concentration and size - the use of 5mg/mL of Poloxamer 407 yields nanoemulsions smaller than 100nm. Molecular dynamics and fluorescent tagging of the tri-block copolymer highlight their mechanistic role on the size of emulsions. This novel method enables the fabrication of highly stable albumin emulsions in the nano-size range, highly desirable for controlled drug delivery. Folic Acid (FA)-tagged protein nanoemulsions were shown to promote specific folate receptor (FR)-mediated targeting in FR positive cells. The novel strategy presented here enables the construction of size controlled, functionalized protein-based nanoemulsions with excellent characteristics for active targeting in cancer therapy.

  4. Molecular size of the canine and human brain D2 dopamine receptor as determined by radiation inactivation

    SciTech Connect

    Lilly, L.; Fraser, C.M.; Jung, C.Y.; Seeman, P.; Venter, J.C.

    1983-07-01

    Target-size analysis (radiation inactivation) has been utilized for determination of the molecular size of the striatal D2 dopamine receptor of both canine and human membranes. The dog and human receptors were found to have a molecular size of 123,000 daltons. The identity of molecular size values is consistent with available pharmacological and biochemical evidence supporting D2 dopamine receptor identity in canine and human tissues. These data suggest that the canine receptor may be a valid model for molecular and structural investigation of the human D2 dopamine receptor.

  5. Effect of environmental conditions on radiation target size analyses.

    PubMed

    Kempner, E S; Miller, J H

    1994-02-01

    Target size determinations from radiation inactivation of proteins is dependent on the physical and chemical environment of the sample during radiation exposure. Effects of temperature and physical state have already been described. Buffers, the effects of protein concentration, and the addition of small molecules are examined for several enzymes. Phosphate buffer is found to have major effects on the rate of inactivation of certain, but not all, proteins. The amount of protein in irradiated samples is significant for all enzymes studied; the nature of the specific protein used is unimportant. Neither sucrose nor other glycitols could substitute for protein in target size determinations. Certain small molecules, especially cysteamine, were effective in sparing the need for high protein levels in radiation inactivation studies of four enzyme systems.

  6. Molecular theory of size exclusion chromatography for wide pore size distributions.

    PubMed

    Sepsey, Annamária; Bacskay, Ivett; Felinger, Attila

    2014-02-28

    Chromatographic processes can conveniently be modeled at a microscopic level using the molecular theory of chromatography. This molecular or microscopic theory is completely general; therefore it can be used for any chromatographic process such as adsorption, partition, ion-exchange or size exclusion chromatography. The molecular theory of chromatography allows taking into account the kinetics of the pore ingress and egress processes, the heterogeneity of the pore sizes and polymer polydispersion. In this work, we assume that the pore size in the stationary phase of chromatographic columns is governed by a wide lognormal distribution. This property is integrated into the molecular model of size exclusion chromatography and the moments of the elution profiles were calculated for several kinds of pore structure. Our results demonstrate that wide pore size distributions have strong influence on the retention properties (retention time, peak width, and peak shape) of macromolecules. The novel model allows us to estimate the real pore size distribution of commonly used HPLC stationary phases, and the effect of this distribution on the size exclusion process. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Size matters: sequential mutations in tumorigenesis may reflect the stochastic effect of mutagen target sizes.

    PubMed

    Long, Kimberly; Abuelenen, Toaa; Pava, Libia; Bastille, Maya; Blanck, George

    2011-10-01

    We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies.

  8. Intravascular Targets for Molecular Contrast-Enhanced Ultrasound Imaging

    PubMed Central

    Moestue, Siver A.; Gribbestad, Ingrid S.; Hansen, Rune

    2012-01-01

    Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, which provide contrast during ultrasound imaging, can be targeted to specific molecular markers. These microbubbles accumulate in tissue with target (over) expression, thereby significantly increasing the ultrasound signal. This concept offers safe and low-cost imaging with high spatial resolution and sensitivity. It is therefore considered to have great potential in cancer imaging, and early-phase clinical trials are ongoing. In this review, we summarize the current literature on targets that have been successfully imaged in preclinical models using molecularly targeted ultrasound contrast agents. Based on preclinical experience, we discuss the potential clinical utility of targeted microbubbles. PMID:22837657

  9. Determination of Molecular Size and Avogadro's Number: A Student Experiment

    ERIC Educational Resources Information Center

    Alexandrakis, George C.

    1978-01-01

    Describes an experiment for estimating molecular size and Avogadro's number. Uses the diffusion length of iodine in air at 100 degrees Celsius as a function of time, and the change in volume of a small quantity of carbon dioxide as it goes from the solid to the gaseous state. (GA)

  10. Determination of Molecular Size and Avogadro's Number: A Student Experiment

    ERIC Educational Resources Information Center

    Alexandrakis, George C.

    1978-01-01

    Describes an experiment for estimating molecular size and Avogadro's number. Uses the diffusion length of iodine in air at 100 degrees Celsius as a function of time, and the change in volume of a small quantity of carbon dioxide as it goes from the solid to the gaseous state. (GA)

  11. Target size matters: target errors contribute to the generalization of implicit visuomotor learning.

    PubMed

    Reichenthal, Maayan; Avraham, Guy; Karniel, Amir; Shmuelof, Lior

    2016-08-01

    The process of sensorimotor adaptation is considered to be driven by errors. While sensory prediction errors, defined as the difference between the planned and the actual movement of the cursor, drive implicit learning processes, target errors (e.g., the distance of the cursor from the target) are thought to drive explicit learning mechanisms. This distinction was mainly studied in the context of arm reaching tasks where the position and the size of the target were constant. We hypothesize that in a dynamic reaching environment, where subjects have to hit moving targets and the targets' dynamic characteristics affect task success, implicit processes will benefit from target errors as well. We examine the effect of target errors on learning of an unnoticed perturbation during unconstrained reaching movements. Subjects played a Pong game, in which they had to hit a moving ball by moving a paddle controlled by their hand. During the game, the movement of the paddle was gradually rotated with respect to the hand, reaching a final rotation of 25°. Subjects were assigned to one of two groups: The high-target error group played the Pong with a small ball, and the low-target error group played with a big ball. Before and after the Pong game, subjects performed open-loop reaching movements toward static targets with no visual feedback. While both groups adapted to the rotation, the postrotation reaching movements were directionally biased only in the small-ball group. This result provides evidence that implicit adaptation is sensitive to target errors. Copyright © 2016 the American Physiological Society.

  12. Target size matters: target errors contribute to the generalization of implicit visuomotor learning

    PubMed Central

    Reichenthal, Maayan; Avraham, Guy; Karniel, Amir

    2016-01-01

    The process of sensorimotor adaptation is considered to be driven by errors. While sensory prediction errors, defined as the difference between the planned and the actual movement of the cursor, drive implicit learning processes, target errors (e.g., the distance of the cursor from the target) are thought to drive explicit learning mechanisms. This distinction was mainly studied in the context of arm reaching tasks where the position and the size of the target were constant. We hypothesize that in a dynamic reaching environment, where subjects have to hit moving targets and the targets' dynamic characteristics affect task success, implicit processes will benefit from target errors as well. We examine the effect of target errors on learning of an unnoticed perturbation during unconstrained reaching movements. Subjects played a Pong game, in which they had to hit a moving ball by moving a paddle controlled by their hand. During the game, the movement of the paddle was gradually rotated with respect to the hand, reaching a final rotation of 25°. Subjects were assigned to one of two groups: The high-target error group played the Pong with a small ball, and the low-target error group played with a big ball. Before and after the Pong game, subjects performed open-loop reaching movements toward static targets with no visual feedback. While both groups adapted to the rotation, the postrotation reaching movements were directionally biased only in the small-ball group. This result provides evidence that implicit adaptation is sensitive to target errors. PMID:27121580

  13. Oligogermanes as molecular precursors for germanium(0) nanoparticles: Size control and size-dependent fluorescence

    SciTech Connect

    Schrick, Aaron C.; Weinert, Charles S.

    2013-10-15

    Graphical abstract: Catenated germanium compounds are employed as molecular precursors for germanium(0) nanoparticles. The size of the nanoparticles, and their fluorescence spectra, depend on the number of catenated germanium atoms present in the precursor. - Highlights: • We have used oligogermanes for the size-specific synthesis of germanium(0) nanoparticles. • The size of the nanomaterials obtained depends directly on the degree of catenation present in the oligogermane precursor. • The nanoparticles are shown to exhibit size-dependent fluorescence. • Oligogermanes will function as useful precursors for the synthesis of a variety of nanomaterials. - Abstract: Germanium nanoparticles were synthesized in solution from novel oligogermane molecular precursors. The size of the nanoparticles obtained is directly related to the number of catenated germanium atoms present in the oligogermane precursor and the nanoparticles exhibit size-dependent fluorescence. The germanium nanoparticles were also characterized by TEM, powder XRD, FTIR, EDS and XPS methods. This method appears to be a promising new route for the synthesis of germanium nanoparticles since the size of the materials obtained can be controlled by the choice of the oligogermane used as the precursor.

  14. Predicting new molecular targets for known drugs

    PubMed Central

    Keiser, Michael J.; Setola, Vincent; Irwin, John J.; Laggner, Christian; Abbas, Atheir; Hufeisen, Sandra J.; Jensen, Niels H.; Kuijer, Michael B.; Matos, Roberto C.; Tran, Thuy B.; Whaley, Ryan; Glennon, Richard A.; Hert, Jérôme; Thomas, Kelan L.H.; Edwards, Douglas D.; Shoichet, Brian K.; Roth, Bryan L.

    2009-01-01

    Whereas drugs are intended to be selective, at least some bind to several physiologic targets, explaining both side effects and efficacy. As many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here, we compared 3,665 FDA-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-HT transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (< 100 nM). The physiological relevance of one such, the drug DMT on serotonergic receptors, was confirmed in a knock-out mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs. PMID:19881490

  15. Targets for molecular therapy of skin cancer.

    PubMed

    Green, Cheryl L; Khavari, Paul A

    2004-02-01

    Cancers of the skin encompass the first and second most common neoplasms in the United States, epidermal basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), respectively, as well as the melanocytic malignancy, malignant melanoma (MM). Recently identified alterations in the function of specific genes in these cancers provide new potential therapeutic targets. These alterations affect conserved regulators of cellular proliferation and viability, including the Sonic Hedgehog, Ras/Raf, ARF/p53, p16(INK4A)/CDK4/Rb and NF-kappaB pathways. New modalities designed to target these specific proteins may represent promising approaches to therapy of human skin cancers.

  16. Radiation inactivation analysis of influenza virus reveals different target sizes for fusion, leakage, and neuraminidase activities

    SciTech Connect

    Gibson, S.; Jung, C.Y.; Takahashi, M.; Lenard, J.

    1986-10-07

    The size of the functional units responsible for several activities carried out by the influenza virus envelope glycoproteins was determined by radiation inactivation analysis. Neuraminidase activity, which resides in the glycoprotein NA, was inactivated exponentially with an increasing radiation dose, yielding a target size of 94 +/- 5 kilodaltons (kDa), in reasonable agreement with that of the disulfide-bonded dimer (120 kDa). All the other activities studied are properties of the HA glycoprotein and were normalized to the known molecular weight of the neuraminidase dimer. Virus-induced fusion activity was measured by two phospholipid dilution assays: relief of energy transfer between N-(7-nitro-2,1,3-benzoxadiazol-4-yl)dipalmitoyl-L-alpha- phosphatidylethanolamine (N-NBD-PE) and N-(lissamine rhodamine B sulfonyl)-dioleoyl-L-alpha-phosphatidylethanolamine (N-Rh-PE) in target liposomes and relief of self-quenching of N-Rh-PE in target liposomes. Radiation inactivation of fusion activity proceeded exponentially with radiation dose, yielding normalized target sizes of 68 +/- 6 kDa by assay i and 70 +/- 4 kDa by assay ii. These values are close to the molecular weight of a single disulfide-bonded (HA1 + HA2) unit (75 kDa), the monomer of the HA trimer. A single monomer is thus inactivated by each radiation event, and each monomer (or some part of it) constitutes a minimal functional unit capable of mediating fusion. Virus-induced leakage of calcein from target liposomes and virus-induced leakage of hemoglobin from erythrocytes (hemolysis) both showed more complex inactivation behavior: a pronounced shoulder was present in both inactivation curves, followed by a steep drop in activity at higher radiation levels.

  17. Method of assembly of molecular-sized nets and scaffolding

    DOEpatents

    Michl, Josef; Magnera, Thomas F.; David, Donald E.; Harrison, Robin M.

    1999-01-01

    The present invention relates to methods and starting materials for forming molecular-sized grids or nets, or other structures based on such grids and nets, by creating molecular links between elementary molecular modules constrained to move in only two directions on an interface or surface by adhesion or bonding to that interface or surface. In the methods of this invention, monomers are employed as the building blocks of grids and more complex structures. Monomers are introduced onto and allowed to adhere or bond to an interface. The connector groups of adjacent adhered monomers are then polymerized with each other to form a regular grid in two dimensions above the interface. Modules that are not bound or adhered to the interface are removed prior to reaction of the connector groups to avoid undesired three-dimensional cross-linking and the formation of non-grid structures. Grids formed by the methods of this invention are useful in a variety of applications, including among others, for separations technology, as masks for forming regular surface structures (i.e., metal deposition) and as templates for three-dimensional molecular-sized structures.

  18. Method of assembly of molecular-sized nets and scaffolding

    DOEpatents

    Michl, J.; Magnera, T.F.; David, D.E.; Harrison, R.M.

    1999-03-02

    The present invention relates to methods and starting materials for forming molecular-sized grids or nets, or other structures based on such grids and nets, by creating molecular links between elementary molecular modules constrained to move in only two directions on an interface or surface by adhesion or bonding to that interface or surface. In the methods of this invention, monomers are employed as the building blocks of grids and more complex structures. Monomers are introduced onto and allowed to adhere or bond to an interface. The connector groups of adjacent adhered monomers are then polymerized with each other to form a regular grid in two dimensions above the interface. Modules that are not bound or adhered to the interface are removed prior to reaction of the connector groups to avoid undesired three-dimensional cross-linking and the formation of non-grid structures. Grids formed by the methods of this invention are useful in a variety of applications, including among others, for separations technology, as masks for forming regular surface structures (i.e., metal deposition) and as templates for three-dimensional molecular-sized structures. 9 figs.

  19. Molecular mechanisms of membrane targeting antibiotics.

    PubMed

    Epand, Richard M; Walker, Chelsea; Epand, Raquel F; Magarvey, Nathan A

    2016-05-01

    The bacterial membrane provides a target for antimicrobial peptides. There are two groups of bacteria that have characteristically different surface membranes. One is the Gram-negative bacteria that have an outer membrane rich in lipopolysaccharide. Several antimicrobials have been found to inhibit the synthesis of this lipid, and it is expected that more will be developed. In addition, antimicrobial peptides can bind to the outer membrane of Gram-negative bacteria and block passage of solutes between the periplasm and the cell exterior, resulting in bacterial toxicity. In Gram-positive bacteria, the major bacterial lipid component, phosphatidylglycerol can be chemically modified by bacterial enzymes to convert the lipid from anionic to cationic or zwitterionic form. This process leads to increased levels of resistance of the bacteria against polycationic antimicrobial agents. Inhibitors of this enzyme would provide protection against the development of bacterial resistance. There are antimicrobial agents that directly target a component of bacterial cytoplasmic membranes that can act on both Gram-negative as well as Gram-positive bacteria. Many of these are cyclic peptides with a rigid binding site capable of binding a lipid component. This binding targets antimicrobial agents to bacteria, rather than being toxic to host cells. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

  20. Size-Minimized Quantum Dots for Molecular and Cellular Imaging

    NASA Astrophysics Data System (ADS)

    Smith, Andrew M.; Wen, Mary M.; Wang, May D.; Nie, Shuming

    Semiconductor quantum dots, tiny light-emitting particles on thenanometer scale, are emerging as a new class of fluorescent labels for a broad range of molecular and cellular applications. In comparison with organic dyes and fluorescent proteins, they have unique optical and electronic properties such as size-tunable light emission, intense signal brightness, resistance to photobleaching, and broadband absorption for simultaneous excitation of multiple fluorescence colors. Here we report new advances in minimizing the hydrodynamic sizes of quantum dots using multidentate and multifunctional polymer coatings. A key finding is that a linear polymer containing grafted amine and thiol coordinating groups can coat nanocrystals and lead to a highly compact size, exceptional colloidal stability, strong resistance to photobleaching, and high fluorescence quantum yields. This has allowed a new generation of bright and stable quantum dots with small hydrodynamic diameters between 5.6 and 9.7 nm with tunable fluorescence emission from the visible (515 nm) to the near infrared (720 nm). These quantum dots are well suited for molecular and cellular imaging applications in which the nanoparticle hydrodynamic size needs to be minimized. Together with the novel properties of new strain-tunable quantum dots, these findings will be especially useful for multicolor and super-resolution imaging at the single-molecule level.

  1. Molecular targeting in childhood malignancies using nanoparticles

    NASA Astrophysics Data System (ADS)

    Satake, Noriko; Barisone, Gustavo; Diaz, Elva; Nitin, Nitin; Nolta, Jan; Lam, Kit

    2012-06-01

    The goal of our project is to develop a new therapy for childhood malignancies using nanoformulated siRNA targeting Mxd3, a molecule in the Sonic Hedgehog signaling pathway, which we believe is important for cell survival. We plan to use cancer-specific ligands and superparamagnetic iron oxide nanoparticles (SPIO NPs) to carry siRNA. This delivery system will be tested in mouse xenograft models that we developed with primary cancer tissues. Our current focus is acute lymphoblastic leukemia (ALL), the most common cancer in children. We report our progress to date.

  2. Twist: a molecular target in cancer therapeutics.

    PubMed

    Khan, Md Asaduzzaman; Chen, Han-chun; Zhang, Dianzheng; Fu, Junjiang

    2013-10-01

    Twist, the basic helix-loop-helix transcription factor, is involved in the process of epithelial to mesenchymal transitions (EMTs), which play an essential role in cancer metastasis. Overexpression of Twist or its promoter methylation is a common scenario in metastatic carcinomas. Twist is activated by a variety of signal transduction pathways, including Akt, signal transducer and activator of transcription 3, mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability. Twist also protects cancer cells from apoptotic cell death. In addition, Twist is responsible for the stemness of cancer cells and the generation of drug resistance. Recently, targeting Twist has gained significant interests in cancer therapeutics. The inactivation of Twist by small RNA technology or chemotherapeutic approach has been proved successful. Moreover, several inhibitors which are antagonistic to the upstream or downstream molecules of Twist signaling pathways have also been identified. Development of potential treatment strategies by targeting Twist has a great promise in cancer therapeutics.

  3. Molecular targeting of obesity pathways in cancer.

    PubMed

    Surmacz, Eva; Otvos, Laszlo

    2015-05-01

    Obesity is a significant risk factor for the development of different cancer types and has been associated with poorer response to oncotherapies and linked to earlier recurrence of the neoplastic disease. While molecular mechanisms of these associations are still under investigation, functional dysregulation of two major fat tissue-derived adipokines, leptin and adiponectin, appears to play an important role. Leptin is known to activate carcinogenic pathways, while adiponectin appears to exert antineoplastic activities and interfere with leptin-induced processes. Because excess body fat is associated with increased leptin expression and adiponectin downregulation, therapeutic rebalancing of these pathways may benefit cancer patients, especially the obese subpopulations. This review focuses on our novel leptin receptor antagonists and adiponectin receptor agonists designed for therapeutic modulation of obesity-associated pathways in cancer.

  4. Molecular Targeted Therapies of Aggressive Thyroid Cancer

    PubMed Central

    Ferrari, Silvia Martina; Fallahi, Poupak; Politti, Ugo; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro

    2015-01-01

    Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in

  5. Molecular sonography with targeted microbubbles: current investigations and potential applications.

    PubMed

    Hwang, Misun; Lyshchik, Andrej; Fleischer, Arthur C

    2010-06-01

    Sonography using targeted microbubbles affords a variety of diagnostic and potentially therapeutic clinical applications. It provides a whole new world of functional information at the cellular and molecular level. This information can then be used to diagnose and possibly prevent diseases at early stages as well as devise therapeutic strategies at the molecular level. It is also useful in monitoring tumor response to therapy and devising treatment timing and plans based on the molecular state of an individual's health. Moreover, targeted microbubble-enhanced sonography has several advantages over other imaging modalities, including widespread availability, low cost, fast acquisition times, and lack of radiation risk. These traits are likely to advance it as one of the imaging methods of choice in future clinical trials examining the impact of molecular imaging on treatment outcome. This review describes the fundamental concepts of targeted microbubble-enhanced sonography as well as its potential clinical applications.

  6. Molecular pathways and therapeutic targets in lung cancer

    PubMed Central

    Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi

    2014-01-01

    Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523

  7. Molecularly targeted therapy for gastrointestinal cancer.

    PubMed

    Wiedmann, Marcus W; Caca, Karel

    2005-05-01

    Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors

  8. The linewidth-size scaling law of molecular gas revisited

    NASA Astrophysics Data System (ADS)

    Falgarone, Edith; McKee, Christopher F.

    The origin of the linewidth-size (LWS) scaling law, first noticed by Larson three decades ago and ascribed to turbulence, is still a highly debated issue. Not unexpectedly, its properties depend on the environment and on the line tracer used. When the optically thick 12CO (J=1-0) line is used, a specific medium is sampled: the translucent molecular gas of moderate density that builds up the bulk of the molecular interstellar medium in galaxies like the Milky Way. The sensitivity of the 12CO line to this gas is such that the LWS is found to hold over almost five orders of magnitude in lengthscale, although with a considerable scatter (+/- 0.5 dex). It also appears to split into two regimes, depending on the gas mass surface density: below a given threshold that is proposed to be linked to the galactic structure, it bears the signature of a turbulent cascade, while above it, the scaling law is ascribed to virial balance. Large deviations from the LWS scaling law are observed at small scales where signatures of turbulent intermittency appear. The mass-size scaling law built with the 12CO (J=1-0) line also splits into two regimes. The mass surface density is uniform (also with a large scatter) above lengthscales ~ 10pc and increases with size at smaller scales, following turbulence predictions. The two thresholds define an average gas density n H ~ 300 cm-3.

  9. Molecular pathways and targets in prostate cancer

    PubMed Central

    Shtivelman, Emma; Beer, Tomasz M.; Evans, Christopher P.

    2014-01-01

    Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge. PMID:25277175

  10. Size of single-wall carbon nanotube affects the folate receptor-mediated cancer cell targeting.

    PubMed

    Charbgoo, Fahimeh; Nikkhah, Maryam; Behmanesh, Mehrdad

    2017-08-30

    Advances in nanobiotechnology and targeting strategy could improve the delivery of therapeutic molecules into cancer cells, leading to improved treatment efficiency with minimal side effects on normal cells. To design an efficient nanocarrier, consideration of parameters that facilitate direct drug delivery into the target cells is important. We studied the effect of single-wall carbon nanotubes (SWNTs) size on their cell internalization level via the folate receptor-mediated pathway through folic acid targeting. Folate-SWNTs were covalently synthesized and characterized. Folate-SWNTs ≤ 450 nm had lower cell internalization level than folate-SWNTs >450 nm with a P value of ≤0.01. This indicated that using folate-SWNT with an average length of ≤450 nm was not suitable for receptor-mediated cancer cell targeting. Receptor-mediated uptake of folate-SWNTs is dependent on the nanoparticle length. However, sub-450 nm SWNTs could serve as a vehicle to transfer nucleic acids into the cells due to direct cell penetrance based on their needle-like structure. We find that SWNTs larger than 450 nm were suitable to target the cells through receptors. These results might provide a promising approach for designing more effective targeted delivery systems based on SWNTs. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  11. New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

    PubMed

    Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

    2016-01-01

    Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

  12. SCF(SAP) controls organ size by targeting PPD proteins for degradation in Arabidopsis thaliana.

    PubMed

    Wang, Zhibiao; Li, Na; Jiang, Shan; Gonzalez, Nathalie; Huang, Xiahe; Wang, Yingchun; Inzé, Dirk; Li, Yunhai

    2016-04-06

    Control of organ size by cell proliferation and growth is a fundamental process, but the mechanisms that determine the final size of organs are largely elusive in plants. We have previously revealed that the ubiquitin receptor DA1 regulates organ size by repressing cell proliferation in Arabidopsis. Here we report that a mutant allele of STERILE APETALA (SAP) suppresses the da1-1 mutant phenotype. We show that SAP is an F-box protein that forms part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex and controls organ size by promoting the proliferation of meristemoid cells. Genetic analyses suggest that SAP may act in the same pathway with PEAPOD1 and PEAPOD2, which are negative regulators of meristemoid proliferation, to control organ size, but does so independently of DA1. Further results reveal that SAP physically associates with PEAPOD1 and PEAPOD2, and targets them for degradation. These findings define a molecular mechanism by which SAP and PEAPOD control organ size.

  13. SCFSAP controls organ size by targeting PPD proteins for degradation in Arabidopsis thaliana

    PubMed Central

    Wang, Zhibiao; Li, Na; Jiang, Shan; Gonzalez, Nathalie; Huang, Xiahe; Wang, Yingchun; Inzé, Dirk; Li, Yunhai

    2016-01-01

    Control of organ size by cell proliferation and growth is a fundamental process, but the mechanisms that determine the final size of organs are largely elusive in plants. We have previously revealed that the ubiquitin receptor DA1 regulates organ size by repressing cell proliferation in Arabidopsis. Here we report that a mutant allele of STERILE APETALA (SAP) suppresses the da1-1 mutant phenotype. We show that SAP is an F-box protein that forms part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex and controls organ size by promoting the proliferation of meristemoid cells. Genetic analyses suggest that SAP may act in the same pathway with PEAPOD1 and PEAPOD2, which are negative regulators of meristemoid proliferation, to control organ size, but does so independently of DA1. Further results reveal that SAP physically associates with PEAPOD1 and PEAPOD2, and targets them for degradation. These findings define a molecular mechanism by which SAP and PEAPOD control organ size. PMID:27048938

  14. Molecular targets of aspirin and cancer prevention

    PubMed Central

    Alfonso, L; Ai, G; Spitale, R C; Bhat, G J

    2014-01-01

    Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug. PMID:24874482

  15. Temporal precision of interceptive action: differential effects of target size and speed.

    PubMed

    Tresilian, R; Oliver, J; Carroll, J

    2003-02-01

    The duration of movements made to intercept moving targets decreases and movement speed increases when interception requires greater temporal precision. Changes in target size and target speed can have the same effect on required temporal precision, but the response to these changes differs: changes in target speed elicit larger changes in response speed. A possible explanation is that people attempt to strike the target in a central zone that does not vary much with variation in physical target size: the "effective size" of the target is relatively constant over changes in physical size. Three experiments are reported that test this idea. Participants performed two tasks: (1). strike a moving target with a bat moved perpendicular to the path of the target; (2). press on a force transducer when the target was in a location where it could be struck by the bat. Target speed was varied and target size held constant in experiment 1. Target speed and size were co-varied in experiment 2, keeping the required temporal precision constant. Target size was varied and target speed held constant in experiment 3 to give the same temporal precision as experiment 1. Duration of hitting movements decreased and maximum movement speed increased with increases in target speed and/or temporal precision requirements in all experiments. The effects were largest in experiment 1 and smallest in experiment 3. Analysis of a measure of effective target size (standard deviation of strike locations on the target) failed to support the hypothesis that performance differences could be explained in terms of effective size rather than actual physical size. In the pressing task, participants produced greater peak forces and shorter force pulses when the temporal precision required was greater, showing that the response to increasing temporal precision generalizes to different responses. It is concluded that target size and target speed have independent effects on performance.

  16. Current status of DILD in molecular targeted therapies.

    PubMed

    Saito, Yoshinobu; Gemma, Akihiko

    2012-12-01

    Molecular targeted drugs have become the mainstream for cancer therapy, and they have contributed to improving the outcome for cancer patients. On the other hand, molecular targeted drugs are associated with a variety of adverse drug reactions. Drug-induced interstitial lung disease (DILD) is a typical adverse drug reaction that has been an important problem with regard to safety management during cancer treatment. In the past, there was a lack of detailed and accurate epidemiological data about DILD. However, most of the molecular targeted drugs have been subject to all-case post-marketing surveillance since gefitinib-induced ILD became a concern. These surveillance data present useful information about DILD, such as frequency of adverse events, mortality, and risk factors, and as a result, the epidemiological profile of DILD associated with molecular targeted drugs has become apparent during the past decade. Further, it has been considered that the principal management for DILD is early detection and cessation of the suspected cause. However, ILD associated with everolimus and temsirolimus requires unusual management; i.e., patients with asymptomatic ILD are allowed to continue treatment with everolimus or temsirolimus, and even after symptomatic ILD, both everolimus and temsirolimus are allowed to be readministered after the resolution of ILD. As a result of the collected data, a change has begun in the field of DILD associated with molecular targeted drugs. The features of DILD can differ for each drug, and clinicians should thus keep this information about DILD in mind while treating patients.

  17. Pathway inhibition: emerging molecular targets for treating glioblastoma

    PubMed Central

    Wick, Wolfgang; Weller, Michael; Weiler, Markus; Batchelor, Tracy; Yung, Alfred W.K.; Platten, Michael

    2011-01-01

    Insights into the molecular pathogenesis of glioblastoma have not yet resulted in relevant clinical improvement. With standard therapy, which consists of surgical resection with concomitant temozolomide in addition to radiotherapy followed by adjuvant temozolomide, the median duration of survival is 12–14 months. Therefore, the identification of novel molecular targets and inhibitory agents has become a focus of research for glioblastoma treatment. Recent results of bevacizumab may represent a proof of principle that treatment with targeted agents can result in clinical benefits for patients with glioblastoma. This review discusses limitations in the existing therapy for glioblastoma and provides an overview of current efforts to identify molecular targets using large-scale screening of glioblastoma cell lines and tumor samples. We discuss preclinical and clinical data for several novel molecular targets, including growth factor receptors, phosphatidylinositol-3 kinase, SRC-family kinases, integrins, and CD95 ligand and agents that inhibit these targets, including erlotinib, enzastaurin, dasatinib, sorafenib, cilengitide, AMG102, and APG101. By combining advances in tumor screening with novel targeted therapies, it is hoped that new treatment options will emerge for this challenging tumor type. PMID:21636705

  18. Diverse Molecular Targets for Chalcones with Varied Bioactivities

    PubMed Central

    Zhou, Bo; Xing, Chengguo

    2015-01-01

    Natural or synthetic chalcones with different substituents have revealed a variety of biological activities that may benefit human health. The underlying mechanisms of action, particularly with respect to the direct cellular targets and the modes of interaction with the targets, have not been rigorously characterized, which imposes challenges to structure-guided rational development of therapeutic agents or chemical probes with acceptable target-selectivity profile. This review summarizes literature evidence on chalcones’ direct molecular targets in the context of their biological activities. PMID:26798565

  19. Particle size dependence of biogenic secondary organic aerosol molecular composition

    NASA Astrophysics Data System (ADS)

    Tu, Peijun; Johnston, Murray V.

    2017-06-01

    Formation of secondary organic aerosol (SOA) is initiated by the oxidation of volatile organic compounds (VOCs) in the gas phase whose products subsequently partition to the particle phase. Non-volatile molecules have a negligible evaporation rate and grow particles at their condensation rate. Semi-volatile molecules have a significant evaporation rate and grow particles at a much slower rate than their condensation rate. Particle phase chemistry may enhance particle growth if it transforms partitioned semi-volatile molecules into non-volatile products. In principle, changes in molecular composition as a function of particle size allow non-volatile molecules that have condensed from the gas phase (a surface-limited process) to be distinguished from those produced by particle phase reaction (a volume-limited process). In this work, SOA was produced by β-pinene ozonolysis in a flow tube reactor. Aerosol exiting the reactor was size-selected with a differential mobility analyzer, and individual particle sizes between 35 and 110 nm in diameter were characterized by on- and offline mass spectrometry. Both the average oxygen-to-carbon (O / C) ratio and carbon oxidation state (OSc) were found to decrease with increasing particle size, while the relative signal intensity of oligomers increased with increasing particle size. These results are consistent with oligomer formation primarily in the particle phase (accretion reactions, which become more favored as the volume-to-surface-area ratio of the particle increases). Analysis of a series of polydisperse SOA samples showed similar dependencies: as the mass loading increased (and average volume-to-surface-area ratio increased), the average O / C ratio and OSc decreased, while the relative intensity of oligomer ions increased. The results illustrate the potential impact that particle phase chemistry can have on biogenic SOA formation and the particle size range where this chemistry becomes important.

  20. Molecular Methods for Identification of Clostridium tetani by Targeting Neurotoxin.

    PubMed

    Nagoba, Basavraj; Dharne, Mahesh; Gohil, Kushal N

    2017-01-01

    Tetanus is a potentially fatal muscle spasm disease. It is an important public health problem, especially in rural/tribal areas of developing countries. Tetanus toxin, a neurotoxin (tetanospasmin ), is the most important virulence factor that plays a key role in the pathogenicity of tetanus . Confirmation of virulence by confirming the production of tetanospasmin by infecting species forms the most important part in the diagnosis of tetanus . Various molecular methods have been devised for confirmation of diagnosis by targeting different genes. The most common molecular methods are tetanospasmin producing (TetX) gene-targeted methods using TetX-specific primers. Here, we describe various molecular methods targeting TetX gene such as polymerase chain reaction, pulsed-field gel electrophoresis, Southern blotting, loop-mediated isothermal amplification assay, etc. to confirm the virulence of Cl. tetani.

  1. Molecular targets that link dioxin exposure to toxicity phenotypes.

    PubMed

    Yoshioka, Wataru; Peterson, Richard E; Tohyama, Chiharu

    2011-10-01

    Many toxicology studies have elucidated health effects associated with exposure to various chemicals, but few have identified the molecular targets that cause specific endpoints of toxicity. Our understanding of the toxicity of dioxins, a group of chemicals capable of causing toxicity at environmentally relevant levels of exposure, is no exception. Dioxins are unique compared to most chemicals that we are exposed to in the environment because they activate a high affinity receptor, aryl hydrocarbon receptor (AhR), that was identified more than three decades ago. In recent years, several lines of experimental evidence have provided clues for opening the "black box" that contains the molecular mechanisms of dioxin action. These clues have emerged by toxicologists beginning to identify the molecular targets that link AhR signaling to tissue-specific toxicity phenotypes. Endpoints of dioxin toxicity for which downstream molecular targets have begun to be elucidated are observed in developmental or tissue regeneration processes, and include impaired prostate development and hydronephrosis in mouse fetuses and pups, reduced midbrain blood flow and jaw malformation in zebrafish embryos, and impaired fin regeneration in larval and adult zebrafish. Significant progress in identifying molecular targets for dioxin-induced hepatotoxicity in adult mice also has occurred. Misregulation of AhR downstream pathways, such as conversion of arachidonic acid to prostanoids via cyclooxygenase-2, and altered Wnt/β-catenin signaling downregulating Sox9, and signaling by receptors for inflammatory cytokines have been implicated in tissue-specific endpoints of dioxin toxicity. These findings may not only begin to clarify the molecular targets of dioxin action but shed light on new molecular events associated with development and disease.

  2. The saccadic size-latency phenomenon explored: Proximal target size is a determining factor in the saccade latency.

    PubMed

    De Vries, J P; Azadi, R; Harwood, M R

    2016-12-01

    Saccade latencies are known to increase for targets presented close to fixation. Recently, it was shown that not only target eccentricity, but the size of a proximal saccade target also plays a crucial role: latencies increase rapidly with increasing target size. Interestingly, these latency increases are greater than those typically found for other supra-threshold manipulations of target properties. Here we evaluate to what extent this phenomenon is distinct from known delays in saccade initiation and whether the phenomenon is truly related to the size of a proximal target. In Experiment 1 we focus on the importance of the required amplitude. Employing a saccade adaptation paradigm we find that the required amplitude is not a determining factor. Focusing on the role of size, in Experiment 2, we find that while latency increases are strongest for targets elongated in the direction of the fovea, elongations perpendicular to this direction also lead to an increase in latencies. Finally, in Experiment 3 we verify that the latency increases are driven by the properties of the saccade target rather than visual input in general. Together these experiments provide converging evidence that the current phenomenon is both novel and a consequence of the relation between proximal target size and its eccentricity.

  3. Traditional Chinese medicines (TCMs) for molecular targeted therapies of tumours.

    PubMed

    Youns, Mahmoud; Hoheisel, Jörg D; Efferth, Thomas

    2010-03-01

    Scientific progress in genetics, cell and molecular biology has greatly ameliorated our comprehensive understanding of the molecular mechanisms of neoplastic transformation and progression. The rapidly advancing identification of molecular targets in human cancers during the last decade has provided an excellent starting point for the development of novel therapeutics. A huge variety of potential molecular targets have been identified, many of which are already in the market for therapeutic purposes. It is now becoming possible to target pathways and/or molecules that are crucial in maintaining the malignant phenotype. Traditional Chinese medicine (TCM) is often considered as alternative or complementary medicine. TCM represents a holistic approach and lacks high-quality scientific evidence on its effectiveness. Therefore, it is frequently regarded with some scepticism by western academic medicine. In this review, we report that application of modern technologies allowed identification of novel molecular targets modulating the anti-tumour activity of natural products derived from TCM. Moreover, we tried to cross the bridge between TCM and Western modern medicine to be able to implement them for the sake of cancer patients.

  4. Discovering Molecular Targets in Cancer with Multiscale Modeling

    PubMed Central

    Wang, Zhihui; Bordas, Veronika; Deisboeck, Thomas S.

    2011-01-01

    Multiscale modeling is increasingly being recognized as a promising research area in computational cancer systems biology. Here, exemplified by two pioneering studies, we attempt to explain why and how such a multiscale approach paired with an innovative cross-scale analytical technique can be useful in identifying high-value molecular therapeutic targets. This novel, integrated approach has the potential to offer a more effective in silico framework for target discovery and represents an important technical step towards systems medicine. PMID:21572568

  5. Molecular Targeted α-Particle Therapy for Oncologic Applications

    PubMed Central

    Wadas, Thaddeus J.; Pandya, Darpan N.; Solingapuram Sai, Kiran Kumar; Mintz, Akiva

    2015-01-01

    OBJECTIVE A significant challenge facing traditional cancer therapies is their propensity to significantly harm normal tissue. The recent clinical success of targeting therapies by attaching them to antibodies that are specific to tumor-restricted biomarkers marks a new era of cancer treatments. CONCLUSION In this article, we highlight the recent developments in α-particle therapy that have enabled investigators to exploit this highly potent form of therapy by targeting tumor-restricted molecular biomarkers. PMID:25055256

  6. Combining molecular targeted agents with radiation therapy for malignant gliomas

    PubMed Central

    Scaringi, Claudia; Enrici, Riccardo Maurizi; Minniti, Giuseppe

    2013-01-01

    The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways. PMID:23966794

  7. Molecular genetics and targeted therapeutics in biliary tract carcinoma.

    PubMed

    Marks, Eric I; Yee, Nelson S

    2016-01-28

    The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

  8. Molecular genetics and targeted therapeutics in biliary tract carcinoma

    PubMed Central

    Marks, Eric I; Yee, Nelson S

    2016-01-01

    The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

  9. Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics.

    PubMed

    Katsanos, Konstantinos H; Papadakis, Konstantinos A

    2017-07-15

    Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches.

  10. Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics

    PubMed Central

    Katsanos, Konstantinos H.; Papadakis, Konstantinos A.

    2017-01-01

    Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches. PMID:28486793

  11. Molecular dynamics study of micelles properties according to their size.

    PubMed

    Lebecque, S; Crowet, J M; Nasir, M N; Deleu, M; Lins, L

    2017-03-01

    Surfactants are molecules able to spontaneously self-assemble to form aggregates with well-defined properties, such as spherical micelles, planar bilayers, cylindrical micelles or vesicles. Micelles have notably several applications in many domains, such as drug delivery or membrane protein solubilization. In this context, the study of micelle formation in relation with the structural and physico-chemical properties of surfactants is of great interest to better control their use in the different application fields. In this work, we use the MD approach developed by Yoshii et al. and extend it to surfactants with different structures. We aim to systematically investigate different micellar properties as a function of the aggregates size by a molecular dynamics approach, to get an insight into the micellar organization and to collect some relevant descriptors about micelle formation. For this, we perform short MD simulations of preformed micelles of various sizes and analyze three parameters for each micelle size, namely the eccentricity of the micelles, the hydrophobic/hydrophilic surface ratio and the hydrophobic tails hydration. If these parameters are known descriptors of micelles, they were not yet studied in this way by MD. We show that eccentricity, used as "validator" parameter, exhibits minimal values when the aggregate size is close to the experimental aggregation number for surfactants that are known to form spherical micelles. This hence indicates that our methodology gives consistent results. The evolution of the two descriptors follows another scheme, with a sharp increase and decrease, respectively, followed by a leveling-off. The aggregate sizes at which this stabilization starts to occur are close to the respective aggregation number of each surfactant. In our approach, we validate the use of these descriptors to follow micelle formation by MD, from "simple" surfactants to more complex structures, like lipopeptides. Our calculations also suggest that

  12. Molecular targets and cancer therapeutics: discovery, development and clinical validation.

    PubMed

    Teicher, Beverly A.

    2000-04-01

    The AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Washington, DC on 16-19 November 1999 provided a forum for cancer research clearly showing evolution of a target and mechanism-driven science. The notion of the tumor as a tissue composed of heterogeneous populations of normal and abnormal cells as viable targets is coming to the fore with the advent of agents directed toward non-malignant cell targets. Growth control rather than eradication as a treatment strategy for malignant disease is being tested preclinically and clinically. Among targets, kinases are in the lead with nuclear, cytoplasmic and membrane kinases being selectively inhibited by small molecules and macromolecules. First generation tumor vasculature-directed agents are progressing through early clinical studies. The interest in tumor vasculature as a target has renewed interest in imaging technology to discern biological effect and in tumor hypoxia. This has resulted in elucidation of molecular responses triggered by a low oxygen environment. Challenges remain in the areas of cellular and immune therapies. Dendritic cell-based vaccines are being tested preclinically in many systems. Interleukin-12 is proceeding through clinical trials. Apoptosis-protective molecules such as bcl-2, and apoptosis-stimulating molecules such as bax, are being pursued as targets for inhibition and activation, respectively. Finally, methods and technology to aid in the identification of new targets were highlighted. This perspective, while it is by no means an exhaustive review of the presentations, brings forward some of the main topics and interests that are current in cancer research. Targets were the topic but methods of target identification and the need for increased chemical diversity to selectively focus agents to targets with small differences were also major topics of discussion. Copyright 2000 Harcourt Publishers Ltd.

  13. Mitochondrial-Targeted Molecular Imaging in Cardiac Disease

    PubMed Central

    Li, Jinhui

    2017-01-01

    The present study aimed to discuss the role of mitochondrion in cardiac function and disease. The mitochondrion plays a fundamental role in cellular processes ranging from metabolism to apoptosis. The mitochondrial-targeted molecular imaging could potentially illustrate changes in global and regional cardiac dysfunction. The collective changes that occur in mitochondrial-targeted molecular imaging probes have been widely explored and developed. As probes currently used in the preclinical setting still have a lot of shortcomings, the development of myocardial metabolic activity, viability, perfusion, and blood flow molecular imaging probes holds great potential for accurately evaluating the myocardial viability and functional reserve. The advantages of molecular imaging provide a perspective on investigating the mitochondrial function of the myocardium in vivo noninvasively and quantitatively. The molecular imaging tracers of single-photon emission computed tomography and positron emission tomography could give more detailed information on myocardial metabolism and restoration. In this study, series mitochondrial-targeted 99mTc-, 123I-, and 18F-labeled tracers displayed broad applications because they could provide a direct link between mitochondrial dysfunction and cardiac disease. PMID:28638829

  14. Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

    PubMed Central

    Jandial, Danielle D.; Blair, Christopher A.; Zhang, Saiyang; Krill, Lauren S.; Zhang, Yan-Bing; Zi, Xiaolin

    2014-01-01

    There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID:24467530

  15. Molecular targeting agents in cancer therapy: science and society.

    PubMed

    Shaikh, Asim Jamal

    2012-01-01

    The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

  16. Clinical Challenges to Current Molecularly Targeted Therapies in Lung Cancer.

    PubMed

    Chhabra, Gagan; Eggert, Ashley; Puri, Neelu

    Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients.

  17. Hedonic Judgments of Chemical Compounds Are Correlated with Molecular Size

    PubMed Central

    Zarzo, Manuel

    2011-01-01

    Different psychophysical works have reported that, when a wide range of odors is assessed, the hedonic dimension is the most salient. Hence, pleasantness is the most basic attribute of odor perception. Recent studies suggest that the molecular size of a given odorant is positively correlated with its hedonic character. This correlation was confirmed in the present study, but further basic molecular features affecting pleasantness were identified by means of multiple linear regression for the compounds contained in five chemical sets. For three of them, hedonic judgments are available in the literature. For a further two chemical sets, hedonic scores were estimated from odor character descriptions based on numerical profiles. Generally speaking, fairly similar equations were obtained for the prediction of hedonic judgments in the five chemical sets, with R2 values ranging from 0.46 to 0.71. The results suggest that larger molecules containing oxygen are more likely to be perceived as pleasant, while the opposite applies to carboxylic acids and sulfur compounds. PMID:22163815

  18. Magnetomotive molecular probes for targeted contrast enhancement and therapy

    NASA Astrophysics Data System (ADS)

    Boppart, Stephen A.

    2011-03-01

    The diagnostic, interrogational, and therapeutic potential of molecular probes is rapidly being investigated and exploited across virtually every biomedical imaging modality. While many types of probes enhance contrast or delivery therapy by static localization to targeted sites, significant potential exists for utilizing dynamic molecular probes. Recent examples include molecular beacons, photoactivatable probes, or controlled switchable drug-releasing particles, to name a few. In this review, we describe a novel class of dynamic molecular probes that rely on the application and control of localized external magnetic fields. These magnetomotive molecular probes can provide optical image contrast through a modulated scattering signal, can interrogate the biomechanical properties of their viscoelastic microenvironment by tracking their underdamped oscillatory step-response to applied fields, and can potentially delivery therapy through nanometer-to-micrometer mechanical displacement or local hyperthermia. This class of magnetomotive agents includes not only magnetic iron-oxide nanoparticles, but also new magnetomotive microspheres or nanostructures with embedded iron-oxide agents. In vitro three-dimensional cell assays and in vivo targeting studies in animal tumor models have demonstrated the potential for multimodal detection and imaging, using magnetic resonance imaging for whole-body localization, and magnetomotive optical coherence tomography for high-resolution localization and imaging.

  19. Molecular Targeted Viral Nanoparticles as Tools for Imaging Cancer

    PubMed Central

    Cho, C.F.; Sourabh, S.; Simpson, E.J.; Steinmetz, N.F.; Luyt, L.G.; Lewis, J.D.

    2015-01-01

    Viral nanoparticles (VNPs) are a novel class of bionanomaterials that harness the natural biocompatibility of viruses for the development of therapeutics, vaccines, and imaging tools. The plant virus, cowpea mosaic virus (CPMV), has been successfully engineered to create novel cancer-targeted imaging agents by incorporating fluorescent dyes, polyethylene glycol (PEG) polymers, and targeting moieties. Using straightforward conjugation strategies, VNPs with high selectivity for cancer-specific molecular targets can be synthesized for in vivo imaging of tumors. Here we describe the synthesis and purification of CPMV-based VNPs, the functionalization of these VNPs using click chemistry, and their use for imaging xenograft tumors in animal models. VNPs decorated with fluorescent dyes, PEG, and targeting ligands can be synthesized in one day, and imaging studies can be performed over hours, days, or weeks, depending on the application. PMID:24243252

  20. Computational molecular biology approaches to ligand-target interactions

    PubMed Central

    Lupieri, Paola; Nguyen, Chuong Ha Hung; Bafghi, Zhaleh Ghaemi; Giorgetti, Alejandro; Carloni, Paolo

    2009-01-01

    Binding of small molecules to their targets triggers complex pathways. Computational approaches are keys for predictions of the molecular events involved in such cascades. Here we review current efforts at characterizing the molecular determinants in the largest membrane-bound receptor family, the G-protein-coupled receptors (GPCRs). We focus on odorant receptors, which constitute more than half GPCRs. The work presented in this review uncovers structural and energetic aspects of components of the cellular cascade. Finally, a computational approach in the context of radioactive boron-based antitumoral therapies is briefly described. PMID:20119480

  1. Lead sulfide near-infrared quantum dot bioconjugates for targeted molecular imaging

    PubMed Central

    Sun, Jiantang; Zhu, Ming-Qiang; Fu, Kun; Lewinski, Nastassja; Drezek, Rebekah A

    2007-01-01

    In this paper, we report the use of lead sulfide quantum dot (PbS QD) bioconjugates as near infrared (NIR) contrast agents for targeted molecular imaging with expanded emission wavelengths beyond 1000 nm. The red-shifted emission band, coupled with the small particle size, which will facilitate clearance, both afford PbS QDs unique properties for noninvasive, high resolution in vivo NIR imaging applications. We have performed imaging experiments at the molecular level using surface-modified PbS NIR QDs, together with our lab-built NIR imaging system. This novel instrumentation and fluorescent contrast agent have enabled us to study the relatively unexplored NIR biomedical imaging spectral region of 900–1200 nm. Preliminary experimental results indicate that PbS-QD/antibody bioconjugates are promising candidates for targeted NIR molecular imaging and future in vivo NIR tissue imaging applications. PMID:17722551

  2. Molecular targets for small-molecule modulators of circadian clocks

    PubMed Central

    He, Baokun; Chen, Zheng

    2016-01-01

    Background Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. Methods Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. Results Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. Conclusion Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases. PMID:26750111

  3. Optimum target sizes for a sequential sawing process

    Treesearch

    H. Dean Claxton

    1972-01-01

    A method for solving a class of problems in random sequential processes is presented. Sawing cedar pencil blocks is used to illustrate the method. Equations are developed for the function representing loss from improper sizing of blocks. A weighted over-all distribution for sawing and drying operations is developed and graphed. Loss minimizing changes in the control...

  4. Target Size and Luminance Effects on Accommodation and Vergence.

    DTIC Science & Technology

    1987-01-01

    st i mu I at ed Voluntary changes in accommodation and verger .( e Sub je(ts have been shown to be able to make vol untarN changes in vergence Oil...v ith a projected cross with smooth sides. This cross ,. Is riide on a 35 mm slide and its size was altered manually i) diaphragm. Both crosses

  5. Application of Monte Carlo Methods in Molecular Targeted Radionuclide Therapy

    SciTech Connect

    Hartmann Siantar, C; Descalle, M-A; DeNardo, G L; Nigg, D W

    2002-02-19

    Targeted radionuclide therapy promises to expand the role of radiation beyond the treatment of localized tumors. This novel form of therapy targets metastatic cancers by combining radioactive isotopes with tumor-seeking molecules such as monoclonal antibodies and custom-designed synthetic agents. Ultimately, like conventional radiotherapy, the effectiveness of targeted radionuclide therapy is limited by the maximum dose that can be given to a critical, normal tissue, such as bone marrow, kidneys, and lungs. Because radionuclide therapy relies on biological delivery of radiation, its optimization and characterization are necessarily different than for conventional radiation therapy. We have initiated the development of a new, Monte Carlo transport-based treatment planning system for molecular targeted radiation therapy as part of the MINERVA treatment planning system. This system calculates patient-specific radiation dose estimates using a set of computed tomography scans to describe the 3D patient anatomy, combined with 2D (planar image) and 3D (SPECT, or single photon emission computed tomography) to describe the time-dependent radiation source. The accuracy of such a dose calculation is limited primarily by the accuracy of the initial radiation source distribution, overlaid on the patient's anatomy. This presentation provides an overview of MINERVA functionality for molecular targeted radiation therapy, and describes early validation and implementation results of Monte Carlo simulations.

  6. The molecular targets of approved treatments for pulmonary arterial hypertension

    PubMed Central

    Humbert, Marc; Ghofrani, Hossein-Ardeschir

    2016-01-01

    Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy. PMID:26219978

  7. [Advances of molecular targeted therapy in squamous cell lung cancer].

    PubMed

    Ma, Li; Zhang, Shucai

    2013-12-01

    Squamous cell lung cancer (SQCLC) is one of the most prevalent subtypes of lung cancer worldwide, about 400,000 persons die from squamous-cell lung cancer around the world, and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, the discoidin domain receptor 2 (DDR2) gene mutation as potential novel targets for the treatment of SQCLCs. Researchers find that there are many specific molecular targeted genes in the genome of squamous-cell lung cancer patients. These changes play a vital role in cell cycle regulation, oxidative stress, cell apoptosis, squamous epithelium differentiation, may be the candidate targeted moleculars in SQCLCs. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.

  8. When size does matter: organelle size influences the properties of transport mediated by molecular motors.

    PubMed

    De Rossi, María Cecilia; Bruno, Luciana; Wolosiuk, Alejandro; Despósito, Marcelo A; Levi, Valeria

    2013-11-01

    Organelle transport is driven by the action of molecular motors. In this work, we studied the dynamics of organelles of different sizes with the aim of understanding the complex relation between organelle motion and microenvironment. We used single particle tracking to obtain trajectories of melanosomes (pigmented organelles in Xenopus laevis melanophores). In response to certain hormones, melanosomes disperse in the cytoplasm or aggregate in the perinuclear region by the combined action of microtubule and actin motors. Melanosome trajectories followed an anomalous diffusion model in which the anomalous diffusion exponent (α) provided information regarding the trajectories' topography and thus of the processes causing it. During aggregation, the directionality of big organelles was higher than that of small organelles and did not depend on the presence of either actin or intermediate filaments (IF). Depolymerization of IF significantly reduced α values of small organelles during aggregation but slightly affect their directionality during dispersion. Our results could be interpreted considering that the number of copies of active motors increases with organelle size. Transport of big organelles was not influenced by actin or IF during aggregation showing that these organelles are moved processively by the collective action of dynein motors. Also, we found that intermediate filaments enhance the directionality of small organelles suggesting that this network keeps organelles close to the tracks allowing their efficient reattachment. The higher directionality of small organelles during dispersion could be explained considering the better performance of kinesin-2 vs. dynein at the single molecule level. © 2013 Elsevier B.V. All rights reserved.

  9. Investigations into the molecular size and shape of tomato extensin.

    PubMed Central

    Brownleader, M D; Byron, O; Rowe, A; Trevan, M; Welham, K; Dey, P M

    1996-01-01

    The molecular characteristics of soluble extensin from tomato have been investigated. An apparent molecular mass greater than 240 kDa has been previously observed with the shape-dependent method of gel-filtration chromatography [Brownleader and Dey (1993) Planta (Berlin) 191, 457-469]. Tomato extensin is a heavily glycosylated protein that does not migrate into SDS/polyacrylamide gels. This shape-dependent behaviour raises doubts about agreement between the observed apparent mass and the absolute value. The molecular mass measured with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was 72.3 kDa, with no evidence of any other species except a doubly charged ion. The sample was therefore considered to be monodisperse under the conditions used. Electron microscopy of soluble extensin showed the presence of particles 40-50 nm in length and 2.0-2.5 nm in width. A minority of these particles showed a central 'kink'. A number of smaller and generally wider particles (20 nm x 2-4 nm) were considered to be folded monomers and larger particles were thought to be dimers. Sedimentation analysis showed that extensin exists in a rapid monomer-dimer equilibrium in the concentration range and buffer used. Sedimentation equilibrium data gave a Kd of 8.5 microM and sedimentation velocity data generated a Kd between 1 and 10 microM. The concentration dependence of the measured sedimentation coefficient was used, together with hydrodynamic bead modelling, to define plausible shapes for monomer and dimer. This suggests that monomeric extensin is an elongated rod of length 40 nm and width 2 nm, which forms staggered dimers of average length 50 nm and width 3 nm. Extensin is an integral component of the primary cell wall. The physical characteristics (size, shape and form) of the rod-like extensin have been evaluated in this paper so that the role that extensin plays in primary cell wall architecture and during plant disease resistance can be

  10. Drugs That Target Dynamic Microtubules: A New Molecular Perspective

    PubMed Central

    Stanton, Richard A.; Gernert, Kim M.; Nettles, James H.; Aneja, Ritu

    2011-01-01

    Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work. PMID:21381049

  11. Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia

    PubMed Central

    Gray, John A.; Roth, Bryan L.

    2007-01-01

    Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently precede the onset of other positive symptoms, persist even with successful treatment of positive symptoms, and account for a significant portion of functional impairment in schizophrenia. While the atypical antipsychotics have produced incremental improvements in the cognitive function of patients with schizophrenia, overall treatment remains inadequate. In recent years, there has been an increased interest in developing novel strategies for treating the cognitive deficits in schizophrenia, focusing on ameliorating impairments in working memory, attention, and social cognition. Here we review various molecular targets that are actively being explored for potential drug discovery efforts in schizophrenia and cognition. These molecular targets include dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the γ-aminobutyric acid (GABA) system. PMID:17617664

  12. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

    PubMed Central

    2010-01-01

    In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients. PMID:20385023

  13. Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma

    PubMed Central

    Wachsmann, Jason; Peng, Fangyu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC. PMID:26755872

  14. Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma.

    PubMed

    Wachsmann, Jason; Peng, Fangyu

    2016-01-07

    Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC.

  15. Multimodality molecular imaging--from target description to clinical studies.

    PubMed

    Schober, O; Rahbar, K; Riemann, B

    2009-02-01

    This highlight lecture was presented at the closing session of the Annual Congress of the European Association of Nuclear Medicine (EANM) in Munich on 15 October 2008. The Congress was a great success: there were more than 4,000 participants, and 1,597 abstracts were submitted. Of these, 1,387 were accepted for oral or poster presentation, with a rejection rate of 14%. In this article a choice was made from 100 of the 500 lectures which received the highest scores by the scientific review panel. This article outlines the major findings and trends at the EANM 2008, and is only a brief summary of the large number of outstanding abstracts presented. Among the great number of oral and poster presentations covering nearly all fields of nuclear medicine some headlines have to be defined highlighting the development of nuclear medicine in the 21st century. This review focuses on the increasing impact of molecular and multimodality imaging in the field of nuclear medicine. In addition, the question may be asked as to whether the whole spectrum of nuclear medicine is nothing other than molecular imaging and therapy. Furthermore, molecular imaging will and has to go ahead to multimodality imaging. In view of this background the review was structured according to the single steps of molecular imaging, i.e. from target description to clinical studies. The following topics are addressed: targets, radiochemistry and radiopharmacy, devices and computer science, animals and preclinical evaluations, and patients and clinical evaluations.

  16. Improving the embryo implantation via novel molecular targets.

    PubMed

    Li, Jingjie; Liang, Xiaoyan; Chen, Zijiang

    2013-07-01

    With the development of modern assisted reproductive technology(ART), the treatment of infertility and the pregnant outcome by ART have been significantly improved. However, implantation failure, particularly the unexplained repeated implantation failure (RIF), is still the unsolved and principal problem to affect the outcome of ART. The completed embryo, the receptive uterus and a series of precisely controlled molecular events between the blastocyst and endometrium are all indispensable for the success of implantation. Thus, deep insight into the molecular mechanisms that impact the endometrial receptivity and embryo implantation is an effective way to improve the implantation rate. Here the novel molecular targets and biomarkers have been reviewed that are reported and proved during more recent years in the aspects of ion channels, aquaporins, long noncoding RNAs and microRNAs, kruppel like factors, metabolism related molecules and the endogenous retroviruses. Evaluation of implantation markers may help clinicians to predict pregnancy outcome and detect occult implantation deficiency. Moreover, these novel molecular targets are expected to apply to the clinical practice from bench to bedside and improve the implantation efficiency in ART and natural conception.

  17. Nanomedicine strategies for molecular targets with MRI and optical imaging

    PubMed Central

    Pan, Dipanjan; Caruthers, Shelton D; Chen, Junjie; Winter, Patrick M; SenPan, Angana; Schmieder, Anne H; Wickline, Samuel A

    2010-01-01

    The science of ‘theranostics’ plays a crucial role in personalized medicine, which represents the future of patient management. Over the last decade an increasing research effort has focused on the development of nanoparticle-based molecular-imaging and drug-delivery approaches, emerging as a multidisciplinary field that shows promise in understanding the components, processes, dynamics and therapies of a disease at a molecular level. The potential of nanometer-sized agents for early detection, diagnosis and personalized treatment of diseases is extraordinary. They have found applications in almost all clinically relevant biomedical imaging modality. In this review, a number of these approaches will be presented with a particular emphasis on MRI and optical imaging-based techniques. We have discussed both established molecular-imaging approaches and recently developed innovative strategies, highlighting the seminal studies and a number of successful examples of theranostic nanomedicine, especially in the areas of cardiovascular and cancer therapy. PMID:20485473

  18. Nanobubble-Affibody: Novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor.

    PubMed

    Yang, Hengli; Cai, Wenbin; Xu, Lei; Lv, Xiuhua; Qiao, Youbei; Li, Pan; Wu, Hong; Yang, Yilin; Zhang, Li; Duan, Yunyou

    2015-01-01

    Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 ± 29.7 nm with polydispersity index of 0.164 ± 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 ± 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy.

    PubMed

    Ding, Li; Tian, Caiping; Feng, Song; Fida, Guissi; Zhang, Congying; Ma, Yuxiang; Ai, Guanhua; Achilefu, Samuel; Gu, Yueqing

    2015-01-01

    Targeting tumors using miniature antibodies is a novel and attractive therapeutic approach, as these biomolecules exhibit low immunogenicity, rapid clearance, and high targeting specificity. However, most of the small-sized antibodies in existence do not exhibit marked anti-tumor effects, which limit their use in targeted cancer immunotherapy. To overcome this difficulty in targeting multiple biomarkers by combination therapies, we designed a new bifunctional antibody, named MaAbNA (multivalent antibody comprised of nanobody and affibody moieties), capable of targeting EGFR1 and HER2, which are widely overexpressed in a variety of tumor types. The small-sized (29 kDa) MaAbNA, which was expressed in E.coli, consists of one anti-EGFR1 nanobody and two anti-HER2 affibodies, and possesses high affinity (KD) for EGFR1 (~4.1 nM) and HER2 (~4.7 nM). In order to enhance its anti-tumor activity, MaAbNA was conjugated with adriamycin (ADM) using a PEG2000 linker, forming a new complex anticancer drug, MaAbNA-PEG2000-ADM. MaAbNA exhibited high inhibitory effects on tumor cells over-expressing both EGFR1 and HER2, but displayed minimal cytotoxicity in cells expressing low levels of EGFR1 and HER2. Moreover, MaAbNA-PEG2000-ADM displayed increased tumoricidal effects than ADM or MaAbNA alone, as well exhibited greater antitumor efficacy than EGFR1 (Cetuximab) and HER2 (Herceptin) antibody drugs. The ability of MaAbNA to regulate expression of downstream oncogenes c-jun, c-fos, c-myc, as well as AEG-1 for therapeutic potential was evaluated by qPCR and western-blot analyses. The antitumor efficacy of MaAbNA and its derivative MaAbNA-PEG2000-ADM were validated in vivo, highlighting the potential for use of MaAbNA as a highly tumor-specific dual molecular imaging probe and targeted cancer therapeutic.

  20. Antiepileptic drug effects on mood and behavior: molecular targets.

    PubMed

    Perucca, Piero; Mula, Marco

    2013-03-01

    With almost 100 years of clinical experience, antiepileptic drugs (AEDs) remain the mainstay of epilepsy treatment. They suppress epileptic seizures by acting on a variety of mechanisms and molecular targets involved in the regulation of neuronal excitability. These include inhibitory-GABAergic and excitatory-glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. On the other hand, accruing evidence indicates that these mechanisms and targets are also implicated in the regulation of mood and behavior, which may explain why each AED is associated with specific psychotropic effects. These effects, however, cannot be explained solely on the basis of the known mode of action of each AED, and other mechanisms or targets are likely to be implicated. In this article, we review positive and negative effects of AEDs on mood and behavior, discuss putative underlying mechanisms, and highlight knowledge gaps which should be addressed in future studies.

  1. Central and Peripheral Molecular Targets for Anti-Obesity Pharmacotherapy

    PubMed Central

    Valentino, Michael A.; Lin, Jieru E.; Waldman, Scott A.

    2011-01-01

    Obesity has emerged as one of the principle worldwide health concerns of the modern era, and there exists a tremendous unmet clinical need for safe and effective therapies to combat this global pandemic. The prevalence of obesity and its associated co-morbidities, including cardiovascular and metabolic diseases, has focused drug discovery and development on generating effective modalities for the treatment and prevention of obesity. Early efforts in the field of obesity pharmacotherapy centered on agents with indeterminate mechanisms of action producing treatment paradigms characterized by significant off-target effects. During the past two decades, new insights have been made into the physiologic regulation of energy balance and the subordinate central and peripheral circuits coordinating appetite, metabolism, and lipogenesis. These studies have revealed previously unrecognized molecular targets for controlling appetite and managing weight from which has emerged a new wave of targeted pharmacotherapies to prevent and control obesity. PMID:20445536

  2. Central and peripheral molecular targets for antiobesity pharmacotherapy.

    PubMed

    Valentino, M A; Lin, J E; Waldman, S A

    2010-06-01

    Obesity has emerged as one of the principal worldwide health concerns of the modern era, and there exists a tremendous unmet clinical need for safe and effective therapies to combat this global pandemic. The prevalence of obesity and its associated comorbidities, including cardiovascular and metabolic diseases, has focused the attention of those in drug discovery and development on generating effective modalities for the treatment and prevention of obesity. Early efforts in the field of obesity pharmacotherapy centered on the development of agents with indeterminate mechanisms of action. This led to treatment paradigms characterized by significant off-target effects. In the past two decades, new insights have been made into the physiologic regulation of energy balance and the subordinate central and peripheral circuits coordinating appetite, metabolism, and lipogenesis. These studies have revealed previously unrecognized molecular targets for controlling appetite and managing weight from which has emerged a new wave of targeted pharmacotherapies to prevent and control obesity.

  3. Signal Transduction and Molecular Targets of Selected Flavonoids

    PubMed Central

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  4. Non-linear molecular pattern classification using molecular beacons with multiple targets.

    PubMed

    Lee, In-Hee; Lee, Seung Hwan; Park, Tai Hyun; Zhang, Byoung-Tak

    2013-12-01

    In vitro pattern classification has been highlighted as an important future application of DNA computing. Previous work has demonstrated the feasibility of linear classifiers using DNA-based molecular computing. However, complex tasks require non-linear classification capability. Here we design a molecular beacon that can interact with multiple targets and experimentally shows that its fluorescent signals form a complex radial-basis function, enabling it to be used as a building block for non-linear molecular classification in vitro. The proposed method was successfully applied to solving artificial and real-world classification problems: XOR and microRNA expression patterns. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets.

    PubMed

    Rotsinger, Joseph E; Celada, Lindsay J; Polosukhin, Vasiliy V; Atkinson, James B; Drake, Wonder P

    2016-07-01

    Sarcoidosis is a granulomatous disease of unknown cause. Prior molecular and immunologic studies have confirmed the presence of mycobacterial virulence factors, such as catalase peroxidase and superoxide dismutase A, within sarcoidosis granulomas. Molecular analysis of granulomas can identify targets of known antibiotics classes. Currently, major antibiotics are directed against DNA synthesis, protein synthesis, and cell wall formation. We conducted molecular analysis of 40 sarcoidosis diagnostic specimens and compared them with 33 disease control specimens for the presence of mycobacterial genes that encode antibiotic targets. We assessed for genes involved in DNA synthesis (DNA gyrase A [gyrA] and DNA gyrase B), protein synthesis (RNA polymerase subunit β), cell wall synthesis (embCAB operon and enoyl reductase), and catalase peroxidase. Immunohistochemical analysis was conducted to investigate the locale of mycobacterial genes such as gyrA within 12 sarcoidosis specimens and 12 disease controls. Mycobacterial DNA was detected in 33 of 39 sarcoidosis specimens by quantitative real-time polymerase chain reaction compared with 2 of 30 disease control specimens (P < 0.001, two-tailed Fisher's test). Twenty of 39 were positive for three or more mycobacterial genes, compared with 1 of 30 control specimens (P < 0.001, two-tailed Fisher's test). Immunohistochemistry analysis localized mycobacterial gyrA nucleic acids to sites of granuloma formation in 9 of 12 sarcoidosis specimens compared with 1 of 12 disease controls (P < 0.01). Microbial genes encoding enzymes that can be targeted by currently available antimycobacterial antibiotics are present in sarcoidosis specimens and localize to sites of granulomatous inflammation. Use of antimicrobials directed against target enzymes may be an innovative treatment alternative.

  6. Chemotherapy and molecular targeting therapy for recurrent cervical cancer

    PubMed Central

    Tsuda, Naotake; Watari, Hidemichi; Ushijima, Kimio

    2016-01-01

    For patients with primary stage ⅣB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords: “uterine cervical cancer”, “chemotherapy”, and “targeted therapies”. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase Ⅲ trials. To examine the best agent to combine with cisplatin, several landmark phase Ⅲ clinical trials were conducted by Gynecologic Oncology Group (GOG) and Japan Clinical Oncology Group (JCOG). Through, GOG204 and JCOG0505, paclitaxel/cisplatin (TP) and paclitaxel/carboplatin (TC) are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival (OS). Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments

  7. Chemotherapy and molecular targeting therapy for recurrent cervical cancer.

    PubMed

    Tsuda, Naotake; Watari, Hidemichi; Ushijima, Kimio

    2016-04-01

    For patients with primary stage ⅣB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords: "uterine cervical cancer", "chemotherapy", and "targeted therapies". Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase Ⅲ trials. To examine the best agent to combine with cisplatin, several landmark phase Ⅲ clinical trials were conducted by Gynecologic Oncology Group (GOG) and Japan Clinical Oncology Group (JCOG). Through, GOG204 and JCOG0505, paclitaxel/cisplatin (TP) and paclitaxel/carboplatin (TC) are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival (OS). Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only

  8. Quantifying the Ebbinghaus figure effect: target size, context size, and target-context distance determine the presence and direction of the illusion.

    PubMed

    Knol, Hester; Huys, Raoul; Sarrazin, Jean-Christophe; Jirsa, Viktor K

    2015-01-01

    Over the last 20 years, visual illusions, like the Ebbinghaus figure, have become widespread to investigate functional segregation of the visual system. This segregation reveals itself, so it is claimed, in the insensitivity of movement to optical illusions. This claim, however, faces contradictory results (and interpretations) in the literature. These contradictions may be due to methodological weaknesses in, and differences across studies, some of which may hide a lack of perceptual illusion effects. Indeed, despite the long history of research with the Ebbinghaus figure, standardized configurations to predict the illusion effect are missing. Here, we present a complete geometrical description of the Ebbinghaus figure with three target sizes compatible with Fitts' task. Each trial consisted of a stimulus and an isolated probe. The probe was controlled by the participant's response through a staircase procedure. The participant was asked whether the probe or target appeared bigger. The factors target size, context size, target-context distance, and a control condition resulted in a 3 × 3 × 3+3 factorial design. The results indicate that the illusion magnitude, the perceptual distinctiveness, and the response time depend on the context size, distance, and especially, target size. In 33% of the factor combinations there was no illusion effect. The illusion magnitude ranged from zero to (exceptionally) 10% of the target size. The small (or absent) illusion effects on perception and its possible influence on motor tasks might have been overlooked or misinterpreted in previous studies. Our results provide a basis for the application of the Ebbinghaus figure in psychophysical and motor control studies.

  9. Quantifying the Ebbinghaus figure effect: target size, context size, and target-context distance determine the presence and direction of the illusion

    PubMed Central

    Knol, Hester; Huys, Raoul; Sarrazin, Jean-Christophe; Jirsa, Viktor K.

    2015-01-01

    Over the last 20 years, visual illusions, like the Ebbinghaus figure, have become widespread to investigate functional segregation of the visual system. This segregation reveals itself, so it is claimed, in the insensitivity of movement to optical illusions. This claim, however, faces contradictory results (and interpretations) in the literature. These contradictions may be due to methodological weaknesses in, and differences across studies, some of which may hide a lack of perceptual illusion effects. Indeed, despite the long history of research with the Ebbinghaus figure, standardized configurations to predict the illusion effect are missing. Here, we present a complete geometrical description of the Ebbinghaus figure with three target sizes compatible with Fitts' task. Each trial consisted of a stimulus and an isolated probe. The probe was controlled by the participant's response through a staircase procedure. The participant was asked whether the probe or target appeared bigger. The factors target size, context size, target-context distance, and a control condition resulted in a 3 × 3 × 3+3 factorial design. The results indicate that the illusion magnitude, the perceptual distinctiveness, and the response time depend on the context size, distance, and especially, target size. In 33% of the factor combinations there was no illusion effect. The illusion magnitude ranged from zero to (exceptionally) 10% of the target size. The small (or absent) illusion effects on perception and its possible influence on motor tasks might have been overlooked or misinterpreted in previous studies. Our results provide a basis for the application of the Ebbinghaus figure in psychophysical and motor control studies. PMID:26583002

  10. Anti-cancer chalcones: Structural and molecular target perspectives.

    PubMed

    Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar; Asati, Vivek

    2015-06-15

    Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold remained a fascination among researchers in the 21st century due to its simple chemistry, ease of synthesis and a wide variety of promising biological activities. Several natural and (semi) synthetic chalcones have shown anti-cancer activity due to their inhibitory potential against various targets namely ABCG2/P-gp/BCRP, 5α-reductase, aromatase, 17-β-hydroxysteroid dehydrogenase, HDAC/Situin-1, proteasome, VEGF, VEGFR-2 kinase, MMP-2/9, JAK/STAT signaling pathways, CDC25B, tubulin, cathepsin-K, topoisomerase-II, Wnt, NF-κB, B-Raf and mTOR etc. In this review, a comprehensive study on molecular targets/pathways involved in carcinogenesis, mechanism of actions (MOAs), structure activity relationships (SARs) and patents granted have been highlighted. With the knowledge of molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-cancer chalcones.

  11. Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery

    PubMed Central

    Zhou, Jihan; Li, Dong; Wen, Hao; Zheng, Shuquan; Su, Cuicui; Yi, Fan; Wang, Jue; Liang, Zicai; Tang, Tao; Zhou, Demin; Zhang, Li-He; Liang, Dehai; Du, Quan

    2016-01-01

    Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications. PMID:26955887

  12. Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery

    NASA Astrophysics Data System (ADS)

    Zhou, Jihan; Li, Dong; Wen, Hao; Zheng, Shuquan; Su, Cuicui; Yi, Fan; Wang, Jue; Liang, Zicai; Tang, Tao; Zhou, Demin; Zhang, Li-He; Liang, Dehai; Du, Quan

    2016-03-01

    Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.

  13. Target-size embracing dimension for sensitive detection of viruses with various sizes and influenza virus strains.

    PubMed

    Lin, Ying-Yi; Liao, Jiunn-Der; Yang, Mei-Lin; Wu, Chao-Liang

    2012-05-15

    The focused ion beam (FIB) technique was employed to precisely fabricate hexagon-like Au nano-rods (fibAu_h) arrays as a surface enhanced Raman scattering - active substrate. A "ring diameter" (D(R)) was created by the convergence of three fibAu_h with respect to the dimension of the target viruses (D(T)), such as adenovirus (Adeno), encephalomyocarditis virus (EMCV), influenza virus (H1N1) with different sizes. Three influenza A virus strains were also compared. The results indicate that as that with a D(R)/D(T) ratio of around 1, the discrimination ability for detecting the target viruses and SERS mechanism become obvious. The enhanced lightning rod effect surrounding the seized target virus is anticipated if its size and dimension is suitably embraced within three fibAu_h. Hence the as-designed fibAu_h sample with a target-size embracing dimension provides good discrimination ability for distinguishing virus of various sizes or virus strains. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Target product selection - where can Molecular Pharming make the difference?

    PubMed

    Paul, Mathew J; Teh, Audrey Y H; Twyman, Richard M; Ma, Julian K-C

    2013-01-01

    Four major developments have taken place in the world of Molecular Pharming recently. In the USA, the DARPA initiative challenged plant biotechnology companies to develop strategies for the large-scale manufacture of influenza vaccines, resulting in a successful Phase I clinical trial; in Europe the Pharma-Planta academic consortium gained regulatory approval for a plant-derived monoclonal antibody and completed a first-in-human phase I clinical trial; the Dutch pharmaceutical company Synthon acquired the assets of Biolex Therapeutics, an established Molecular Pharming company with several clinical candidates produced in their proprietary LEX system based on aquatic plants; and finally, the Israeli biotechnology company Protalix Biotherapeutics won FDA approval for the commercial release of a recombinant form of the enzyme glucocerebrosidase produced in carrot cells, the first plant biotechnology-derived biopharmaceutical in the world approved for the market. Commercial momentum is gathering pace with additional candidates now undergoing or awaiting approval for phase III clinical trials. Filling the product pipeline is vital to establish commercial sustainability, and the selection of appropriate target products for Molecular Pharming will be a critical factor. An interesting feature of the four stories outlined above is that they span the use of very different platform technologies addressing different types of molecules which aim to satisfy distinct market demands. In each case, Molecular Pharming was an economically and technically suitable approach, but this decisionmaking process is not necessarily straightforward. Although the various technologies available to Molecular Pharming are broad ranging and flexible, competing technologies are better established, so there needs to be a compelling reason to move into plants. It is most unlikely that plant biotechnology will be the answer for the whole biologics field. In this article, we discuss the current plant

  15. Escorts Take the Lead: Molecular Chaperones as Therapeutic Targets

    PubMed Central

    Williams, Dumaine; Devi, Lakshmi A.

    2011-01-01

    The functional and physiological diversity of transmembrane receptors results from factors that influence the pharmacology, signaling, and trafficking of these receptors. Receptor mutations and other modifications may lead to misfolding, intracellular retention, and ineffective signaling of transmembrane receptors. The importance of such mutations is highlighted by the fact that various diseases have been linked to mutations that lead to ineffective signaling of these receptors, resulting from the retention of receptors in intracellular compartments. Studies focused on understanding the regulation of trafficking and cell surface expression of newly synthesized receptors have highlighted molecular chaperones as key regulators of receptor maturation and sorting. In this chapter, we discuss the functions of molecular chaperones in the regulation of seven-transmembrane-containing G-protein-coupled receptor function and trafficking and explore ways in which chaperones can serve as novel therapeutic targets. PMID:20691961

  16. Targeted agri-environment schemes significantly improve the population size of common farmland bumblebee species.

    PubMed

    Wood, Thomas J; Holland, John M; Hughes, William O H; Goulson, Dave

    2015-04-01

    Changes in agricultural practice across Europe and North America have been associated with range contractions and local extinction of bumblebees (Bombus spp.). A number of agri-environment schemes have been implemented to halt and reverse these declines, predominantly revolving around the provision of additional forage plants. Although it has been demonstrated that these schemes can attract substantial numbers of foraging bumblebees, it remains unclear to what extent they actually increase bumblebee populations. We used standardized transect walks and molecular techniques to compare the size of bumblebee populations between Higher Level Stewardship (HLS) farms implementing pollinator-friendly schemes and Entry Level Stewardship (ELS) control farms. Bumblebee abundance on the transect walks was significantly higher on HLS farms than ELS farms. Molecular analysis suggested maximum foraging ranges of 566 m for Bombus hortorum, 714 m for B. lapidarius, 363 m for B. pascuorum and 799 m for B. terrestris. Substantial differences in maximum foraging range were found within bumblebee species between farm types. Accounting for foraging range differences, B. hortorum (47 vs 13 nests/km(2) ) and B. lapidarius (45 vs 22 nests/km(2) ) were found to nest at significantly greater densities on HLS farms than ELS farms. There were no significant differences between farm type for B. terrestris (88 vs 38 nests/km(2) ) and B. pascuorum (32 vs 39 nests/km(2) ). Across all bumblebee species, HLS management had a significantly positive effect on bumblebee nest density. These results show that targeted agri-environment schemes that increase the availability of suitable forage can significantly increase the size of wild bumblebee populations.

  17. Cytoreductive surgery in the era of targeted molecular therapy

    PubMed Central

    Thomas, Arun Z.; Adibi, Mehrad; Borregales, Leonardo D.; Karam, Jose A.

    2015-01-01

    Cytoreductive nephrectomy (CN) was regarded standard of care for patients with metastatic renal cell carcinoma (mRCC) in the immunotherapy era. With the advent of targeted molecular therapy (TMT) for the treatment of mRCC, the routine use of CN has been questioned. Up to date evidence continues to suggest that CN remains an integral part of treatment in appropriately selected patients. This review details the original context in which the efficacy of CN was established and rationale for the continued use of cytoreductive surgery in the era of TMT. PMID:26815334

  18. Molecular Targets in Alzheimer's Disease: From Pathogenesis to Therapeutics.

    PubMed

    Cheng, Xuan; Zhang, Lu; Lian, Ya-Jun

    2015-01-01

    Alzheimer's disease (AD) is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD.

  19. Affibody molecules: new protein domains for molecular imaging and targeted tumor therapy.

    PubMed

    Nilsson, Fredrik Y; Tolmachev, Vladimir

    2007-03-01

    Molecular imaging shows promise as a useful tool to aid drug discovery and development and also to provide important prognostic and predictive diagnostic information affecting patient management in the clinic. However, the use of molecular imaging diagnostically is not widely adopted, in part due to the lack of suitable targeting agents. Affibody molecules are a class of small and very stable protein domains, which can be used to selectively address a wide range of protein targets. Their small size enables high contrast radionuclide imaging and they can be produced by conventional peptide synthesis methods. Their potential utility in molecular imaging is highlighted in a large number of animal studies using anti-HER2 Affibody tracers and has recently been validated in breast cancer patients with HER2-expressing metastases. The therapeutic efficacy of the Affibody molecules in this indication was demonstrated in preclinical models using a targeted radionuclide as the effector function. This review will focus on the recent use of Affibody molecules for molecular imaging and their application for radioimmunotherapy.

  20. Optimal target VOI size for accurate 4D coregistration of DCE-MRI

    NASA Astrophysics Data System (ADS)

    Park, Brian; Mikheev, Artem; Zaim Wadghiri, Youssef; Bertrand, Anne; Novikov, Dmitry; Chandarana, Hersh; Rusinek, Henry

    2016-03-01

    Dynamic contrast enhanced (DCE) MRI has emerged as a reliable and diagnostically useful functional imaging technique. DCE protocol typically lasts 3-15 minutes and results in a time series of N volumes. For automated analysis, it is important that volumes acquired at different times be spatially coregistered. We have recently introduced a novel 4D, or volume time series, coregistration tool based on a user-specified target volume of interest (VOI). However, the relationship between coregistration accuracy and target VOI size has not been investigated. In this study, coregistration accuracy was quantitatively measured using various sized target VOIs. Coregistration of 10 DCE-MRI mouse head image sets were performed with various sized VOIs targeting the mouse brain. Accuracy was quantified by measures based on the union and standard deviation of the coregistered volume time series. Coregistration accuracy was determined to improve rapidly as the size of the VOI increased and approached the approximate volume of the target (mouse brain). Further inflation of the VOI beyond the volume of the target (mouse brain) only marginally improved coregistration accuracy. The CPU time needed to accomplish coregistration is a linear function of N that varied gradually with VOI size. From the results of this study, we recommend the optimal size of the VOI to be slightly overinclusive, approximately by 5 voxels, of the target for computationally efficient and accurate coregistration.

  1. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.

    PubMed

    Capurso, Gabriele; Archibugi, Livia; Delle Fave, Gianfranco

    2015-08-01

    Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

  2. [Bioinformatics of tumor molecular targets from big data].

    PubMed

    Huang, Jinyan; Yu, Yingyan

    2015-01-01

    The big data from high throughput research disclosed 4V features: volume of data, variety of data, value for deep mining, and velocity of processing speed. Regarding the whole genome sequencing for human sample, at average 30x of coverage, a total of 100 GB of original data (compression FASTQ format) could be produced. Replying to the binary BAM format, a total of 150 GB data could be produced. In the analysis of high throughput data, we need to combine both clinical information and pathological features. In addition, the data sources of medical research involved in ethical and privacy of patients. At present, the costs are gradually cheaper. For example, a whole genome sequencing by Illumina X Ten with 30x coverage costs about 10,000 RMB, and RNA-seq costs 5000 RMB for a single sample. Therefore, cancer genome research provides opportunities for discovery of molecular targets, but also brings enormous challenges on the data integration and utilization. This article introduces methodologies for high throughput data analysis and processing, and explains possible application on molecular target discovery.

  3. A robust close-range photogrammetric target extraction algorithm for size and type variant targets

    NASA Astrophysics Data System (ADS)

    Nyarko, Kofi; Thomas, Clayton; Torres, Gilbert

    2016-05-01

    The Photo-G program conducted by Naval Air Systems Command at the Atlantic Test Range in Patuxent River, Maryland, uses photogrammetric analysis of large amounts of real-world imagery to characterize the motion of objects in a 3-D scene. Current approaches involve several independent processes including target acquisition, target identification, 2-D tracking of image features, and 3-D kinematic state estimation. Each process has its own inherent complications and corresponding degrees of both human intervention and computational complexity. One approach being explored for automated target acquisition relies on exploiting the pixel intensity distributions of photogrammetric targets, which tend to be patterns with bimodal intensity distributions. The bimodal distribution partitioning algorithm utilizes this distribution to automatically deconstruct a video frame into regions of interest (ROI) that are merged and expanded to target boundaries, from which ROI centroids are extracted to mark target acquisition points. This process has proved to be scale, position and orientation invariant, as well as fairly insensitive to global uniform intensity disparities.

  4. Targeting chk2 kinase: molecular interaction maps and therapeutic rationale.

    PubMed

    Pommier, Yves; Sordet, Olivier; Rao, V Ashutosh; Zhang, Hongliang; Kohn, Kurt W

    2005-01-01

    Most anticancer drugs presently used clinically target genomic DNA. The selectivity of these anticancer drugs for tumor tissues is probably due to tumor-specific defects suppressing cell cycle checkpoints and DNA repair, and enhancing apoptotic response in the tumor. We will review the molecular interactions within the ATM-Chk2 pathway implicating the DNA damage sensor kinases (ATM, ATR and DNA-PK), the adaptor BRCT proteins (Nbs1, Brca1, 53BP1, MDC1) and the effector kinases (Chk2, Chk1, Plk3, JNK, p38). The molecular interaction map convention (MIM) will be used for presenting this molecular network (http://discover.nci.nih.gov/mim/). A characteristic of the ATM-Chk2 pathway is its redundancy. First, ATM and Chk2 phosphorylate common substrates including p53, E2F1, BRCA1, and Chk2 itself, which suggests that Chk2 (also known as CHECK2, Cds1 in fission yeast, and Dmchk2 or Dmnk or Loki in the fruit fly) acts as a relay for ATM and/or as a salvage pathway when ATM is inactivated. Secondly, redundancy is apparent for the substrates, which can be phosphorylated/activated at similar residues by Chk2, Chk1, and the polo kinases (Plk's). Functionally, Chk2 can activate both apoptosis (via p53, E2F1 and PML) and cell cycle checkpoint (via Cdc25A and Cdc25C, p53, and BRCA1). We will review the short list of published Chk2 inhibitors. We will also propose a novel paradigm for screening interfacial inhibitors of Chk2. Chk2 inhibitors might be used to enhance the tumor selectivity of DNA targeted agents in p53-deficient tumors, and for the treatment of tumors whose growth depends on enhanced Chk2 activity.

  5. CD19 as a molecular target in CNS autoimmunity

    PubMed Central

    Stüve, Olaf; Warnke, Clemens; Deason, Krystin; Stangel, Martin; Kieseier, Bernd C.; Hartung, Hans-Peter; von Büdingen, Hans-Christian; Centonze, Diego; Forsthuber, Thomas G.; Kappertz, Volker

    2015-01-01

    Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the most prevalent neuroinflammatory diseases of the central nervous system (CNS). The immunological cascade of these disorders is complex, and the exact spatial and temporal role of different immune cells is not fully understood. Although MS has been considered for many years to be primarily T cell driven, it is well established that B cells and the humoral immune response play an important role in its pathogenesis. This has long been evident from laboratory findings that include the presence of oligoclonal bands in the CSF. In NMO the importance of the humoral immune system appears even more obvious as evidenced by pathogenic antibodies against aquaporin 4 (AQP4). Besides their capacity to mature into antibody-producing plasma cells, B cells are potent antigen presenting cells to T lymphocytes and they can provide soluble factors for cell activation and differentiation to other immune-competent cells. In MS and NMO, there are substantial data from clinical trials that B cell depletion with CD20-directed agents is effective and relatively safe. Plasma cells, which produce antibodies against molecular targets expressed by the host, but which also provide humeral immune responses against pathogens, are not targeted by anti-CD20 therapies. Therefore the depletion of CD19-expressing cells would offer potential advantages with regard to efficacy, but potentially higher risks with regard to infectious complications. This review will outline the rationale for CD19 as a molecular target in CNS autoimmunity. The current stage of drug development is illustrated. Potential safety concerns will be discussed. PMID:24993505

  6. Molecular pathways: targeted α-particle radiation therapy.

    PubMed

    Baidoo, Kwamena E; Yong, Kwon; Brechbiel, Martin W

    2013-02-01

    An α-particle, a (4)He nucleus, is exquisitely cytotoxic and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α-radiation, the result of its high mean energy deposition [high linear energy transfer (LET)] and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells [targeted α-therapy (TAT)] with minimal normal tissue effects. A burgeoning interest in the development of TAT is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematologic cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double-strand DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly affect cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT-induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as (225)Ac, (211)At, (213)Bi, (212)Pb, and (223)Ra.

  7. Molecular Pathways: Targeted α-Particle Radiation Therapy

    PubMed Central

    Baidoo, Kwamena E.; Yong, Kwon; Brechbiel, Martin W.

    2012-01-01

    An α-particle, a 4He nucleus, is exquisitely cytotoxic, and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α radiation, the result of its high mean energy deposition (high linear energy transfer, LET) and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells (targeted α-therapy (TAT)) with minimal normal tissue effects. There is a burgeoning interest in the development of TAT that is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high-LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double strand (ds) DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly impact cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as 225Ac, 211At, 213Bi, 212Pb and 223Ra. PMID:23230321

  8. Molecular Pathways: The Necrosome-A Target for Cancer Therapy.

    PubMed

    Seifert, Lena; Miller, George

    2017-03-01

    Necroptosis is a caspase-8-independent cell death that requires coactivation of receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3) kinases. The necrosome is a complex consisting of RIP1, RIP3, and Fas-associated protein with death domain leading to activation of the pseudokinase mixed lineage kinase like followed by a rapid plasma membrane rupture and inflammatory response through the release of damage-associated molecular patterns and cytokines. The necrosome has been shown to be relevant in multiple tumor types, including pancreatic adenocarcinoma, melanoma, and several hematologic malignancies. Preclinical data suggest that targeting this complex can have differential impact on tumor progression and that the effect of necroptosis on oncogenesis is cell-type and context dependent. The emerging data suggest that targeting the necrosome may lead to immunogenic reprogramming in the tumor microenvironment in multiple tumors and that combining therapies targeting the necrosome with either conventional chemotherapy or immunotherapy may have beneficial effects. Thus, understanding the interplay of necroptotic cell death, transformed cells, and the immune system may enable the development of novel therapeutic approaches. Clin Cancer Res; 23(5); 1132-6. ©2016 AACR.

  9. Targeting Neuroendocrine Prostate Cancer: Molecular and Clinical Perspectives

    PubMed Central

    Vlachostergios, Panagiotis J.; Papandreou, Christos N.

    2015-01-01

    Neuroendocrine prostate carcinoma, either co-present with the local adenocarcinoma disease or as a result of transdifferentiation later in time, was described as one major process of emerging resistance to androgen deprivation therapies, and at the clinical level it is consistent with the development of rapidly progressive visceral disease, often in the absence of elevated serum prostate-specific antigen level. Until present, platinum-based chemotherapy has been the only treatment modality, able to produce a fair amount of responses but of short duration. Recently, several efforts for molecular characterization of this lethal phenotype have resulted in identification of novel signaling factors involved in microenvironment interactions, mitosis, and neural reprograming as potential therapeutic targets. Ongoing clinical testing of specific inhibitors of these targets, for example, Aurora kinase A inhibitors, in carefully selected patients and exploitation of expression changes of the target before and after manipulation is anticipated to increase the existing data and facilitate therapeutic decision making at this late stage of the disease when hormonal manipulations, even with the newest androgen-directed therapies are no longer feasible. PMID:25699233

  10. Radiation inactivation analysis of enzymes. Effect of free radical scavengers on apparent target sizes

    SciTech Connect

    Eichler, D.C.; Solomonson, L.P.; Barber, M.J.; McCreery, M.J.; Ness, G.C.

    1987-07-15

    In most cases the apparent target size obtained by radiation inactivation analysis corresponds to the subunit size or to the size of a multimeric complex. In this report, we examined whether the larger than expected target sizes of some enzymes could be due to secondary effects of free radicals. To test this proposal we carried out radiation inactivation analysis on Escherichia coli DNA polymerase I, Torula yeast glucose-6-phosphate dehydrogenase, Chlorella vulgaris nitrate reductase, and chicken liver sulfite oxidase in the presence and absence of free radical scavengers (benzoic acid and mannitol). In the presence of free radical scavengers, inactivation curves are shifted toward higher radiation doses. Plots of scavenger concentration versus enzyme activity showed that the protective effect of benzoic acid reached a maximum at 25 mM then declined. Mannitol alone had little effect, but appeared to broaden the maximum protective range of benzoic acid relative to concentration. The apparent target size of the polymerase activity of DNA polymerase I in the presence of free radical scavengers was about 40% of that observed in the absence of these agents. This is considerably less than the minimum polypeptide size and may reflect the actual size of the polymerase functional domain. Similar effects, but of lesser magnitude, were observed for glucose-6-phosphate dehydrogenase, nitrate reductase, and sulfite oxidase. These results suggest that secondary damage due to free radicals generated in the local environment as a result of ionizing radiation can influence the apparent target size obtained by this method.

  11. Identifying Molecular Targets of Lifestyle Modifications in Colon Cancer Prevention

    PubMed Central

    Derry, Molly M.; Raina, Komal; Agarwal, Chapla; Agarwal, Rajesh

    2013-01-01

    One in four deaths in the United States is cancer-related, and colorectal cancer (CRC) is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; approximately 20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological, and behavioral processes that could influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals. PMID:23675573

  12. Identifying molecular targets of lifestyle modifications in colon cancer prevention.

    PubMed

    Derry, Molly M; Raina, Komal; Agarwal, Chapla; Agarwal, Rajesh

    2013-01-01

    One in four deaths in the United States is cancer-related, and colorectal cancer (CRC) is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; approximately 20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological, and behavioral processes that could influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals.

  13. Breast Cancer: Current Molecular Therapeutic Targets and New Players.

    PubMed

    Nagini, Siddavaram

    2017-01-01

    Breast cancer is the most common cancer and the most frequent cause of cancer death among women worldwide. Breast cancer is a complex, heterogeneous disease classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features. Endocrine therapy, the mainstay of treatment for hormone-responsive breast cancer involves use of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs) and aromatase inhibitors (AIs). Agents that target estrogen receptor (ER) and HER2 such as tamoxifen and trastuzumab have been the most extensively used therapeutics for breast cancer. Crosstalk between ER and other signalling networks as well as epigenetic mechanisms have been envisaged to contribute to endocrine therapy resistance. TNBC, a complex, heterogeneous, aggressive form of breast cancer in which the cells do not express ER, progesterone receptor or HER2 is refractory to therapy. Several molecular targets are being explored to target TNBC including androgen receptor, epidermal growth factor receptor (EGFR), poly(ADP-ribose) polymerase (PARP), and vascular endothelial growth factor (VEGF). Receptors, protein tyrosine kinases, phosphatases, proteases, PI3K/Akt signalling pathway, microRNAs (miRs) and long noncoding RNAs (lncRNAs) are potential therapeutic targets. miR-based therapeutic approaches include inhibition of oncomiRs by antisense oligonucleotides, restoration of tumour suppressors using miR mimics, and chemical modification of miRs. The lnRNAs HOTAIR, SPRY4-IT1, GAS5, and PANDAR, new players in tumour development and prognosis may have theranostic applications in breast cancer. Several novel classes of mechanism-based drugs have been designed and synthesised for treatment of breast cancer. Integration of nucleic acid sequencing studies with mass spectrometry-based peptide sequencing and posttranslational modifications as

  14. Acoustic Molecular Imaging and Targeted Drug Delivery with Perfluorocarbon Nanoparticles

    NASA Astrophysics Data System (ADS)

    Lanza, Gregory M.; Hughes, Michael. S.; Marsh, Jon N.; Scott, Michael J.; Zhang, Huiying; Lacy, Elizabeth K.; Allen, John S.; Wickline, Samuel A.

    2005-03-01

    Advances in molecular biology and cellular biochemistry are providing new opportunities for diagnostic medical imaging to "see" beyond the anatomical manifestations of disease to the earliest biochemical signatures of disease. Liquid perfluorocarbon nanoparticles provide inherent acoustic contrast when bound to targets, e.g., fibrin deposits in a thrombus, but unbound nanoparticles are undetectable. This nanoparticle platform may be further functionalized with paramagnetic metals, such as gadolinium, or radionuclides, with homing ligands, like anti-αvβ3-integrins, and therapeutic agents. Acoustic imaging of densely distributed biomarkers, e.g., fibrin epitopes, is readily accommodated with fundamental imaging, but for sparse biomarkers, e.g., integrins, we have developed and implemented novel, nonlinear imaging techniques based upon information-theoretic receivers (i.e., thermodynamic receivers). These novel receivers allow sensitive direct imaging of contrast development.

  15. Molecular Mechanisms of Diabetic Retinopathy: Potential Therapeutic Targets

    PubMed Central

    Coucha, Maha; Elshaer, Sally L.; Eldahshan, Wael S.; Mysona, Barbara A.; El-Remessy, Azza B.

    2015-01-01

    Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in United States. Research indicates an association between oxidative stress and the development of diabetes complications. However, clinical trials with general antioxidants have failed to prove effective in diabetic patients. Mounting evidence from experimental studies that continue to elucidate the damaging effects of oxidative stress and inflammation in both vascular and neural retina suggest its critical role in the pathogenesis of DR. This review will outline the current management of DR as well as present potential experimental therapeutic interventions, focusing on molecules that link oxidative stress to inflammation to provide potential therapeutic targets for treatment or prevention of DR. Understanding the biochemical changes and the molecular events under diabetic conditions could provide new effective therapeutic tools to combat the disease. PMID:25949069

  16. Stroma-directed molecular targeted therapy in gastric cancer.

    PubMed

    Kitadai, Yasuhiko; Kodama, Michiyo; Shinagawa, Kei

    2011-12-08

    Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone, but also by a variety of stromal cells. Tumor stroma contains abundant extracellular matrix and several types of cells, including carcinoma-associated fibroblasts (CAFs), endothelial cells, pericytes and inflammatory cells including macrophages. In gastric cancer tissues, tumor cells express platelet-derived growth factor (PDGF)-B. Stromal cells, including CAFs, pericytes and lymphatic endothelial cells, express PDGF receptor (PDGFR)-β. Administration of PDGFR tyrosine kinase inhibitor significantly decreases stromal reaction, lymphatic vessel area and pericyte coverage of tumor microvessels. Administration of PDGFR tyrosine kinase inhibitor in combination with cytotoxic chemotherapeutic drug(s) impairs the progressive growth and metastasis of gastric cancer. Activated stroma might serve as a novel therapeutic target in cases of gastric cancer.

  17. Prostate cancer heterogeneity: Discovering novel molecular targets for therapy.

    PubMed

    Ciccarese, Chiara; Massari, Francesco; Iacovelli, Roberto; Fiorentino, Michelangelo; Montironi, Rodolfo; Di Nunno, Vincenzo; Giunchi, Francesca; Brunelli, Matteo; Tortora, Giampaolo

    2017-03-01

    Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies. In the future, the identification of driver mutations present at a specific stage of the disease, the classification PCa based on specific molecular alterations, and the selection of the most appropriate therapy based on biomarkers predictors of response represent the foundations for an increasingly more accurate personalized medicine.

  18. Hepatitis B virus receptors and molecular drug targets.

    PubMed

    Verrier, Eloi R; Colpitts, Che C; Sureau, Camille; Baumert, Thomas F

    2016-07-01

    Chronic hepatitis B virus (HBV) infection is a leading cause of liver disease worldwide. Virus-induced diseases include cirrhosis, liver failure and hepatocellular carcinoma. Current therapeutic strategies may at best control infection without reaching cure. Complementary antiviral strategies aimed at viral cure are therefore urgently needed. HBV entry is the first step of the infection cycle, which leads to the formation of cccDNA and the establishment of chronic infection. Viral entry may thus represent an attractive target for antiviral therapy. This review summarizes the molecular virology and cell biology of HBV entry, including the discovery and development of new HBV entry inhibitors, and discusses their potential in future treatment of HBV infection.

  19. DNA ligase IV as a new molecular target for temozolomide

    SciTech Connect

    Kondo, Natsuko; Takahashi, Akihisa; Mori, Eiichiro; Ohnishi, Ken; McKinnon, Peter J.; Sakaki, Toshisuke; Nakase, Hiroyuki; Ohnishi, Takeo

    2009-10-02

    Temozolomide (TMZ) is a methylating agent used in chemotherapy against glioblastoma. This work was designed to clarify details in repair pathways acting to remove DNA double-strand breaks (DSBs) induced by TMZ. Cultured mouse embryonic fibroblasts were used which were deficient in DSB repair genes such as homologous recombination repair-related genes X-ray repair cross-complementing group 2 (XRCC2)and radiation sensitive mutant54 (Rad54), non-homologous end joining repair-related gene DNAligase IV (Lig4). Cell sensitivity to drug treatments was assessed using colony forming assays. The most effective molecular target which was correlated with TMZ cell sensitivity was Lig4. In addition, it was found that small interference RNAs (siRNA) for Lig4 efficiently enhanced cell lethality induced by TMZ in human glioblastoma A172 cells. These findings suggest that down regulation of Lig4 might provide a useful tool for cell sensitization during TMZ chemotherapy.

  20. Chitosan Nanoparticles for Nuclear Targeting: The Effect of Nanoparticle Size and Nuclear Localization Sequence Density.

    PubMed

    Tammam, Salma N; Azzazy, Hassan M E; Breitinger, Hans G; Lamprecht, Alf

    2015-12-07

    Many recently discovered therapeutic proteins exert their main function in the nucleus, thus requiring both efficient uptake and correct intracellular targeting. Chitosan nanoparticles (NPs) have attracted interest as protein delivery vehicles due to their biocompatibility and ability to escape the endosomes offering high potential for nuclear delivery. Molecular entry into the nucleus occurs through the nuclear pore complexes, the efficiency of which is dependent on NP size and the presence of nuclear localization sequence (NLS). Chitosan nanoparticles of different sizes (S-NPs ≈ 25 nm; L-NP ≈ 150 nm) were formulated, and they were modified with different densities of the octapeptide NLS CPKKKRKV (S-NPs, 0.25, 0.5, 2.0 NLS/nm(2); L-NPs, 0.6, 0.9, 2 NLS/nm(2)). Unmodified and NLS-tagged NPs were evaluated for their protein loading capacity, extent of cell association, cell uptake, cell surface binding, and finally nuclear delivery efficiency in L929 fibroblasts. To avoid errors generated with cell fractionation and nuclear isolation protocols, nuclear delivery was assessed in intact cells utilizing Förster resonance energy transfer (FRET) fluorometry and microscopy. Although L-NPs showed ≈10-fold increase in protein loading per NP when compared to S-NPs, due to higher cell association and uptake S-NPs showed superior protein delivery. NLS exerts a size and density dependent effect on nanoparticle uptake and surface binding, with a general reduction in NP cell surface binding and an increase in cell uptake with the increase in NLS density (up to 8.4-fold increase in uptake of High-NLS-L-NPs (2 NLS/nm(2)) compared to unmodified L-NPs). However, for nuclear delivery, unmodified S-NPs show higher nuclear localization rates when compared to NLS modified NPs (up to 5-fold by FRET microscopy). For L-NPs an intermediate NLS density (0.9 NLS/nm(2)) seems to provide highest nuclear localization (3.7-fold increase in nuclear delivery compared to High

  1. Nutraceuticals: Potential for Chondroprotection and Molecular Targeting of Osteoarthritis

    PubMed Central

    Leong, Daniel J.; Choudhury, Marwa; Hirsh, David M.; Hardin, John A.; Cobelli, Neil J.; Sun, Hui B.

    2013-01-01

    Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for OA, and no effective treatments which arrest or slow its progression. Current pharmacologic treatments such as analgesics may improve pain relief but do not alter OA disease progression. Prolonged consumption of these drugs can result in severe adverse effects. Given the nature of OA, life-long treatment will likely be required to arrest or slow its progression. Consequently, there is an urgent need for OA disease-modifying therapies which also improve symptoms and are safe for clinical use over long periods of time. Nutraceuticals—food or food products that provide medical or health benefits, including the prevention and/or treatment of a disease—offer not only favorable safety profiles, but may exert disease- and symptom-modification effects in OA. Forty-seven percent of OA patients use alternative medications, including nutraceuticals. This review will overview the efficacy and mechanism of action of commonly used nutraceuticals, discuss recent experimental and clinical data on the effects of select nutraceuticals, such as phytoflavonoids, polyphenols, and bioflavonoids on OA, and highlight their known molecular actions and limitations of their current use. We will conclude with a proposed novel nutraceutical-based molecular targeting strategy for chondroprotection and OA treatment. PMID:24284399

  2. Molecular chaperones as rational drug targets for Parkinson's disease therapeutics.

    PubMed

    Kalia, S K; Kalia, L V; McLean, P J

    2010-12-01

    Parkinson's disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson's disease and of genetic susceptibility variants for idiopathic Parkinson's disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the cochaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson's disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson's disease.

  3. Evolving molecularly targeted therapies for advanced-stage thyroid cancers.

    PubMed

    Bible, Keith C; Ryder, Mabel

    2016-07-01

    Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research.

  4. TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis.

    PubMed

    Dickinson, Sally E; Wondrak, Georg T

    2017-08-28

    Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention. The role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation has now been recognized, and recently published evidence suggests that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention. Specifically, it has been shown that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. A number of TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified and are at various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Target transverse size and laser polarization effects on pair production during ultra-relativistic-intense laser interaction with solid targets

    NASA Astrophysics Data System (ADS)

    Yuan, T.; Chen, M.; Yu, J. Y.; Liu, W. Y.; Luo, W.; Weng, S. M.; Sheng, Z. M.

    2017-06-01

    Pair production from the Breit-Wheeler process in ultra-intense laser pulse interactions with solid targets are studied by particle-in-cell simulations using the EPOCH code including the quantum electrodynamics module. We find that the pair yield depends on both the target transverse size and the laser pulse duration. For a short laser pulse, the highest pair yield is achieved with a target as wide as the laser spot size. For a long laser pulse, however, the optimal target size for the pair production increases with the pulse duration due to a self-generated cone by the hole-boring process. The effect of laser polarization upon the pair production is also studied. It is found that a circularly polarized laser pulse is more efficient in the ion acceleration rather than in the pair production. With the same laser energy, we find that a linearly polarized laser pulse can generate two times more positrons than the circularly polarized laser pulse does. These findings may benefit the future researches on the laser plasma based electron-positron production.

  6. Fitts' law model and target size of pointing devices in a vibration environment.

    PubMed

    Liu, Chi No; Lin, Chiuhsiang Joe; Chao, Chin Jung

    2007-12-01

    This study examined models of Fitts' law and effective target widths of three pointing devices in vibration environments. From a research institute 10 employees, ages 26 to 31 years were recruited as paid subjects. Pointing tasks consisted of four square target sizes, four movement distances, and four target angles and were performed on a motion platform using a touch screen, a mouse, and a track ball. The platform simulated two levels of sea wave vibration environments besides a static one. Analysis showed effective target widths increased with vibration, indicating increased variability of the pointing task under vibration. The increase in the track ball was smaller, indicating resistance to motion disturbance. The study also suggests an enlarged target (button) size for the touch screen under the vibration environment. The findings have implications in motor control and human-computer interfacing.

  7. Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size.

    PubMed

    Vermeer, W M; Steenhuis, I H M; Poelman, M P

    2014-07-01

    In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a 'super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes.

  8. Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size

    PubMed Central

    Vermeer, W M; Steenhuis, I H M; Poelman, M P

    2014-01-01

    In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a ‘super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes. PMID:25033959

  9. Molecular targets of curcumin for cancer therapy: an updated review.

    PubMed

    Kasi, Pandima Devi; Tamilselvam, Rajavel; Skalicka-Woźniak, Krystyna; Nabavi, Seyed Fazel; Daglia, Maria; Bishayee, Anupam; Pazoki-Toroudi, Hamidreza; Nabavi, Seyed Mohammad

    2016-10-01

    In recent years, natural edible products have been found to be important therapeutic agents for the treatment of chronic human diseases including cancer, cardiovascular disease, and neurodegeneration. Curcumin is a well-known diarylheptanoid constituent of turmeric which possesses anticancer effects under both pre-clinical and clinical conditions. Moreover, it is well known that the anticancer effects of curcumin are primarily due to the activation of apoptotic pathways in the cancer cells as well as inhibition of tumor microenvironments like inflammation, angiogenesis, and tumor metastasis. In particular, extensive studies have demonstrated that curcumin targets numerous therapeutically important cancer signaling pathways such as p53, Ras, PI3K, AKT, Wnt-β catenin, mTOR and so on. Clinical studies also suggested that either curcumin alone or as combination with other drugs possess promising anticancer effect in cancer patients without causing any adverse effects. In this article, we critically review the available scientific evidence on the molecular targets of curcumin for the treatment of different types of cancer. In addition, we also discuss its chemistry, sources, bioavailability, and future research directions.

  10. Molecular targets in arthritis and recent trends in nanotherapy.

    PubMed

    Roy, Kislay; Kanwar, Rupinder Kaur; Kanwar, Jagat Rakesh

    2015-01-01

    Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy.

  11. RNA stabilizing proteins as molecular targets in cardiovascular pathologies

    PubMed Central

    Babu, Sahana Suresh; Joladarashi, Darukeshwara; Jeyabal, Prince; Thandavarayan, Rajarajan Amirthalingam; Krishnamurthy, Prasanna

    2015-01-01

    The stability of mRNA has emerged as a key step in the regulation of eukaryotic gene expression and function. RNA stabilizing proteins (RSPs) contain several RNA recognition motifs, and selectively bind to Adenylate- and uridylate- Rich Elements in the 3′ untranslated region of several mRNAs leading to altered processing, stability and translation. These post-transcriptional gene regulations play a critical role in cellular homeostasis; therefore act as molecular switch between ‘normal cell’ and ‘disease state’. Many mRNA binding proteins have been discovered to date, which either stabilize (HuR/HuA, HuB, HuC, HuD) or destabilize (AUF1, Tristetraprolin, KSRP) the target transcripts. Although the function of RSPs has been widely studied in cancer biology, its role in cardiovascular pathologies is only beginning to evolve. The current review provides an overall understanding of the potential role of RSP, specifically HuR-mediated mRNA stability in myocardial infarction, hypertension and hypertrophy. Also, the effect of RSPs on various cellular processes including inflammation, fibrosis, angiogenesis, cell-death and proliferation and its relevance to cardiovascular pathophysiological processes is presented. We also discuss the potential clinical implications of RSPs as therapeutic targets in cardiovascular diseases. PMID:25801788

  12. Molecular targets in arthritis and recent trends in nanotherapy

    PubMed Central

    Roy, Kislay; Kanwar, Rupinder Kaur; Kanwar, Jagat Rakesh

    2015-01-01

    Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy. PMID:26345140

  13. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    PubMed Central

    Fillat, Cristina; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano

    2011-01-01

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed. PMID:24212620

  14. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

    PubMed Central

    2015-01-01

    Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

  15. Biologic Therapy and Novel Molecular Targets of Severe Asthma.

    PubMed

    Pepper, Amber N; Renz, Harald; Casale, Thomas B; Garn, Holger

    Treatment options for severe or uncontrolled asthma are increasing, especially pertaining to novel biologic therapies. The 2 primary asthma endotypes, T2 high and T2 low, are defined by the level of type 2 T helper and innate lymphoid cell activity and mediators. Most therapies for severe asthma target T2 high asthma, including the 3 biologics approved for use in the United States and Europe: omalizumb, mepolizumb, and reslizumab. Other biologics, with various molecular targets, are under investigation. Unfortunately, treatment options for T2 low asthma are limited. Although these therapies may improve asthma symptoms, exacerbation rates, and lung function parameters, they have not been shown to modify the disease process or provide lasting benefits after discontinuation. Biomarkers identified thus far to help guide individualized therapy in severe asthma are helpful, but imperfect discriminators for picking the best option for individual patients. This review will discuss the mechanisms of action, indications, and therapeutic effects of currently available and emerging biologics for the treatment of severe or uncontrolled asthma. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  16. Motor preparation of manual aiming at a visual target manipulated in size, luminance contrast, and location.

    PubMed

    Ishihara, Masami; Imanaka, Kuniyasu

    2007-01-01

    We conducted two experiments to investigate whether the motor preparation of manual aiming to a visual target is affected by either the physical characteristics (size or luminance contrast) or spatial characteristics (location) of the target. Reaction time (RT) of both finger lifting (ie stimulus-detection time) and manual aiming (ie movement-triggering time) to the onset of the target was measured. The difference of RT (DRT) between two tasks (ie the difference of task complexity) was examined to clarify the temporal characteristics of manual aiming per se during visuomotor integration. Results show classical characteristics: RT decreased as either the target size or luminance contrast increased. Furthermore, the task-complexity and target-location factors significantly interacted with each other, where the aiming RT was longer than the finger-lifting RT and the effects of target location on RT differed for each task. However, the task factor did not interact with either the size or luminance-contrast factor, implying that the motor preparation of manual aiming is associated with the spatial characteristics rather than the physical characteristics of the target. Inspection of DRT revealed that the time needed for motor preparation for an ipsilateral target was significantly shorter than that for a contralateral target. This was the case both for the left and for the right hand. Foveal targets required longer processing time, implying a disadvantageous function of motor preparation for the gazed target. The left-hand superiority for the target appearing in the left visual field was also observed. Such lateralised effect and left-hand advantage to the left visual field in manual aiming suggest that visuospatial information processing is activated during the preparation of aiming action, with faster processing in the right hemisphere.

  17. Contact dermatitis: in pursuit of sensitizer's molecular targets through proteomics.

    PubMed

    Guedes, Sofia; Neves, Bruno; Vitorino, Rui; Domingues, Rosário; Cruz, Maria Teresa; Domingues, Pedro

    2017-02-01

    Protein haptenation, i.e., the modification of proteins by small reactive chemicals, is the key step in the sensitization phase of allergic contact dermatitis (ACD). Despite the research effort in past decades, the identification of immunogenic hapten-protein complexes that trigger a relevant pathogenic immune response in ACD, as well as the haptenation reaction molecular site, and the elements of a potentially conditioning environment during each of these stages, remain poorly understood. These questions led us to employ a proteomics-based approach to identify modified proteins in the dendritic-like cell line THP-1 sensitized with fluorescein isothiocyanate (FITC), through a combination of 2D-gel electrophoresis, nano-LC and mass spectrometry. A specific set of 39 targeted proteins was identified and comprised proteins from various cellular locations and biological functions. One of FITC targets was identified as MLK, a member of the mixed-lineage kinase family known to act as a mitogen-activated protein kinase kinase kinase and to control the activity of specific mitogen-activated protein kinase pathways, namely p38 and JNK pathways. Haptenated in the vicinity of its active site, our results point to MLK being a relevant target due to a consistent non-activation at early time points of these pathways upon FITC sensitization in THP-1 cells. Moreover, FITC pre-treatment significantly decrease phospho-p38 and phospho-JNK levels induced upon exposure to a classical activator such as lipopolysaccharide or to the sensitizer 2,4-dinitrofluorobenzene. Overall, our data point to specific amino acid residues haptenation within critical proteins as the key step in the subsequent signaling pathways modulation responsible for DC activation and maturation events.

  18. Alopecia in patients treated with molecularly targeted anticancer therapies.

    PubMed

    Belum, V R; Marulanda, K; Ensslin, C; Gorcey, L; Parikh, T; Wu, S; Busam, K J; Gerber, P A; Lacouture, M E

    2015-12-01

    The introduction of molecularly targeted anticancer therapies presents new challenges, among which dermatologic adverse events are noteworthy. Alopecia in particular is frequently reported, but the true incidence is not known. We sought to ascertain the incidence and risk of developing alopecia during treatment with approved inhibitors of oncogenic pathways and molecules [anaplastic lymphoma kinase, breakpoint cluster region-abelson, B-rapidly accelerated fibrosarcoma, Bruton's tyrosine kinase, cytotoxic T-lymphocyte antigen-4, epidermal growth factor receptor, human epidermal growth factor receptor-2, Janus kinase, MAPK/ERK (extracellular signal-regulated kinase) Kinase, mammalian target of rapamycin, smoothened, vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet derived growth factor receptor; proteasomes; CD20, CD30, CD52]. Electronic database (PubMed, Web of Science) and ASCO meeting abstract searches were conducted to identify clinical trials reporting alopecia. Meta-analysis was conducted utilizing fixed- or random-effects models. The calculated overall incidence of all-grade alopecia was 14.7% [95% confidence interval (CI) 12.6% to 17.2%]-lowest with bortezomib, 2.2% (95% CI 0.4% to 10.9%), and highest with vismodegib, 56.9% (95% CI 50.5% to 63.1%). There was an increased risk of all-grade alopecia [relative risk (RR), 7.9 (95% CI 6.2-10.09, P ≤ 0.01)] compared with placebo, but when compared with chemotherapy, the risk was lower [RR, 0.32 (95% CI 0.2-0.55, P ≤ 0.01)]. Targeted therapies are associated with an increased risk of alopecia. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Alopecia in patients treated with molecularly targeted anticancer therapies

    PubMed Central

    Belum, V. R.; Marulanda, K.; Ensslin, C.; Gorcey, L.; Parikh, T.; Wu, S.; Busam, K. J.; Gerber, P. A.; Lacouture, M. E.

    2015-01-01

    Background The introduction of molecularly targeted anticancer therapies presents new challenges, among which dermatologic adverse events are noteworthy. Alopecia in particular is frequently reported, but the true incidence is not known. Patients and methods We sought to ascertain the incidence and risk of developing alopecia during treatment with approved inhibitors of oncogenic pathways and molecules [anaplastic lymphoma kinase, breakpoint cluster region-abelson, B-rapidly accelerated fibrosarcoma, Bruton's tyrosine kinase, cytotoxic T-lymphocyte antigen-4, epidermal growth factor receptor, human epidermal growth factor receptor-2, Janus kinase, MAPK/ERK (extracellular signal-regulated kinase) Kinase, mammalian target of rapamycin, smoothened, vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet derived growth factor receptor; proteasomes; CD20, CD30, CD52]. Electronic database (PubMed, Web of Science) and ASCO meeting abstract searches were conducted to identify clinical trials reporting alopecia. Meta-analysis was conducted utilizing fixed- or random-effects models. Results The calculated overall incidence of all-grade alopecia was 14.7% [95% confidence interval (CI) 12.6% to 17.2%]—lowest with bortezomib, 2.2% (95% CI 0.4% to 10.9%), and highest with vismodegib, 56.9% (95% CI 50.5% to 63.1%). There was an increased risk of all-grade alopecia [relative risk (RR), 7.9 (95% CI 6.2–10.09, P ≤ 0.01)] compared with placebo, but when compared with chemotherapy, the risk was lower [RR, 0.32 (95% CI 0.2–0.55, P ≤ 0.01)]. Conclusions Targeted therapies are associated with an increased risk of alopecia. PMID:26387145

  20. Analysis of progress and challenges for various patterns of c-MET-targeted molecular imaging: a systematic review.

    PubMed

    Han, Zhaoguo; Wu, Yongyi; Wang, Kai; Xiao, Yadi; Cheng, Zhen; Sun, Xilin; Shen, Baozhong

    2017-12-01

    Mesenchymal-epithelial transition factor also named c-MET is a receptor tyrosine kinase for the hepatocyte growth factor that plays a pivotal role in tumorigenesis. c-MET-targeted therapies have been tested in preclinical models and patients, with significant benefits for cancer treatment. In recent years, many studies have shown that the expression level and activation status of c-MET are closely correlated to c-MET-targeted therapy response and clinical prognosis, thus highlighting the importance of evaluating the c-MET status during and prior to targeted therapy. Molecular imaging allows the monitoring of abnormal alterations of c-MET in real time and in vivo. In this review, we initially summarize the recent advances in c-MET-targeted molecular imaging, with a special focus on the development of imaging agents ranging in size from monoclonal antibody to small molecule. The aim of this review is to report the preclinical results and clinical application of all molecular imaging studies completed until now for in vivo detection of c-MET in cancer, in order to be beneficial to development of molecular probe and the combination of molecular imaging technologies for in vivo evaluation of c-MET. Various molecular probe targeted to c-MET possesses distinctive advantages and disadvantages. For example, antibody-based probes have high binding affinity but with long metabolic cycle as well as remarkable immunogenicity. Although studies for c-MET-targeted molecular imaging have made many important advances, most of imaging agents specifically target to extracellular area of c-MET receptor; however, it is difficult to reflect entirely activation of c-MET. Therefore, small molecule probes based on tyrosine kinase inhibitors, which could target to intracellular area of c-MET without any immunogenicity, should be paid more attention.

  1. Impedance modulation and feedback corrections in tracking targets of variable size and frequency.

    PubMed

    Selen, Luc P J; van Dieën, Jaap H; Beek, Peter J

    2006-11-01

    Humans are able to adjust the accuracy of their movements to the demands posed by the task at hand. The variability in task execution caused by the inherent noisiness of the neuromuscular system can be tuned to task demands by both feedforward (e.g., impedance modulation) and feedback mechanisms. In this experiment, we studied both mechanisms, using mechanical perturbations to estimate stiffness and damping as indices of impedance modulation and submovement scaling as an index of feedback driven corrections. Eight subjects tracked three differently sized targets (0.0135, 0.0270, and 0.0405 rad) moving at three different frequencies (0.20, 0.25, and 0.33 Hz). Movement variability decreased with both decreasing target size and movement frequency, whereas stiffness and damping increased with decreasing target size, independent of movement frequency. These results are consistent with the theory that mechanical impedance acts as a filter of noisy neuromuscular signals but challenge stochastic theories of motor control that do not account for impedance modulation and only partially for feedback control. Submovements during unperturbed cycles were quantified in terms of their gain, i.e., the slope between their duration and amplitude in the speed profile. Submovement gain decreased with decreasing movement frequency and increasing target size. The results were interpreted to imply that submovement gain is related to observed tracking errors and that those tracking errors are expressed in units of target size. We conclude that impedance and submovement gain modulation contribute additively to tracking accuracy.

  2. Microcavity single virus detection and sizing with molecular sensitivity

    NASA Astrophysics Data System (ADS)

    Dantham, V. R.; Holler, S.; Kolchenko, V.; Wan, Z.; Arnold, S.

    2013-02-01

    We report the label-free detection and sizing of the smallest individual RNA virus, MS2 by a spherical microcavity. Mass of this virus is ~6 ag and produces a theoretical resonance shift ~0.25 fm upon adsorbing an individual virus at the equator of the bare microcavity, which is well below the r.m.s background noise of 2 fm. However, detection was accomplished with ease (S/N = 8, Q = 4x105) using a single dipole stimulated plasmonic-nanoshell as a microcavity wavelength shift enhancer. Analytical expressions based on the "reactive sensing principle" are developed to extract the radius of the virus from the measured signals. Estimated limit of detection for these experiments was ~0.4 ag or 240 kDa below the size of all known viruses, largest globular and elongated proteins [Phosphofructokinase (345 kDa) and Fibrinogen (390 kDa), respectively].

  3. Investigations of internal noise levels for different target sizes, contrasts, and noise structures

    NASA Astrophysics Data System (ADS)

    Han, Minah; Choi, Shinkook; Baek, Jongduk

    2014-03-01

    To describe internal noise levels for different target sizes, contrasts, and noise structures, Gaussian targets with four different sizes (i.e., standard deviation of 2,4,6 and 8) and three different noise structures(i.e., white, low-pass, and highpass) were generated. The generated noise images were scaled to have standard deviation of 0.15. For each noise type, target contrasts were adjusted to have the same detectability based on NPW, and the detectability of CHO was calculated accordingly. For human observer study, 3 trained observers performed 2AFC detection tasks, and correction rate, Pc, was calculated for each task. By adding proper internal noise level to numerical observer (i.e., NPW and CHO), detectability of human observer was matched with that of numerical observers. Even though target contrasts were adjusted to have the same detectability of NPW observer, detectability of human observer decreases as the target size increases. The internal noise level varies for different target sizes, contrasts, and noise structures, demonstrating different internal noise levels should be considered in numerical observer to predict the detection performance of human observer.

  4. Interpretation of size-exclusion chromatography for the determination of molecular-size distribution of human immunoglobulins.

    PubMed

    Christians, S; Schluender, S; van Treel, N D; Behr-Gross, M-E

    2016-01-01

    Molecular-size distribution by size-exclusion chromatography (SEC) [1] is used for the quantification of unwanted aggregated forms in therapeutic polyclonal antibodies, referred to as human immunoglobulins (Ig) in the European Pharmacopoeia. Considering not only the requirements of the monographs for human normal Ig (0338, 0918 and 2788) [2-4], but also the general chapter on chromatographic techniques (2.2.46) [5], several chromatographic column types are allowed for performing this test. Although the EDQM knowledge database gives only 2 examples of suitable columns as a guide for the user, these monographs permit the use of columns with different lengths and diameters, and do not prescribe either particle size or pore size, which are considered key characteristics of SEC columns. Therefore, the columns used may differ significantly from each other with regard to peak resolution, potentially resulting in ambiguous peak identity assignment. In some cases, this may even lead to situations where the manufacturer and the Official Medicines Control Laboratory (OMCL) in charge of Official Control Authority Batch Release (OCABR) have differing molecular-size distribution profiles for aggregates of the same batch of Ig, even though both laboratories follow the requirements of the relevant monograph. In the present study, several formally acceptable columns and the peak integration results obtained therewith were compared. A standard size-exclusion column with a length of 60 cm and a particle size of 10 µm typically detects only 3 Ig fractions, namely monomers, dimers and polymers. This column type was among the first reliable HPLC columns on the market for this test and very rapidly became the standard for many pharmaceutical manufacturers and OMCLs for batch release testing. Consequently, the distribution of monomers, dimers and polymers was established as the basis for the interpretation of the results of the molecular-size distribution test in the relevant monographs

  5. Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry in vivo.

    PubMed

    Lee, Sangmin; Jung, Seulhee; Koo, Heebeom; Na, Jin Hee; Yoon, Hong Yeol; Shim, Man Kyu; Park, Jooho; Kim, Jong-Ho; Lee, Seulki; Pomper, Martin G; Kwon, Ick Chan; Ahn, Cheol-Hee; Kim, Kwangmeyung

    2017-09-18

    Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated N-azidoacetyl-d-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated 'artificial chemical receptors' containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells in vivo after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as 'artificial chemical receptors' that were conjugated to bioorthogonal chemical group-containing liposomes via in vivo click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Smaller Fixation Target Size Is Associated with More Stable Fixation and Less Variance in Threshold Sensitivity

    PubMed Central

    Okano, Kana; Koshiji, Risako; Funaki, Wakana; Shoji, Nobuyuki

    2016-01-01

    The aims of this randomized observational case control study were to quantify fixation behavior during standard automated perimetry (SAP) with different fixation targets and to evaluate the relationship between fixation behavior and threshold variability at each test point in healthy young participants experienced with perimetry. SAP was performed on the right eyes of 29 participants using the Octopus 900 perimeter, program 32, dynamic strategy. The fixation targets of Point, Cross, and Ring were used for SAP. Fixation behavior was recorded using a wearable eye-tracking glass. All participants underwent SAP twice with each fixation target in a random fashion. Fixation behavior was quantified by calculating the bivariate contour ellipse area (BCEA) and the frequency of deviation from the fixation target. The BCEAs (deg2) of Point, Cross, and Ring targets were 1.11, 1.46, and 2.02, respectively. In all cases, BCEA increased significantly with increasing fixation target size (p < 0.05). The logarithmic value of BCEA demonstrated the same tendency (p < 0.05). A positive correlation was identified between fixation behavior and threshold variability for the Point and Cross targets (ρ = 0.413–0.534, p < 0.05). Fixation behavior increased with increasing fixation target size. Moreover, a larger fixation behavior tended to be associated with a higher threshold variability. A small fixation target is recommended during the visual field test. PMID:27829030

  7. Yeast and horse liver alcohol dehydrogenases: potential problems in target size analysis and evidence for a monomer active unit

    SciTech Connect

    Suarez, M.D.; Ferguson-Miller, S.

    1987-06-16

    Yeast and horse alcohol dehydrogenases are commonly used as standards for radiation inactivation analysis of proteins, usually assuming that the minimal functional unit corresponds to the physical size in solution, a tetramer (M/sub r/ = 148,000) and a dimer (M/sub r/ = 80,000), respectively. Results described in this paper demonstrate that molecular weight overestimates may be obtained for the yeast protein as a result of its unusual sensitivity to secondary radiation products. Irradiation in the presence of sulhydryl reagents results in a smaller functional size estimate (67,000 +/- 3000) than that obtained in their absence (128,000 +/- 5000), indicating that some sulfhydryl groups in the enzyme may be particularly susceptible to attack by radiolytic species. Analysis of the horse liver enzyme reveals that although it has structural and functional similarities to the yeast protein, it is not as prone to secondary radiation damage and gives a minimal functional size estimate (33,000 +/= 1000) that most closely corresponds to a monomer. Quantitation of disappearance of the protein from a sodium dodecyl sulfate gel as a function of radiation dose also gives a target size (48,000 +/- 3000) in reasonable agreement with the monomer molecular weight. These results indicate that the individual subunits of horse liver alcohol dehydrogenase have independent catalytic capacity and imply that the same may be true for the yeast enzyme.

  8. Calibration of the human immunoglobulin BRPs for ACA and molecular size (batch 1) and for Fc function and molecular size (batches 1 & 2).

    PubMed

    Sandberg, E; Costanzo, A; Daas, A; Buchheit, K-H

    2012-04-01

    The current European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation batch 3 (BRP3) for Human Immunoglobulin was established in 2005. Stocks of this BRP are dwindling and a replacement batch is needed to serve as working standard in the tests for distribution of molecular size by HPLC, anticomplementary activity (ACA) and Fc function, in accordance with the requirements of the Ph. Eur. monographs Human normal immunoglobulin (0338) and Human normal immunoglobulin for intravenous administration (0918). The European Directorate for the Quality of Medicines & HealthCare (EDQM) carried out a project (BSP099) to establish replacement batches for this BRP. The project was run in 2 phases, a prequalification phase (Phase 1) and an international collaborative study (Phase 2) involving 19 laboratories. Three batches of candidate materials of various sizes, Samples A, B and C, were procured from 2 different manufacturers on the European market. Based on the results of the study, Sample A was shown to be suitable as a reference standard for the ACA test and for molecular size determination by HPLC, whereas Samples B and C were demonstrated to be suitable for the Fc function test and for the molecular size determination by HPLC. All 3 BRPs are to be used in conjunction with the monographs Human normal immunoglobulin (0338) and Human normal immunoglobulin for intravenous administration (0918). The BRPs were adopted by the Ph. Eur. Commission at its 141st session in November 2011 as official Ph. Eur. Human Immunoglobulin BRPs for ACA and molecular size Batch 1 (Sample A) and Fc function and molecular size Batch 1 and Batch 2 (Samples B and C respectively).

  9. The particle size magnifier closing the gap between measurement of molecules, molecular clusters and aerosol particles

    NASA Astrophysics Data System (ADS)

    Mikkilä, Jyri; Lehtipalo, Katrianne; Kangasluoma, Juha; Franchin, Alessandro; Sipilä, Mikko; Jokinen, Tuija; Sarnela, Nina; Schobesberger, Siegfried; Junninen, Heikki; Kulmala, Markku; Worsnop, Douglas; Petäjä, Tuukka

    2013-05-01

    The Particle Size Magnifier lowers the cut-off size of a Condensation Particle Counter even down to about 1 nm in mobility diameter. By scanning the supersaturation also size information of the particles can be gained. We demonstrated that the PSM can detect particles starting from molecular sizes. By combining the data with newly developed mass spectrometric methods particle formation and growth can be followed molecule by molecule.

  10. Extinction can be estimated from moderately sized molecular phylogenies.

    PubMed

    Beaulieu, Jeremy M; O'Meara, Brian C

    2015-04-01

    Hundreds of studies have been dedicated to estimating speciation and extinction from phylogenies of extant species. Although it has long been known that estimates of extinction rates using trees of extant organisms are often uncertain, an influential paper by Rabosky (2010) suggested that when birth rates vary continuously across the tree, estimates of the extinction fraction (i.e., extinction rate/speciation rate) will appear strongly bimodal, with a peak suggesting no extinction and a peak implying speciation and extinction rates are approaching equality. On the basis of these results, and the realistic nature of this form of rate variation, it is now generally assumed by many practitioners that extinction cannot be understood from molecular phylogenies alone. Here, we reevaluated and extended the analyses of Rabosky (2010) and come to the opposite conclusion-namely, that it is possible to estimate extinction from molecular phylogenies, even with model violations due to heritable variation in diversification rate. Note that while it may be tempting to interpret our study as advocating the application of simple birth-death models, our goal here is to show how a particular model violation does not necessitate the abandonment of an entire field: use prudent caution, but do not abandon all hope. © 2015 The Author(s).

  11. Interactions between target location and reward size modulate the rate of microsaccades in monkeys.

    PubMed

    Joshua, Mati; Tokiyama, Stefanie; Lisberger, Stephen G

    2015-11-01

    We have studied how rewards modulate the occurrence of microsaccades by manipulating the size of an expected reward and the location of the cue that sets the expectations for future reward. We found an interaction between the size of the reward and the location of the cue. When monkeys fixated on a cue that signaled the size of future reward, the frequency of microsaccades was higher if the monkey expected a large vs. a small reward. When the cue was presented at a site in the visual field that was remote from the position of fixation, reward size had the opposite effect: the frequency of microsaccades was lower when the monkey was expecting a large reward. The strength of pursuit initiation also was affected by reward size and by the presence of microsaccades just before the onset of target motion. The gain of pursuit initiation increased with reward size and decreased when microsaccades occurred just before or after the onset of target motion. The effect of the reward size on pursuit initiation was much larger than any indirect effects reward might cause through modulation of the rate of microsaccades. We found only a weak relationship between microsaccade direction and the location of the exogenous cue relative to fixation position, even in experiments where the location of the cue indicated the direction of target motion. Our results indicate that the expectation of reward is a powerful modulator of the occurrence of microsaccades, perhaps through attentional mechanisms. Copyright © 2015 the American Physiological Society.

  12. Minimum radiation force target size for power measurements in focused ultrasonic fields with circular symmetry.

    PubMed

    Beissner, K

    2010-12-01

    The time-averaged ultrasonic power emitted by medical ultrasonic equipment is mostly measured using a radiation force balance, and the question of the necessary target size is of practical importance. The question is answered here by calculations based on a Rayleigh integral algorithm for fields from circular, focusing transducers. This case occurs particularly in the field of high-intensity therapeutic ultrasound. The calculation yields the necessary size of an absorbing target so that the radiation force is 98% of that exerted on an absorber of infinite lateral size, and this as a function of the transducer-to-target distance, of the transducer radius in comparison with the wavelength and of the focus (half-)angle. Several distributions of the transducer vibration amplitude are considered. The Rayleigh integral strictly applies only to planar transducers, but among the amplitude distributions there is also one that allows the simulation of the spherically curved transducer type often found in practice.

  13. Tea polyphenols, their biological effects and potential molecular targets.

    PubMed

    Chen, D; Milacic, V; Chen, M S; Wan, S B; Lam, W H; Huo, C; Landis-Piwowar, K R; Cui, Q C; Wali, A; Chan, T H; Dou, Q P

    2008-04-01

    Tea is the most popular beverage in the world, second only to water. Tea contains an infusion of the leaves from the Camellia sinensis plant rich in polyphenolic compounds known as catechins, the most abundant of which is (-)-EGCG. Although tea has been consumed for centuries, it has only recently been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. The results of several investigations indicate that green tea consumption may be of modest benefit in reducing the plasma concentration of cholesterol and preventing atherosclerosis. Additionally, the cancer-preventive effects of green tea are widely supported by results from epidemiological, cell culture, animal and clinical studies. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols were shown to affect several biological pathways, including growth factor-mediated pathway, the mitogen-activated protein (MAP) kinase-dependent pathway, and ubiquitin/proteasome degradation pathways. Various animal studies have revealed that treatment with green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Recently, phase I and II clinical trials have been conducted to explore the anticancer effects of green tea in humans. A major challenge of cancer prevention is to integrate new molecular findings into clinical practice. Therefore, identification of more molecular targets and biomarkers for tea polyphenols is essential for improving the design of green tea trials and will greatly assist in a better understanding of the mechanisms underlying its anti-cancer activity.

  14. Scientometrics of drug discovery efforts: pain-related molecular targets.

    PubMed

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I-III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I-II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009-2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004-2008 period. In addition, publications representing Phase I-III trials of investigational drugs (2009-2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics, when its

  15. Scientometrics of drug discovery efforts: pain-related molecular targets

    PubMed Central

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I–III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I–II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009–2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004–2008 period. In addition, publications representing Phase I–III trials of investigational drugs (2009–2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics

  16. Linked changes in marine dissolved organic carbon molecular size and radiocarbon age

    NASA Astrophysics Data System (ADS)

    Walker, B. D.; Primeau, F. W.; Beaupré, S. R.; Guilderson, T. P.; Druffel, E. R. M.; McCarthy, M. D.

    2016-10-01

    Marine dissolved organic carbon (DOC) is a major global carbon reservoir, yet its cycling remains poorly understood. Previous work suggests that DOC molecular size and chemical composition can significantly affect its bioavailability. Thus, DOC size and composition may control DOC cycling and radiocarbon age (via Δ14C). Here we show that DOC molecular size is correlated to DOC Δ14C in the Pacific Ocean. Our results, based on a series of increasing molecular size fractions from three depths in the Pacific, show increasing DOC Δ14C with increasing molecular size. We use a size-age distribution model to predict the DOC and Δ14C of ultrafiltered DOC. The model predicts both large and small surface DOC with high Δ14C and a narrow range (200-500 Da) of low Δ14C DOC. Deep model offsets suggest different size distributions and/or Δ14C sources at 670-915 m. Our results suggest that molecular size and composition are linked to DOC reactivity and storage in the ocean.

  17. Localized signal-to-noise ratio of man and vehicle size targets

    NASA Astrophysics Data System (ADS)

    Estrera, Joseph P.

    2009-05-01

    This paper presents analysis of digital images from single and dual sensor systems of man and vehicle size targets at low light conditions (at or below starlight conditions, 10-4 foot candles). More specifically, the image analysis will focus on measurement and interpretation of localized signal to noise ratio (LSNR) from these targets and connection to target contrast and spatial range. First, this paper will define localized signal to noise ratio and its context to information rich and poor targets to various background scenes. Then this definition will be applied to an artificially generated target to background scene composed of various gray scale square targets with various contrasts and Gaussian noise levels embedded on gray scale background with defined contrast and Gaussian noise level. The next section defines the field experiment and equipment setup to measure localized SNR for actual man and vehicle size targets in low light level conditions using a fused dual sensor system. Initial results of this field experiment shows line shape behavior of localized SNR is better represented by a decaying exponential function to spatial range likely related to Beer-Lambert Law of atmospheric radiation propagation. Finally, localized SNR is greater for fused dual sensor system as compared to its respective single sensor system modes for man and vehicle targets specified in this paper. Paper has been cleared by DOD/OSR for Public Release under OSR Ref: 07-S-1131 on April 16, 2007.

  18. PPARgamma: a novel molecular target in lung disease.

    PubMed

    Hart, C Michael; Roman, Jesse; Reddy, Raju; Sime, Patricia J

    2008-02-01

    Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled "PPARgamma: A Novel Molecular Target in Lung Disease" was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARgamma in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodulatory role of PPARgamma in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARgamma in pulmonary vascular disease. This brief introduction

  19. PPARγ: A Novel Molecular Target in Lung Disease

    PubMed Central

    Hart, C. Michael; Roman, Jesse; Reddy, Raju; Sime, Patricia J.

    2015-01-01

    Interest in peroxisome proliferator–activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled “PPARγ: A Novel Molecular Target in Lung Disease” was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARγ in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodula-tory role of PPARγ in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARγ ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARγ in pulmonary vascular disease. This brief introduction to the

  20. Aptamer-Targeted Gold Nanoparticles As Molecular-Specific Contrast Agents for Reflectance Imaging

    PubMed Central

    2008-01-01

    Targeted metallic nanoparticles have shown potential as a platform for development of molecular-specific contrast agents. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In this study, we investigated the development of aptamer-based gold nanoparticles as contrast agents, using aptamers as targeting agents and gold nanoparticles as imaging agents. We devised a novel conjugation approach using an extended aptamer design where the extension is complementary to an oligonucleotide sequence attached to the surface of the gold nanoparticles. The chemical and optical properties of the aptamer−gold conjugates were characterized using size measurements and oligonucleotide quantitation assays. We demonstrate this conjugation approach to create a contrast agent designed for detection of prostate-specific membrane antigen (PSMA), obtaining reflectance images of PSMA(+) and PSMA(−) cell lines treated with the anti-PSMA aptamer−gold conjugates. This design strategy can easily be modified to incorporate multifunctional agents as part of a multimodal platform for reflectance imaging applications. PMID:18512972

  1. Corner rounding in EUV photoresist: tuning through molecular weight, PAG size, and development time

    SciTech Connect

    Anderson, Christopher; Daggett, Joe; Naulleau, Patrick

    2009-12-31

    In this paper, the corner rounding bias of a commercially available extreme ultraviolet photoresist is monitored as molecular weight, photoacid generator (PAG) size, and development time are varied. These experiments show that PAG size influences corner biasing while molecular weight and development time do not. Large PAGs are shown to exhibit less corner biasing, and in some cases, lower corner rounding, than small PAGs. In addition, heavier resist polymers are shown to exhibit less corner rounding than lighter ones.

  2. Relationships between tumor size and curablity for uniformly targeted therapy with beta-emitting radionuclides

    SciTech Connect

    O`Donoghue, J.A.; Bardies, M.; Wheldon, T.E. |

    1995-10-01

    Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors. We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout. For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume. We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as {sup 199}Au and {sup 33}P to several centimeters for long-range emitters such as {sup 90}Y and {sup 188}Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide. 17 refs., 8 figs., 3 tabs.

  3. MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

    PubMed Central

    2010-01-01

    Background Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). Methods We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. Results Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). Conclusions Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a

  4. Intravascular photoacoustic imaging of macrophages using molecularly targeted gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Wang, Bo; Joshi, Pratixa; Sapozhnikova, Veronika; Amirian, James; Litovsky, Silvio H.; Smalling, Richard; Sokolov, Konstantin; Emelianov, Stanislav

    2010-02-01

    Using contrast agents with desired targeting moiety and optical absorption, intravascular photoacoustic imaging may be used to identify various biomarkers expressed during the progression of atherosclerotic lesions. In this paper, we present intravascular photoacoustic imaging of macrophages in the atherosclerotic lesions using bio-conjugated gold nanoparticles as the contrast agent. Atherosclerotic lesions were created in the aorta of a New Zealand white rabbit subjected to a high cholesterol diet and balloon injury. The rabbit was injected with 20 nm spherical gold nanoparticles conjugated with antibodies. The macrophages with internalized gold nanoparticles were imaged by intravascular photoacoustic imaging in the near infrared range; this was possible because of plasmon resonance coupling between closely spaced gold nanoparticles internalized by macrophages. The multi-wavelength intravascular photoacoustic images of the diseased aorta were analyzed to identify the presence and location of macrophages labeled with gold nanoparticles. Spectroscopic intravascular photoacoustic image showing the distribution of gold nanoparticles was further confirmed by the gold-specific silver staining of the tissue crosssection. The results of our study suggest that molecular intravascular photoacoustic imaging can be used to image macrophages in atherosclerosis.

  5. Chemokine receptors as new molecular targets for antiviral therapy.

    PubMed

    Santoro, F; Vassena, L; Lusso, P

    2004-04-01

    Extraordinary advancements have been made over the past decade in our understanding of the molecular mechanism of human immunodeficiency virus (HIV) entry into cells. The external HIV envelope glycoprotein, gp120, sequentially interacts with two cellular receptor molecules, the CD4 glycoprotein and a chemokine receptor, such as CCR5 or CXCR4, leading to the activation of the fusogenic domain of the transmembrane viral glycoprotein, gp41, which changes its conformation to create a hairpin structure that eventually triggers fusion between the viral and cellular membranes. Each of these discrete steps in the viral entry process represents a potential target for new antiviral agents. Current efforts to develop safe and effective HlV entry inhibitors are focused on naturally occurring proteins (e.g., chemokines, antibodies), engineered or modified derivatives of natural proteins (e.g., multimerized soluble CD4, gp41--or chemokine--derived synthetic peptides), as well as small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design. The recent introduction in therapy of the first fusion inhibitor, the gp41-derived synthetic peptide T20, heralds a new era in the treatment of AIDS, which will hopefully lead to more effective multi-drug regimens with reduced adverse effects for the patients.

  6. Emerging molecular biomarker targets for amyotrophic lateral sclerosis.

    PubMed

    Costa, Júlia; de Carvalho, Mamede

    2016-04-01

    Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis. Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis. Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.

  7. Electron beam-target interaction and spot size stabilization in flash x-ray radiography

    NASA Astrophysics Data System (ADS)

    Kwan, Thomas J. T.; Snell, Charles M.; Christenson, Peggy J.

    2000-05-01

    A high current relativistic electron beam incident on a high-Z target to produce bremsstrahlung photons for radiographic applications can be subjected to charge neutralization by target plasma ion production due to energy deposition by the electron beam. This partial charge neutralization can lead to premature focusing of the electron beam at a distance away from the target and subsequent radial divergence. Furthermore, as the ion column continues to expand, the focal point moves upstream along the path of the electron beam, causing the beam spot on the target to grow in time. The increase in radiation spot size is detrimental to the spatial resolution of radiographic images. The ion effects were confirmed via particle-in-cell simulations and analysis, and methods were investigated to suppress the growth of the electron beam spot size in single- and multiple-pulse radiographic applications. The concept of a self-biased target was proposed and validated by computer simulation showing that the electron beam can be used in a configuration to establish an electric potential between the target and the collimator. This potential can effectively trap the ions, limit the ion column length, and thereby maintain the electron beam spot size. Another approach is the placement of a thin metallic foil at 1-2 cm in front of the target, which serves as a barrier to the ions but is essentially transparent to the incoming electron beam. Our study also showed that optimized confinement of plasma ions with the electromagnetic or the mechanical method can provide an additional ion-focusing effect which leads to a desirable further reduction of the beam spot size.

  8. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

    PubMed Central

    Nunes, Renata Rachide; Costa, Marina dos Santos; Santos, Bianca dos Reis; da Fonseca, Amanda Luisa; Ferreira, Lorena Sales; Chagas, Rafael Cesar Russo; da Silva, Alisson Marques; Varotti, Fernando de Pilla; Taranto, Alex Gutterres

    2016-01-01

    The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays. PMID:27982302

  9. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets.

    PubMed

    Nunes, Renata Rachide; Costa, Marina Dos Santos; Santos, Bianca Dos Reis; Fonseca, Amanda Luisa da; Ferreira, Lorena Sales; Chagas, Rafael Cesar Russo; Silva, Alisson Marques da; Varotti, Fernando de Pilla; Taranto, Alex Gutterres

    2016-12-01

    The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.

  10. Experiments for the Undergraduate Laboratory that Illustrate the Size-Exclusion Properties of Zeolite Molecular Sieves

    ERIC Educational Resources Information Center

    Cooke, Jason; Henderson, Eric J.

    2009-01-01

    Experiments are presented that demonstrate the size-exclusion properties of zeolites and reveal the reason for naming zeolites "molecular sieves". If an IR spectrometer is available, the adsorption or exclusion of alcohols of varying sizes from dichloromethane or chloroform solutions can be readily demonstrated by monitoring changes in the…

  11. Experiments for the Undergraduate Laboratory that Illustrate the Size-Exclusion Properties of Zeolite Molecular Sieves

    ERIC Educational Resources Information Center

    Cooke, Jason; Henderson, Eric J.

    2009-01-01

    Experiments are presented that demonstrate the size-exclusion properties of zeolites and reveal the reason for naming zeolites "molecular sieves". If an IR spectrometer is available, the adsorption or exclusion of alcohols of varying sizes from dichloromethane or chloroform solutions can be readily demonstrated by monitoring changes in the…

  12. Visual Feedback and Target Size Effects on Reach-to-Grasp Tasks in Children with Autism

    ERIC Educational Resources Information Center

    Yang, Hsiu-Ching; Lee, I-Chen; Lee, I-Ching

    2014-01-01

    This study explores the effects of visual condition and target size during four reach-to-grasp tasks between autistic children and healthy controls. Twenty children with autism and 20 healthy controls participated in the study. Qualisys motion capture system and kinematic measures were used to record movement. Autistic group showed significantly…

  13. Classification of video sequences into chosen generalized use classes of target size and lighting level.

    PubMed

    Leszczuk, Mikołaj; Dudek, Łukasz; Witkowski, Marcin

    The VQiPS (Video Quality in Public Safety) Working Group, supported by the U.S. Department of Homeland Security, has been developing a user guide for public safety video applications. According to VQiPS, five parameters have particular importance influencing the ability to achieve a recognition task. They are: usage time-frame, discrimination level, target size, lighting level, and level of motion. These parameters form what are referred to as Generalized Use Classes (GUCs). The aim of our research was to develop algorithms that would automatically assist classification of input sequences into one of the GUCs. Target size and lighting level parameters were approached. The experiment described reveals the experts' ambiguity and hesitation during the manual target size determination process. However, the automatic methods developed for target size classification make it possible to determine GUC parameters with 70 % compliance to the end-users' opinion. Lighting levels of the entire sequence can be classified with an efficiency reaching 93 %. To make the algorithms available for use, a test application has been developed. It is able to process video files and display classification results, the user interface being very simple and requiring only minimal user interaction.

  14. Radiation inactivation target size of rat adipocyte glucose transporters in the plasma membrane and intracellular pools

    SciTech Connect

    Jacobs, D.B.; Berenski, C.J.; Spangler, R.A.; Jung, C.Y.

    1987-06-15

    The in situ assembly states of the glucose transport carrier protein in the plasma membrane and in the intracellular (microsomal) storage pool of rat adipocytes were assessed by studying radiation-induced inactivation of the D-glucose-sensitive cytochalasin B binding activities. High energy radiation inactivated the glucose-sensitive cytochalasin B binding of each of these membrane preparations by reducing the total number of the binding sites without affecting the dissociation constant. The reduction in total number of binding sites was analyzed as a function of radiation dose based on target theory, from which a radiation-sensitive mass (target size) was calculated. When the plasma membranes of insulin-treated adipocytes were used, a target size of approximately 58,000 daltons was obtained. For adipocyte microsomal membranes, we obtained target sizes of approximately 112,000 and 109,000 daltons prior to and after insulin treatment, respectively. In the case of microsomal membranes, however, inactivation data showed anomalously low radiation sensitivities at low radiation doses, which may be interpreted as indicating the presence of a radiation-sensitive inhibitor. These results suggest that the adipocyte glucose transporter occurs as a monomer in the plasma membrane while existing in the intracellular reserve pool either as a homodimer or as a stoichiometric complex with a protein of an approximately equal size.

  15. Visual Feedback and Target Size Effects on Reach-to-Grasp Tasks in Children with Autism

    ERIC Educational Resources Information Center

    Yang, Hsiu-Ching; Lee, I-Chen; Lee, I-Ching

    2014-01-01

    This study explores the effects of visual condition and target size during four reach-to-grasp tasks between autistic children and healthy controls. Twenty children with autism and 20 healthy controls participated in the study. Qualisys motion capture system and kinematic measures were used to record movement. Autistic group showed significantly…

  16. Phase equilibrium calculations of ternary liquid mixtures with binary interaction parameters and molecular size parameters determined from molecular dynamics.

    PubMed

    Oh, Suk Yung; Bae, Young Chan

    2010-07-15

    The method presented in this paper was developed to predict liquid-liquid equilibria in ternary liquid mixtures by using a combination of a thermodynamic model and molecular dynamics simulations. In general, common classical thermodynamic models have many parameters which are determined by fitting a model with experimental data. This proposed method, however, provides a simple procedure for calculating liquid-liquid equilibria utilizing binary interaction parameters and molecular size parameters determined from molecular dynamics simulations. This method was applied to mixtures containing water, hydrocarbons, alcohols, chlorides, ketones, acids, and other organic liquids over various temperature ranges. The predicted results agree well with the experimental data without the use of adjustable parameters.

  17. Granule size control and targeting in pulsed spray fluid bed granulation.

    PubMed

    Ehlers, Henrik; Liu, Anchang; Räikkönen, Heikki; Hatara, Juha; Antikainen, Osmo; Airaksinen, Sari; Heinämäki, Jyrki; Lou, Honxiang; Yliruusi, Jouko

    2009-07-30

    The primary aim of the study was to investigate the effects of pulsed liquid feed on granule size. The secondary aim was to increase knowledge of this technique in granule size targeting. Pulsed liquid feed refers to the pump changing between on- and off-positions in sequences, called duty cycles. One duty cycle consists of one on- and off-period. The study was performed with a laboratory-scale top-spray fluid bed granulator with duty cycle length and atomization pressure as studied variables. The liquid feed rate, amount and inlet air temperature were constant. The granules were small, indicating that the powder has only undergone ordered mixing, nucleation and early growth. The effect of atomizing pressure on granule size depends on inlet air relative humidity, with premature binder evaporation as a reason. The duty cycle length was of critical importance to the end product attributes, by defining the extent of intermittent drying and rewetting. By varying only the duty cycle length, it was possible to control granule nucleation and growth, with a wider granule size target range in increased relative humidity. The present study confirms that pulsed liquid feed in fluid bed granulation is a useful tool in end product particle size targeting.

  18. Threshold segmentation for PET target volume delineation in radiation treatment planning: the role of target-to-background ratio and target size.

    PubMed

    Brambilla, M; Matheoud, R; Secco, C; Loi, G; Krengli, M; Inglese, E

    2008-04-01

    A multivariable approach was adopted to study the dependence of the percentage threshold [TH(%)] used to define the boundaries of 18F-FDG positive tissue on emission scan duration (ESD) and activity at the start of acquisition (Aacq) for different target sizes and target-to-background (T/B) ratios. An anthropomorphic model, at least for counting rate characteristics, was used to study this dependence in conditions resembling the ones that can be encountered in the clinical studies. An annular ring of water bags of 3 cm thickness was fitted over an International Electro-technical Commission (IEC) phantom in order to obtain counting rates similar to those found in average patients. The scatter fraction of the modified IEC phantom was similar to the mean scatter fraction measured on patients, with a similar scanner. A supplemental set of microhollow spheres was positioned inside the phantom. The NEMA NU 2-2001 scatter phantom was positioned at the end of the IEC phantom to approximate the clinical situation of having activity that extends beyond the scanner field of view. The phantoms were filled with a solution of water and 18F (12 kBq/mL) and the spheres with various T/B ratios of 22.5, 10.3, and 3.6. Sequential imaging was performed to acquire PET images with varying background activity concentrations of about 12, 9, 6.4, 5.3, and 3.1 kBq/mL. The ESD was set to 60, 120, 180, and 240 s/bed. Data were fitted using two distinct multiple linear regression models for sphere ID < or = 10 mm and sphere ID > 10 mm. The fittings of both models were good with an R2 of 0.86 in both cases. Neither ESD nor Aacq resulted as significant predictors of the TH(%). For sphere ID < or =10 mm the target size was the most significant predictor of the TH(%), followed by the T/B ratio, while for sphere ID > 10 mm the explanatory power of the target size and T/B ratio were reversed, the T/B ratio being now the most important predictor of the TH(%). Both the target size and T/B ratio play a

  19. Ranking of Molecular Biomarker Interaction with Targeted DNA Nucleobases via Full Atomistic Molecular Dynamics

    PubMed Central

    Zhang, Wenjun; Wang, Ming L.; Cranford, Steven W.

    2016-01-01

    DNA-based sensors can detect disease biomarkers, including acetone and ethanol for diabetes and H2S for cardiovascular diseases. Before experimenting on thousands of potential DNA segments, we conduct full atomistic steered molecular dynamics (SMD) simulations to screen the interactions between different DNA sequences with targeted molecules to rank the nucleobase sensing performance. We study and rank the strength of interaction between four single DNA nucleotides (Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)) on single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with acetone, ethanol, H2S and HCl. By sampling forward and reverse interaction paths, we compute the free-energy profiles of eight systems for the four targeted molecules. We find that dsDNA react differently than ssDNA to the targeted molecules, requiring more energy to move the molecule close to DNA as indicated by the potential of mean force (PMF). Comparing the PMF values of different systems, we obtain a relative ranking of DNA base for the detection of each molecule. Via the same procedure, we could generate a library of DNA sequences for the detection of a wide range of chemicals. A DNA sensor array built with selected sequences differentiating many disease biomarkers can be used in disease diagnosis and monitoring. PMID:26750747

  20. Ranking of Molecular Biomarker Interaction with Targeted DNA Nucleobases via Full Atomistic Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Zhang, Wenjun; Wang, Ming L.; Cranford, Steven W.

    2016-01-01

    DNA-based sensors can detect disease biomarkers, including acetone and ethanol for diabetes and H2S for cardiovascular diseases. Before experimenting on thousands of potential DNA segments, we conduct full atomistic steered molecular dynamics (SMD) simulations to screen the interactions between different DNA sequences with targeted molecules to rank the nucleobase sensing performance. We study and rank the strength of interaction between four single DNA nucleotides (Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)) on single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with acetone, ethanol, H2S and HCl. By sampling forward and reverse interaction paths, we compute the free-energy profiles of eight systems for the four targeted molecules. We find that dsDNA react differently than ssDNA to the targeted molecules, requiring more energy to move the molecule close to DNA as indicated by the potential of mean force (PMF). Comparing the PMF values of different systems, we obtain a relative ranking of DNA base for the detection of each molecule. Via the same procedure, we could generate a library of DNA sequences for the detection of a wide range of chemicals. A DNA sensor array built with selected sequences differentiating many disease biomarkers can be used in disease diagnosis and monitoring.

  1. Molecular size distribution of compost-derived humates as a function of concentration and different counterions.

    PubMed

    Maia, Claudia M B F; Piccolo, Alessandro; Mangrich, Antonio S

    2008-11-01

    Conformational changes in the structures of humic acids (HA) extracted from compost with varying degrees of maturity were monitored by high performance size exclusion chromatography (HPSEC). The molecular size distribution of HA was compared in solutions containing sodium or ammonium counterions at pH 7 and pH 4.5. These findings indicate that the humates' molecular size depended not only on the nature of the counterions but also on their concentration in the solution. The physicochemical nature of sodium counterions determined smaller molecular sizes than those of the more hydrated ammonium counterions, at low concentrations of humates. Conversely, at higher humate concentrations, the more compact conformation of sodium humates produced larger molecular sizes than those of ammonium humates due to the aggregation of more hydrophobic surfaces in the sodium humates. Composting led to the degradation of labile microbial components with accumulation of hydrophobic constituents. This caused self-association of hydrophobic compounds into humic superstructures of larger molecular size over composting time. At lower pH, changes in conformational stability by the addition of acetic acid to humate solutions were explained by the supramolecular model of humified organic matter.

  2. Retinal proteins modified by 4-hydroxynonenal: identification of molecular targets.

    PubMed

    Kapphahn, Rebecca J; Giwa, Babatomiwa M; Berg, Kristin M; Roehrich, Heidi; Feng, Xiao; Olsen, Timothy W; Ferrington, Deborah A

    2006-07-01

    The reactive aldehyde, 4-hydroxynonenal (HNE), is a product of lipid peroxidation that can covalently modify and inactivate proteins. Previously, we reported increased HNE modification of select retinal proteins resolved by one-dimensional gel electrophoresis in aged Fisher 344 x Brown Norway rats (Louie, J.L., Kapphahn, R.J., Ferrington, D.A., 2002. Proteasome function and protein oxidation in the aged retina. Exp. Eye Res. 75, 271-284). In the current study, quantitative assessment of HNE molar content using slot blot immunoassays showed HNE content is increased 30% in aged rat retina. In contrast, there was no age-related difference in HNE content in individual spots resolved by 2D gel electrophoresis suggesting the increased modification is likely on membrane proteins that are missing on 2D gels. The HNE-immunoreactive proteins resolved by 2D gel electrophoresis were identified by MALDI-TOF mass spectrometry. These proteins are involved in metabolism, chaperone function, and fatty acid transport. Proteins that were frequently modified and had the highest molar content of HNE included triosephosphate isomerase, alpha enolase, heat shock cognate 70 and betaB2 crystallin. Immunochemical detection of HNE adducts on retinal sections showed greater immune reaction in ganglion cells, photoreceptor inner segment, and the inner plexiform layer. Identification of HNE modified proteins in two alternative model systems, human retinal pigment epithelial cells in culture (ARPE19) and human donor eyes, indicated that triosephosphate isomerase and alpha enolase are generally modified. These results identify a common subset of proteins that contain HNE adducts and suggest that select retinal proteins are molecular targets for HNE modification.

  3. Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer.

    PubMed

    Dolly, Saoirse O; Collins, Dearbhaile C; Sundar, Raghav; Popat, Sanjay; Yap, Timothy A

    2017-04-04

    Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.

  4. miR-11 regulates pupal size of Drosophila melanogaster via directly targeting Ras85D.

    PubMed

    Li, Yao; Li, Shengjie; Jin, Ping; Chen, Liming; Ma, Fei

    2017-01-01

    MicroRNAs play diverse roles in various physiological processes during Drosophila development. In the present study, we reported that miR-11 regulates pupal size during Drosophila metamorphosis via targeting Ras85D with the following evidences: pupal size was increased in the miR-11 deletion mutant; restoration of miR-11 in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant; ectopic expression of miR-11 in brain insulin-producing cells (IPCs) and whole body shows consistent alteration of pupal size; Dilps and Ras85D expressions were negatively regulated by miR-11 in vivo; miR-11 targets Ras85D through directly binding to Ras85D 3'-untranslated region in vitro; removal of one copy of Ras85D in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant. Thus, our current work provides a novel mechanism of pupal size determination by microRNAs during Drosophila melanogaster metamorphosis. Copyright © 2017 the American Physiological Society.

  5. Tuning of AcurosXB source size setting for small intracranial targets.

    PubMed

    Gardner, Stephen J; Lu, Siming; Liu, Chang; Wen, Ning; Chetty, Indrin J

    2017-05-01

    This study details a method to evaluate the source size selection for small field intracranial stereotactic radiosurgery (SRS) deliveries in Eclipse treatment planning system (TPS) for AcurosXB dose calculation algorithm. Our method uses end-to-end dosimetric data to evaluate a total of five source size selections (0.50 mm, 0.75 mm, 1.00 mm, 1.25 mm, and 1.50 mm). The dosimetric leaf gap (DLG) was varied in this analysis (three DLG values were tested for each scenario). We also tested two MLC leaf designs (standard and high-definition MLC) and two delivery types for intracranial SRS (volumetric modulated arc therapy [VMAT] and dynamic conformal arc [DCA]). Thus, a total of 10 VMAT plans and 10 DCA plans were tested for each machine type (TrueBeam [standard MLC] and Edge [high-definition MLC]). Each plan was mapped to a solid water phantom and dose was calculated with each iteration of source size and DLG value (15 total dose calculations for each plan). To measure the dose, Gafchromic film was placed in the coronal plane of the solid water phantom at isocenter. The phantom was localized via on-board CBCT and the plans were delivered at planned gantry, collimator, and couch angles. The planned and measured film dose was compared using Gamma (3.0%, 0.3 mm) criteria. The vendor-recommended 1.00 mm source size was suitable for TrueBeam planning (both VMAT and DCA planning) and Edge DCA planning. However, for Edge VMAT planning, the 0.50 mm source size yielded the highest passing rates. The difference in dose calculation among the source size variations manifested primarily in two regions of the dose calculation: (1) the shoulder of the high-dose region, and (2) for small targets (volume ≤ 0.30 cc), in the central portion of the high-dose region. Selection of a larger than optimal source size can result in increased blurring of the shoulder for all target volume sizes tested, and can result in central axis dose discrepancies in excess of 10% for target volumes sizes

  6. A molecular receptor targeted, hydroxyapatite nanocrystal based multi-modal contrast agent.

    PubMed

    Ashokan, Anusha; Menon, Deepthy; Nair, Shantikumar; Koyakutty, Manzoor

    2010-03-01

    Multi-modal molecular imaging can significantly improve the potential of non-invasive medical diagnosis by combining basic anatomical descriptions with in-depth phenotypic characteristics of disease. Contrast agents with multifunctional properties that can sense and enhance the signature of specific molecular markers, together with high biocompatibility are essential for combinatorial molecular imaging approaches. Here, we report a multi-modal contrast agent based on hydroxyapatite nanocrystals (nHAp), which is engineered to show simultaneous contrast enhancement for three major molecular imaging techniques such as magnetic resonance imaging (MRI), X-ray imaging and near-infrared (NIR) fluorescence imaging. Monodispersed nHAp crystals of average size approximately 30 nm and hexagonal crystal structure were in situ doped with multiple rare-earth impurities by a surfactant-free, aqueous wet-chemical method at 100 degrees C. Doping of nHAp with Eu(3+) (3 at%) resulted bright near-infrared fluorescence (700 nm) due to efficient (5)D(0)-(7)F(4) electronic transition and co-doping with Gd(3+) resulted enhanced paramagnetic longitudinal relaxivity (r(1) approximately 12 mM(-1) s(-1)) suitable for T(1) weighted MR imaging together with approximately 80% X-ray attenuation suitable for X-ray contrast imaging. Capability of MF-nHAp to specifically target and enhance the signature of molecular receptors (folate) in cancer cells was realized by carbodiimide grafting of cell-membrane receptor ligand folic acid (FA) on MF-nHAp surface aminized with dendrigraft polymer, polyethyleneimine (PEI). The FA-PEI-MF-nHAp conjugates showed specific aggregation on FR(+ve) cells while leaving the negative control cells untouched. Nanotoxicity evaluation of this multifunctional nHAp carried out on primary human endothelial cells (HUVEC), normal mouse lung fibroblast cell line (L929), human nasopharyngeal carcinoma (KB) and human lung cancer cell line (A549) revealed no apparent toxicity even

  7. [Molecular model of anthrax toxin translocation into target-cells].

    PubMed

    Noskov, A N

    2014-01-01

    Anthrax toxin is formed from three components: protective antigen (PA), lethal (LF) and edema (EF) factors. PA83 is cleaved by cell surface protease furin to produce a 63-kDa fragment (PA63). PA63 and LF/EF molecules are assembled to anthrax toxin complexes: oligomer PA63 x 7 + LF/EF x 3. Assembly is occurred during of binding with cellular receptor or near surface of target-cell. This toxin complex forms pore and induces receptor-mediated endocytosis. Formed endosome consists extracellular liquid with LF/EF and membrane-associated ferments (H+ and K+/Na+-ATPases) and proteins (receptors and others). H+ concentration is increased into endosome as result of K/Na-ATPase-dependent- activity of H+-ATPase. Difference of potentials (between endosome and intracellular liquid) is increased and LF/EF molecules are moved to pore and bound with PA63-oligomer to PA63 x 7 + LF/EF x 7 and full block pore (ion-selective channel). Endosome is increased in volume and induces increasing of PA63-oligomer pore to.size of effector complex: LF/EF x 7 + PAl7 x 7 = 750 kDa. Effector complex is translocated from endosome to cytosol by means high difference of potentials (H+) and dissociates from PA47 x 7 complex after cleavage of FFD315-sait by intracellular chymotrypsin-like proteases in all 7 molecules PA63. PA47 x 7 complex (strongly fixed in membrane with debris of hydrophobic loops) return into endosome and pore is destroyed. Endosome pH is decreased rapidly and PA47 x 7 complex is destroyed by endosomal/lysosomal proteases. Receptor-mediated endocytosis is ended by endosome recycling in cell-membrane.

  8. [Preparation and in vitro study of a high molecular weight contrast agent targeting hepatoma cells].

    PubMed

    Yang, Jing; Zeng, Yan; Guo, Da-Jing; Fang, Zheng; Zhao, Jian-Nong; Wang, Zhi-Gang

    2013-01-01

    To prepare a specific high molecular weight polymer contrast agent capable of specifically targeting hepatocarcinoma cells (HCC) and to investigate its affinity in vitro using HepG2 cells. The high molecular weight polymer polylactic-co-glycolic acid (PLAG)-COOH was prepared by the double emulsion technique. PLAG-COOH microbubbles were combined with glypican-3 (GPC3) antibody to generate HCC targeting high molecular polymer ultrasound contrast agents by the carbodiimide method. The affinity for HCC cells was confirmed by measuring attachment to cultured HepG2 cells by flow cytometry and comparing the results with the properties observed for non-targeted high molecular weight polymer ultrasound contrast agents. The average diameter of the targeted high molecular weight polymer ultrasound contrast agents was (800+/-10) nm. In vitro targeting of HepG2 cells showed that many of the targeted high molecular weight polymer ultrasound contrast agents attached tightly to the cell surface and that the GPC3-PLGA has a particularly strong targeting ability. A HCC-specific high molecular contrast agent, GPC3-PLGA, was synthesized and evidenced a strong targeting ability towards HepG2 cells in vitro. This new agent may be exploited to improve diagnosis of liver cancer at the molecular level.

  9. Molecular Targeted Therapy in Modern Oncology: Imaging Assessment of Treatment Response and Toxicities

    PubMed Central

    Braschi-Amirfarzan, Marta; DiPiro, Pamela J.; Jagannathan, Jyothi P.; Shinagare, Atul B.

    2017-01-01

    Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities. PMID:28096716

  10. A High-Throughput Size Exclusion Chromatography Method to Determine the Molecular Size Distribution of Meningococcal Polysaccharide Vaccine

    PubMed Central

    Khan, Imran; Rahman, K. M. Taufiqur; Siraj, S. M. Saad Us; Karim, Mahbubul; Muktadir, Abdul; Maheshwari, Arpan; Kabir, Md Azizul; Nahar, Zebun

    2016-01-01

    Molecular size distribution of meningococcal polysaccharide vaccine is a readily identifiable parameter that directly correlates with the immunogenicity. In this paper, we report a size exclusion chromatography method to determine the molecular size distribution and distribution coefficient value of meningococcal polysaccharide serogroups A, C, W, and Y in meningococcal polysaccharide (ACWY) vaccines. The analyses were performed on a XK16/70 column packed with sepharose CL-4B with six different batches of Ingovax® ACWY, a meningococcal polysaccharide vaccine produced by Incepta Vaccine Ltd., Bangladesh. A quantitative rocket immunoelectrophoresis assay was employed to determine the polysaccharide contents of each serogroup. The calculated distribution coefficient values of serogroups A, C, W, and Y were found to be 0.26 ± 0.16, 0.21 ± 0.11, 0.21 ± 0.11, and 0.14 ± 0.12, respectively, and met the requirements of British Pharmacopeia. The method was proved to be robust for determining the distribution coefficient values which is an obligatory requirement for vaccine lot release. PMID:27688770

  11. Particle size effect on velocity of gold particle embedded laser driven plastic targets

    NASA Astrophysics Data System (ADS)

    Dhareshwar, L. J.; Chaurasia, S.; Manmohan, K.; Badziak, J.; Wolowski, J.; Kasperczuk, A.; Pisarczyk, T.; Ryc, L.; Rosinski, M.; Parys, P.; Pisarczyk, P.; Ullschmidt, J.; Krousky, E.; Masek, K.

    2013-11-01

    A scheme to enhance the target foil velocity has been investigated for a direct drive inertial fusion target. Polymer PVA (polyvinyl alcohol or (C2H4O)n) target foils of thickness 15-20 μm were used in plain form and also embedded with gold in the nano-particle (Au-np) or micro-particle (Au-mp) form. Nano-particles were of 20-50 nm and micro-particles of 2-3 μm in size. 17% higher target velocity was measured for foils embedded with nano-particle gold (Au-np) as compared to targets embedded with micro-particles gold (Au-mp). The weight of gold in both cases was in the range 40-55% of the full target weight (atomic percentage of about 22%). Experiments were performed with the single beam of the Prague Asterix Laser System (PALS) at 0.43 μm wavelength (3ω of the fundamental wavelength), 120 Joule energy and 300 psec pulse duration. Laser intensity on the target was about 1015 W/cm2. A simple model has been proposed to explain the experimental results.

  12. Dimethylnitrosamine-demethylase: molecular size-dependence of repression by polynuclear hydrocarbons. Nonhydrocarbon repressors.

    PubMed

    Arcos, J C; Valle, R T; Bryant, G M; Buu-Hoi, N P; Argus, M F

    1976-01-01

    Studies with 58 polynuclear aromatic hydrocarbons have shown that to repress demethylation of dimethylnitrosamine (DMN) in rat liver, the hydrocarbons must satisfy specific requirements of molecular geometry regarding size, shape, and coplanarity. Expressing the molecular size of these planar compounds by the two-dimensional area occupied, the size for maximal repressor activity ranges between about 85 and 150 A2. In addition to being within the correct molecular size range the hydrocarbons must have an elongated-rather than compact-molecular shape; circularly shaped and/or highly symmetrical hydrocarbons, such as coronene, triphenylene, ovalene, and tetrabenzonaphthalene, have very low activity or are inactive, in spite of being in the optimum size range. Coplanarity of the molecule is a critical requirement; thus, the potent carcinogen, 9,10-dimethyl-1,2-benzanthracene, is inactive as repressor of DMN-demethylase synthesis. Two exceptions, fluoranthene and benzol[ghi] fluoranthene, showed significant induction of DMN-demethylase. The molecular size distribution of hydrocarbons that repress the DMN-demethylase shows a mirror-image relationship with respect to the earlier reported molecular size requirement for indcution of azo dye N-demethylase. Compounds other than hydrocarbons also show the mirror-image relationship in the sense that pregnenolene-16alpha-carbonitrile, alpha- and beta-naphthoflavone, and Aroclor 1254 (known to be inducers of various mixed-function oxidases) are strong repressors of DMN-demethylase. Aminoacetonitrile, a strong inhibitor of carcinogenesis by DMN, is also a potent repressor of DMN-demethylase. The enzyme is inhibited by pretreatment of the animals with cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450. Pregnenolone-16alpha-carbonitrile and 3-methylcholanthrene, despite their similarity of action on DMN-demethylase, have different effects on azo reductase, which is repressed by the former and induced by the latter

  13. Analytical performance of molecular beacons on surface immobilized gold nanoparticles of varying size and density.

    PubMed

    Uddayasankar, Uvaraj; Krull, Ulrich J

    2013-11-25

    The high quenching efficiency of metal nanoparticles has facilitated its use as quenchers in molecular beacons. To optimize this system, a good understanding of the many factors that influence molecular beacon performance is required. In this study, molecular beacon performance was evaluated as a function of gold nanoparticle size and its immobilization characteristics. Gold nanoparticles of 4 nm, 15 nm and 87 nm diameter, were immobilized onto glass slides. Each size regime offered distinctive optical properties for fluorescence quenching of molecular dyes that were conjugated to oligonucleotides that were immobilized to the gold nanoparticles. Rigid double stranded DNA was used as a model to place fluorophores at different distances from the gold nanoparticles. The effect of particle size and also the immobilization density of nanoparticles was evaluated. The 4 nm and 87 nm gold nanoparticles offered the highest sensitivity in terms of the change in fluorescence intensity as a function of distance (3-fold improvement for Cy5). The optical properties of the molecular fluorophore was of significance, with Cy5 offering higher contrast ratios than Cy3 due to the red-shifted emission spectrum relative to the plasmon peak. A high density of gold nanoparticles reduced contrast ratios, indicating preference for a monolayer of immobilized nanoparticles when considering analytical performance. Molecular beacon probes were then used in place of the double stranded oligonucleotides. There was a strong dependence of molecular beacon performance on the length of a linker used for attachment to the nanoparticle surface. The optimal optical performance was obtained with 4 nm gold nanoparticles that were immobilized as monolayers of low density (5.7×10(11)particles cm(-2)) on glass surfaces. These nanoparticle surfaces offered a 2-fold improvement in analytical performance of the molecular beacons when compared to other nanoparticle sizes investigated. The principles developed

  14. Herbal bioactivation, molecular targets and the toxicity relevance.

    PubMed

    Chen, Xiao-Wu; Serag, Erini S; Sneed, Kevin B; Zhou, Shu-Feng

    2011-07-15

    There have been increasing reports on the adverse reactions associated with herbal consumption. For many of these adverse reactions, the underlying biochemical mechanisms are unknown, but bioactivation of herbal compounds to generate reactive intermediates have been implicated. This minireview updates our knowledge on metabolic activation of herbal compounds, molecular targets and the toxicity relevance. A number of studies have documented that some herbal compounds can be converted to toxic or even carcinogenic metabolites by Phase I [e.g. cytochrome P450s (CYPs)] and less frequently by Phase II enzymes. For example, aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras and myc oncogenes and gene mutation in renal cells and finally carcinogenesis of the kidneys. Teucrin A and teuchamaedryn A, two diterpenoids found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming herbal supplements that caused severe hepatotoxicity, are converted by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase and inactivate them. Some naturally occurring alkenylbenzenes (e.g. safrole, methyleugenol and estragole) and flavonoids (e.g. quercetin) can undergo bioactivation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts. Extensive pulegone metabolism generated p-cresol that is a glutathione depletory. The hepatotoxicity of kava is possibly due to intracellular glutathione depletion and/or quinone formation. Moreover, several herbal compounds including capsaicin from chili peppers, dially sulfone in garlic, methysticin and dihydromethysticin in kava, oleuropein in olive oil, and resveratrol found in grape seeds are mechanism-based (suicide

  15. Identification of disease-relevant genes for molecularly-targeted drug discovery.

    PubMed

    Kauselmann, G; Dopazo, A; Link, W

    2012-01-01

    The current paradigm for cancer therapy is undergoing a change from non-specific cytotoxic agents to more specific approaches based on unique molecular features of cancer cells. The identification and validation of disease relevant targets are crucial for the development of molecularly targeted anticancer therapies. Advances in our understanding of the molecular basis of cancer together with novel approaches to interfere with signal transduction pathways have opened new horizons for anticancer target discovery. In particular, the image-based large scale analysis of cellular phenotypes that arise from genetic or chemical perturbations paved the way for the identification and validation of disease relevant molecular targets independent of preconceived notions of mechanistic relationships. In addition, novel and sophisticated techniques of genome manipulation allow for the use of mouse models that faithfully recapitulate critical elements of human cancer for target validation in vivo. We believe that these advances will translate into more and better validated drug targets.

  16. 48 CFR 52.219-21 - Small Business Size Representation for Targeted Industry Categories Under the Small Business...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Representation for Targeted Industry Categories Under the Small Business Competitiveness Demonstration Program... Competitiveness Demonstration Program. As prescribed in 19.1008(c), insert the following provision: Small Business Size Representation for Targeted Industry Categories Under the Small Business...

  17. Targeted Molecular Imaging in Oncology: Focus on Radiation Therapy

    PubMed Central

    Nimmagadda, Sridhar; Ford, Eric C.; Wong, John W.; Pomper, Martin G.

    2008-01-01

    Anatomically based technologies (CT, MR, etc.) are in routine use in radiotherapy for planning and assessment purposes. Even with improvements in imaging, however, radiotherapy is still limited in efficacy and toxicity in certain applications. Further advances may be provided by technologies that image the molecular activities of tumors and normal tissues. Possible uses for molecular imaging include better localization of tumor regions and early assay for the radiation response of tumors and normal tissues. Critical to the success of this approach is the identification and validation of molecular probes that are suitable in the radiotherapy context. Recent developments in molecular imaging probes and integration of functional imaging with radiotherapy are promising. This review focuses on recent advances in molecular imaging strategies and probes that may aid in improving the efficacy of radiotherapy. PMID:18314068

  18. The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas1

    PubMed Central

    Wang, Hongxiang; Xu, Tao; Jiang, Ying; Xu, Hanchong; Yan, Yong; Fu, Da; Chen, Juxiang

    2015-01-01

    Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy. PMID:25810009

  19. All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

    PubMed Central

    2016-01-01

    Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Here, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets. PMID:27128262

  20. Molecular size and solubility conditions of polysilane macromolecules with different topology

    PubMed Central

    Mavrič, Andraž; Badasyan, Artem; Fanetti, Mattia; Valant, Matjaz

    2016-01-01

    Solubility of polysilane macromolecules has so far been a scientific as well as technological problem due to a lack of understanding of their proper molecular size and agglomeration/de-agglomeration conditions. Here we show that, in contrary to previous reports, the polysilane molecules are inherently small enough to be, under right conditions, dissolved. We used a dynamic light scattering and a differential scanning calorimetry to show that even under a dilute regime the polymer molecules are agglomerated at room temperature and undergo de-agglomeration at slightly elevated temperatures of around 40 °C. The de-agglomeration results in formation of stable solutions of the polymer molecules of different topological structure in different organic solvents. We determined the polymer molecular sizes to be around 20 nm, much lower than previously reported. The measured molecular size was confirmed by transmission electron microscope imaging of the individual molecules. PMID:27748444

  1. Some effects of Field Of View (FOV) and target size on lateral tracking at hover

    NASA Technical Reports Server (NTRS)

    Breul, H. T.

    1981-01-01

    An exploratory flight-simulator experiment examined the gross effects of several factors potentially important to the design of a visual display system for aiding VTOL pilots in the difficult task of landing on a small sea-control ship. Field of view (FOV) and target size were the primary variables examined for a lateral tracking task in a full motion 5 degree-of-freedom hover simulation. The mean absolute value of tracking error was used to measure tracking performance, and cross spectral transfer function analysis was performed to determine the pilot's ability to generate good open-loop transfer function characteristics as a function of the experimental variables. It was found that FOV and target size can have a large effect on the pilot's ability to generate open-loop gain, and on his tracking performance.

  2. Variable size small targets detection using density-based clustering combined with backtracking strategy

    NASA Astrophysics Data System (ADS)

    Zhang, Haiying; Lin, Yonggui; Xiao, Fangxiong

    2016-10-01

    The series problem of infrared small target detection in heavy clutter is a challenging work in active vision. During different imaging environments the size and gray intensity of target will keep changing which lead to unstable detection. Focus on mining more robust feature of small targets and following the sequential detection framework, we propose a novel research scheme based on density-based clustering and backtracking strategy in this paper. First, point of interest is extracted by the speeded up robust feature (SURF) detector for its better performance in digging features invariant to uniform scaling, orientation and illumination changes. Second, due to the local aggregation property of target trajectory in space, a new proposed density-based clustering method is introduced to segment the target trajectory, so that the target detection problem is transformed into the extract the target trajectory. Then, In order to keep the integral and independence of the trace as much as possible, two factors: percent and are exploited to help deciding the clustering granularity. Later, the backtracking strategy is adopted to search for the target trajectory with pruning function on the basis of the consistence and continuity of the short-time target trajectory in temporal-spatial. Extended experiments show the validity of our method. Compared with the data association methods executed on the huge candidate trajectory space, the time-consuming is reduced obviously. Additional, the feature detection is more stable for the use of SURF and the false alarm suppression rate is superior to most baseline and state-of-arts methods.

  3. Molecular Composition and Photochemical Reactivity of Size-Fractionated Dissolved Organic Matter.

    PubMed

    Maizel, Andrew C; Remucal, Christina K

    2017-02-21

    The photochemical production of reactive species, such as triplet dissolved organic matter ((3)DOM) and singlet oxygen ((1)O2), contributes to the degradation of aquatic contaminants and is related to an array of DOM structural characteristics, notably molecular weight. In order to relate DOM molecular weight, optical properties, and reactive species production, Suwannee River (SRFA) and Pony Lake fulvic acid (PLFA) isolates are fractionated by sequential ultrafiltration, and the resultant fractions are evaluated in terms of molecular composition and photochemical reactivity. UV-visible measurements of aromaticity increase with molecular weight in both fulvic acids, while PLFA molecular weight fractions are shown to be structurally similar by Fourier-transform ion cyclotron resonance mass spectrometry. In addition, Bray-Curtis dissimilarity analysis of formulas identified in the isolates and their size fractions reveal that SRFA and PLFA have distinct molecular compositions. Quantum yields of (3)DOM, measured by electron and energy transfer probes, and (1)O2 decreased with molecular weight. Decreasing [(3)DOM]ss with molecular weight is shown to derive from elevated quenching in high molecular weight fractions, rather than increased (3)DOM formation. This work has implications for the photochemistry of waters undergoing natural or engineered treatment processes that alter DOM molecular weight, such as photooxidation and biological degradation.

  4. Micro- versus nano-sized molecularly imprinted polymers in MALDI-TOF mass spectrometry analysis of peptides.

    PubMed

    Cenci, Lucia; Bertolla, Maddalena; Anesi, Andrea; Ambrosi, Emmanuele; Guella, Graziano; Bossi, Alessandra Maria

    2017-08-16

    The integration of molecularly imprinted polymers (MIPs) with MALDI-TOF mass spectrometry (MS) combines MIP selectivity with MS sensitivity. Whether the size of the MIP material-micro versus nano-has an effect on the MS analysis was the object of the study. MIPs, targeting respectively the epitope peptide NR11 of cardiac troponin I and the peptide CK13 of human serum transferrin, were synthesized and characterized. The size-related performance of the MIP materials hyphenated with MALDI-TOF-MS analysis was studied by the incubation of the target peptide with the respective micro- or nano-MIP, followed by rinsing to remove non-specific deposition of the MIP to the MALDI target plate, co-crystallization with the organic matrix, and mass analysis. The quality of the MS analysis was assessed comparing the S/N of the mass peaks of the MIP-bound peptide to that of the same quantity of free peptide. Sweet spots and lower S/N (~ 1 order of magnitude) were observed for micro-MIP materials, while in the case of nano-MIP-bound peptide, the S/N was comparable to that of the free peptide, indicating higher compatibility of the nano-MIPs to MALDI-TOF-MS. The nano-MIP/MALDI-TOF-MS permitted the selective determination of the target peptide in real serum samples. Graphical abstract ᅟ.

  5. Concurrent directional adaptation of reactive saccades and hand movements to target displacements of different size.

    PubMed

    Borisova, Steliana; Bock, Otmar; Grigorova, Valentina

    2014-01-01

    When eye and hand movements are concurrently aimed at double-step targets that call for equal and opposite changes of response direction (-10° for the eyes, +10° for the hand), adaptive recalibration of both motor systems is strongly attenuated; instead, hand but not eye movements are changed by corrective strategies (V. Grigorova et al., 2013a). The authors introduce a complementary paradigm, where double-step targets call for a -10° change of eye and a -30° change for hand movements. If compared to control subjects adapting only the eyes or only the hand, adaptive improvements were comparable for the eyes but were twice as large for the hand; in contrast, eye and hand aftereffects were comparable to those in control subjects. The authors concluded that concurrent exposure of eyes and hand to steps of the same direction but different size facilitated hand strategies, but didn't affect recalibration. This finding together with previous one (V. Grigorova et al., 2013a), suggests that concurrent adaptation of eyes and hand reveals different mechanisms of recalibration for step sign and step size, which are shared by reactive saccades and hand movements. However, hand mostly benefits from strategies provoked by the difference in target step sign and size.

  6. Targeted Delivery Systems for Molecular Therapy in Skeletal Disorders

    PubMed Central

    Dang, Lei; Liu, Jin; Li, Fangfei; Wang, Luyao; Li, Defang; Guo, Baosheng; He, Xiaojuan; Jiang, Feng; Liang, Chao; Liu, Biao; Badshah, Shaikh Atik; He, Bing; Lu, Jun; Lu, Cheng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation. PMID:27011176

  7. Threshold size for optimal passive pulmonary targeting and retention of rigid microparticles in rats

    PubMed Central

    Kutscher, Hilliard L.; Chao, Piyun; Deshmukh, Manjeet; Singh, Yashveer; Hu, Peidi; Joseph, Laurie B.; Reimer, David C.; Stein, Stanley; Laskin, Debra L.; Sinko, Patrick J.

    2010-01-01

    The relationship between microparticle (MP) size and lung targeting efficiency, intra-lung distribution and retention time was systematically studied after intravenous administration of rigid fluorescent polystyrene MPs of various sizes (2, 3, 6 and 10μm) to Sprague-Dawley rats. Total fluorescence was assessed and it was found that 2μm and 3μm MPs readily passed through the lung to the liver and spleen while 10μm MPs were completely entrapped in the lung for the one-week duration of the study. Approximately 84% of 6μm MPs that were initially entrapped in the lung were cleared over the next 2 days and 15% were cleared over the remaining 5 days. A Caliper IVIS® 100 small animal imaging system confirmed that 3μm MPs were not retained in the lung but that 6μm and 10μm MPs were widely distributed throughout the lung. Moreover, histologic examination showed MP entrapment in capillaries but not arterioles. These studies suggest that for rigid MPs the optimal size range required to achieve transient but highly efficiently targeting to pulmonary capillaries after IV injection is >6μm but <10μm in rats and that systemic administration of optimally sized MPs may be an efficient alternative to currently used inhalation-based delivery to the lung. PMID:20043961

  8. Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer

    PubMed Central

    Liu, H; Lu, J; Hua, Y; Zhang, P; Liang, Z; Ruan, L; Lian, C; Shi, H; Chen, K; Tu, Z

    2015-01-01

    -dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. PMID:25590805

  9. Size and number of DNA molecules from Chinese hamster ovary cells determined by molecular autoradiography

    SciTech Connect

    Todd, M.B.

    1980-06-01

    A new method for visualization of separable subunits of DNA is described. Autoradiography of tritium-labeled DNA from one or a few nuclei, lysed with detergent, moderate salt, and proteases, and gently deposited on a filter, allows determination of subunit molecular weight, size distribution, number per nucleus, and organization. The shape of the size distribution of CHO subunit images is similar to that of CHO mitotic chromosomes, and the numbers of subunits per nucleus supports a model of eight subunits per chromosome.

  10. On the domain size effect of thermal conductivities from equilibrium and nonequilibrium molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Wang, Zuyuan; Ruan, Xiulin

    2017-01-01

    Equilibrium molecular dynamics (EMD) simulations with the Green-Kubo formula and nonequilibrium molecular dynamics (NEMD) simulations with the Fourier's Law are two widely used methods for calculating thermal conductivities of materials. It is well known that both methods suffer from domain size effects, especially for NEMD. But the underlying mechanisms and their comparison have not been much quantitatively studied before. In this paper, we investigate their domain size effects by using crystalline silicon at 1000 K, graphene at 300 K, and silicene at 300 K as model material systems. The thermal conductivity of silicon from EMD simulations increases normally with the increasing domain size and converges at a size of around 4 ×4 ×4 nm3 . The converging trend agrees well with the wavelength-accumulated thermal conductivity. The thermal conductivities of graphene and silicene from EMD simulations decrease abnormally with the increasing domain size and converge at a size of around 10 ×10 nm2 . We ascribe the anomalous size effect to the fact that as the domain size increases, the effect of more phonon scattering processes (particularly the flexural phonons) dominates over the effect of more phonon modes contributing to the thermal conductivity. The thermal conductivities of the three material systems from NEMD simulations all show normal domain size effects, although their dependences on the domain size differ. The converging trends agree with the mean free path accumulation of thermal conductivity. This study provides new insights that other than some exceptions, the domain size effects of EMD and NEMD are generally associated with wavelength and mean free path accumulations of thermal conductivity, respectively. Since phonon wavelength spans over a much narrower range than mean free path, EMD usually has less significant domain size effect than NEMD.

  11. Feasibility of using molecular docking-based virtual screening for searching dual target kinase inhibitors.

    PubMed

    Zhou, Shunye; Li, Youyong; Hou, Tingjun

    2013-04-22

    Multitarget agents have been extensively explored for solving limited efficacies, poor safety, and resistant profiles of an individual target. Theoretical approaches for searching and designing multitarget agents are critically useful. Here, the performance of molecular docking to search dual-target inhibitors for four kinase pairs (CDK2-GSK3B, EGFR-Src, Lck-Src, and Lck-VEGFR2) was assessed. First, the representative structures for each kinase target were chosen by structural clustering of available crystal structures. Next, the performance of molecular docking to distinguish inhibitors from noninhibitors for each individual kinase target was evaluated. The results show that molecular docking-based virtual screening illustrates good capability to find known inhibitors for individual targets, but the prediction accuracy is structurally dependent. Finally, the performance of molecular docking to identify the dual-target kinase inhibitors for four kinase pairs was evaluated. The analyses show that molecular docking successfully filters out most noninhibitors and achieves promising performance for identifying dual-kinase inhibitors for CDK2-GSK3B and Lck-VEGFR2. But a high false-positive rate leads to low enrichment of true dual-target inhibitors in the final list. This study suggests that molecular docking serves as a useful tool in searching inhibitors against dual or even multiple kinase targets, but integration with other virtual screening tools is necessary for achieving better predictions.

  12. Membrane Lipid Screen to Identify Molecular Targets of Biomolecules.

    PubMed

    Jimah, John R; Schlesinger, Paul H; Tolia, Niraj H

    2017-08-05

    Proteins that bind to and disrupt cell membranes may target specific phospholipids. Here we describe a protocol to identify the lipid targets of proteins and biomolecules. First, we describe a screen to identify lipids in membranes that are specifically bound by the biomolecule of interest. Second, we describe a method for determining if the presence of these lipids within membranes is necessary for membrane disruption. The methods described here were used to determine that the malaria vaccine candidate CelTOS disrupts cell membranes by specifically targeting phosphatidic acid (Jimah et al., 2016). This protocol has a companion protocol: 'Liposome disruption assay to examine lytic properties of biomolecules' which can be applied to examine the ability of the biomolecule to disrupt membranes composed of the lipid target identified by following this protocol (Jimah et al., 2017).

  13. Melanoma: the intersection of molecular targeted therapy and immune checkpoint inhibition.

    PubMed

    Lau, Peter Kar Han; Ascierto, Paolo A; McArthur, Grant

    2016-04-01

    Melanoma is at the forefront of development of systemic therapeutics with both molecular targeted therapies and immune checkpoint inhibitors as cornerstones of treatment. Although responses to molecularly targeted therapy is largely from blockade of oncogenic pathways, evidence is emerging of the immunomodulatory effects from BRAF inhibition. Additionally programmed-death-1 (PD-1) inhibitors have revolutionized the treatment of melanoma and are set to pave future improvements in other solid tumors. Combinations of PD-1 inhibitors with novel immune checkpoints or with molecularly targeted therapies are under investigation and may improve on the considerable progress made. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. The effect of target group size on risk judgments and comparative optimism: the more, the riskier.

    PubMed

    Price, Paul C; Smith, Andrew R; Lench, Heather C

    2006-03-01

    In 5 experiments, college students exhibited a group size effect on risk judgments. As the number of individuals in a target group increased, so did participants' judgments of the risk of the average member of the group for a variety of negative life events. This happened regardless of whether the stimuli consisted of photographs of real peers or stick-figure representations of peers. As a result, the degree to which participants exhibited comparative optimism (i.e., judged themselves to be at lower risk than their peers) also increased as the size of the comparison group increased. These results suggest that the typical comparative optimism effect reported so often in the literature might be, at least in part, a group size effect. Additional results include a group size effect on judgments of the likelihood that the average group member will experience positive and neutral events and a group size effect on perceptual judgments of the heights of stick figures. These latter results, in particular, support the existence of a simple, general cognitive mechanism that integrates stimulus numerosity into quantitative judgments about that stimulus.

  15. Biodegradability enhancement and detoxification of cork processing wastewater molecular size fractions by ozone.

    PubMed

    Santos, Diana C; Silva, Lúcia; Albuquerque, António; Simões, Rogério; Gomes, Arlindo C

    2013-11-01

    Cork boiling wastewater pollutants were fractionated by sequential use of four ultrafiltration membranes and five fractions were obtained: four retentates (>100, 50-100, 20-50 and 10-20 kDa) and one permeate (<10 kDa); which were used to study the correlation of molecular size with biodegradability and toxicity before and after ozonation. The results show that molecular size is correlated with organic load and restrains biodegradability. The fraction with >100 kDa corresponds to 56% of the organic load and the one with <10 kDa only 8%. The biodegradability of fractions increased 182% with fractions molecular size reduction from >100 to <10 kDa and the chemical oxygen demand (COD) was from 3436 to 386 mg L(-1). For biodegradability enhancement the best outcome of ozonation was obtained with compounds having molecular size >20 kDa and range from 5% up to 175% for applied ozone doses to COD ratios between 0.15 and 0.38.

  16. Molecular Targeted Approaches for Treatment of Pancreatic Cancer

    PubMed Central

    Huang, Z.Q.; Saluja, A.K.; Dudeja, V.; Vickers, S.M.; Buchsbaum, D.J.

    2012-01-01

    Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research. Many targeted therapies are under development. However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models. Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy. Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis. Sensitivity to therapy may also vary for cancer cells at different stages. The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells. In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed. However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge. Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects. These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages. Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy. PMID:21777178

  17. Targeted molecular trait stacking in cotton through targeted double-strand break induction

    PubMed Central

    D'Halluin, Kathleen; Vanderstraeten, Chantal; Van Hulle, Jolien; Rosolowska, Joanna; Van Den Brande, Ilse; Pennewaert, Anouk; D'Hont, Kristel; Bossut, Martine; Jantz, Derek; Ruiter, Rene; Broadhvest, Jean

    2013-01-01

    Recent developments of tools for targeted genome modification have led to new concepts in how multiple traits can be combined. Targeted genome modification is based on the use of nucleases with tailor-made specificities to introduce a DNA double-strand break (DSB) at specific target loci. A re-engineered meganuclease was designed for specific cleavage of an endogenous target sequence adjacent to a transgenic insect control locus in cotton. The combination of targeted DNA cleavage and homologous recombination–mediated repair made precise targeted insertion of additional trait genes (hppd, epsps) feasible in cotton. Targeted insertion events were recovered at a frequency of about 2% of the independently transformed embryogenic callus lines. We further demonstrated that all trait genes were inherited as a single genetic unit, which will simplify future multiple-trait introgression. PMID:23777410

  18. Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy.

    PubMed

    Tassa, Carlos; Shaw, Stanley Y; Weissleder, Ralph

    2011-10-18

    Advances in our understanding of the genetic basis of disease susceptibility coupled with prominent successes for molecular targeted therapies have resulted in an emerging strategy of personalized medicine. This approach envisions risk stratification and therapeutic selection based on an individual's genetic makeup and physiologic state (the latter assessed through cellular or molecular phenotypes). Molecularly targeted nanoparticles can play a key role in this vision through noninvasive assessments of molecular processes and specific cell populations in vivo, sensitive molecular diagnostics, and targeted delivery of therapeutics. A superparamagnetic iron oxide nanoparticle with a cross-linked dextran coating, or CLIO, is a powerful and illustrative nanoparticle platform for these applications. These structures and their derivatives support diagnostic imaging by magnetic resonance (MRI), optical, and positron emission tomography (PET) modalities and constitute a versatile platform for conjugation to targeting ligands. A variety of conjugation methods exist to couple the dextran surface to different functional groups; in addition, a robust bioorthogonal [4 + 2] cycloaddition reaction between 1,2,4,5-tetrazene (Tz) and trans-cyclooctene (TCO) can conjugate nanoparticles to targeting ligands or label pretargeted cells. The ready availability of conjugation methods has given rise to the synthesis of libraries of small molecule modified nanoparticles, which can then be screened for nanoparticles with specificity for a specific cell type. Since most nanoparticles display their targeting ligands in a multivalent manner, a detailed understanding of the kinetics and affinity of a nanoparticle's interaction with its target (as determined by surface plasmon resonance) can yield functionally important insights into nanoparticle design. In this Account, we review applications of the CLIO platform in several areas relevant to the mission of personalized medicine. We demonstrate

  19. Cervical Cancer: Development of Targeted Therapies Beyond Molecular Pathogenesis

    PubMed Central

    Knoff, Jayne; Yang, Benjamin; Hung, Chien-Fu; Wu, T.-C.

    2014-01-01

    It is well known that human papillomavirus (HPV) is the causative agent of cervical cancer. The integration of HPV genes into the host genome causes the upregulation of E6 and E7 oncogenes. E6 and E7 proteins inactivate and degrade tumor suppressors p53 and retinoblastoma, respectively, leading to malignant progression. HPV E6 and E7 antigens are ideal targets for the development of therapies for cervical cancer and precursor lesions because they are constitutively expressed in infected cells and malignant tumors but not in normal cells and they are essential for cell immortalization and transformation. Immunotherapies are being developed to target E6/E7 by eliciting antigen-specific immune responses. siRNA technologies target E6/E7 by modulating the expression of the oncoproteins. Proteasome inhibitors and histone deacetylase inhibitors are being developed to indirectly target E6/E7 by interfering with their oncogenic activities. The ultimate goal for HPV-targeted therapies is the progression through clinical trials to commercialization. PMID:24533233

  20. Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

    PubMed Central

    Weber, Wolfgang A; Czernin, Johannes; Phelps, Michael E; Herschman, Harvey R

    2010-01-01

    SUMMARY Targeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the ‘correct’, biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response. PMID:18097456

  1. Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages.

    PubMed

    Qian, Yuan; Qiao, Sha; Dai, Yanfeng; Xu, Guoqiang; Dai, Bolei; Lu, Lisen; Yu, Xiang; Luo, Qingming; Zhang, Zhihong

    2017-09-06

    Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8(+) T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8(+) T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.

  2. Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent.

    PubMed

    Chen, Zhijin; Yu, Dexin; Liu, Chunxi; Yang, Xiaoyan; Zhang, Na; Ma, Chunhong; Song, Jibin; Lu, Zaijun

    2011-09-01

    A nanoparticle magnetic resonance imaging (MRI) contrast agent targeted to liver was developed by conjugation of gadolinium (Gd) chelate groups onto the biocompatible poly(l-lactide)-block-poly (ethylene glycol) (PLA-PEG) nanoparticles. PLA-PEG conjugated with diethylenetriaminopentaacetic acid (DTPA) was used to formulate PLA-PEG-DTPA nanoparticles by solvent diffusion method, and then Gd was loaded onto the nanoparticles by chelated with the unfolding DTPA on the surface of the PLA-PEG-DTPA nanoparticles. The mean size of the nanoparticles was 265.9 ± 6.7 nm. The relaxivity of the Gd-labeled nanoparticles was measured, and the distribution in vivo was evaluated in rats. Compared with conventional contrast agent (Magnevist), the Gd-labeled PLA-PEG nanoparticles showed significant enhancement both on liver targeting ability and imaging signal intensity. The T(1) and T(2) relaxivities per [Gd] of the Gd-labeled nanoparticles was 18.865 mM(-1) s(-1) and 24.863 mM(-1) s(-1) at 3 T, respectively. In addition, the signal intensity in vivo was stronger comparing with the Gd-DTPA and the T(1) weight time was lasting for 4.5 h. The liver targeting efficiency of the Gd-labeled PLA-PEG nanoparticles in rats was 14.57 comparing with Magnevist injection. Therefore, the Gd-labeled nanoparticles showed the potential as targeting molecular MRI contrast agent for further clinical utilization.

  3. Science to Practice: Molecularly Targeted US of Inflammation-Important Steps toward Clinical Translation.

    PubMed

    Kiessling, Fabian

    2015-09-01

    Dual P- and E-selectin-targeted microbubbles (MBs) have previously been used for ultrasonography (US) of acute inflammatory bowel disease in mice. In the study by Wang and colleagues, such dual-targeted MBs were evaluated in pigs. After induction of ileitis by means of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol installation, early inflammation, as well as mild and severe disease stages, could be distinguished. The molecularly targeted US method was characterized by high reproducibility and matched with histologic findings. This work is considered an important intermediate step in translating molecularly targeted US of inflammation from preclinical toward clinical application.

  4. Molecular Dynamics Study for Channel Size Dependence of Shear Stress Between Droplet and Wall.

    PubMed

    Fukushima, Akinori; Mima, Toshiki; Kinefuchi, Ikuya; Tokumasu, Takashi

    2015-04-01

    In this study, the channel size dependence of the shear stress between water droplets and solid walls in nm-order channel was analyzed. We considered a several different-sized and highly hydrophobic channel whose macroscopic contact angle was about 150 degrees. We have evaluated the shear stress and the normal pressure by molecular dynamics simulation. Analyzing shear stress and normal pressure based on the macroscopic model, we have discussed the difference between the macroscopic model based on hydrodynamics and the microscopic model. As a result, in the high hydrophobic case, it became clear that the shear stress depends on the channel size due to the large Laplace pressure. Furthermore, in the case that the channel size was less than 50 A, the normal pressure by the molecular simulation didn't agree with the expected value from the Young-Laplace equation. From this study it was clear that molecular simulation is needed when the channel size is less than 40 A.

  5. The rate of DNA evolution: effects of body size and temperature on the molecular clock.

    PubMed

    Gillooly, James F; Allen, Andrew P; West, Geoffrey B; Brown, James H

    2005-01-04

    Observations that rates of molecular evolution vary widely within and among lineages have cast doubts on the existence of a single "molecular clock." Differences in the timing of evolutionary events estimated from genetic and fossil evidence have raised further questions about the accuracy of molecular clocks. Here, we present a model of nucleotide substitution that combines theory on metabolic rate with the now-classic neutral theory of molecular evolution. The model quantitatively predicts rate heterogeneity and may reconcile differences in molecular- and fossil-estimated dates of evolutionary events. Model predictions are supported by extensive data from mitochondrial and nuclear genomes. By accounting for the effects of body size and temperature on metabolic rate, this model explains heterogeneity in rates of nucleotide substitution in different genes, taxa, and thermal environments. This model also suggests that there is indeed a single molecular clock, as originally proposed by Zuckerkandl and Pauling [Zuckerkandl, E. & Pauling, L. (1965) in Evolving Genes and Proteins, eds. Bryson, V. & Vogel, H. J. (Academic, New York), pp. 97-166], but that it "ticks" at a constant substitution rate per unit of mass-specific metabolic energy rather than per unit of time. This model therefore links energy flux and genetic change. More generally, the model suggests that body size and temperature combine to control the overall rate of evolution through their effects on metabolism.

  6. Hydrated nonpolar solute volumes: Interplay between size, Attractiveness, and molecular structure.

    PubMed

    Ashbaugh, Henry S; Barnett, J Wesley; da Silva Moura, Natalia; Houser, Hayden E

    2016-06-01

    A solute's partial molar volume determines its response to pressure, which can result in changes in molecular conformation or assembly state. Computing speed advances have made accurate partial molar volume evaluation in water routine, allowing for the dissection of the molecular factors underlying this significant thermodynamic variable. A recent simulation analysis of the volumes of nonpolar molecular solutes in water reported that the apparent solvent-free border thickness enshrouding these solutes grows with increasing solute size, based on the assumption the solute can be treated as an individual sphere [Biophys. Chem. 161 (2012) 46]. This suggests the solvent dewets these solutes as they grow in size. Via simulations of dewetted repulsive spherical solutes, we show that the border thicknesses of the largest non-polar molecular solutes tend towards that of a repulsive sphere. When attractive interactions are accounted for, however, the spherical solute border thicknesses fall below that of the largest molecular solutes. We demonstrate that if the molecular solutes are treated with atomic detail rather than approximated as an individual sphere, the border thickness variation is minimal. A geometric model is put forward that reproduces the inferred border thickening, indicating the implied dewetting results from a breakdown in the spherical volume approximation.

  7. Molecular mechanisms of protein and lipid targeting to ciliary membranes

    PubMed Central

    Emmer, Brian T.; Maric, Danijela; Engman, David M.

    2010-01-01

    Cilia are specialized surface regions of eukaryotic cells that serve a variety of functions, ranging from motility to sensation and to regulation of cell growth and differentiation. The discovery that a number of human diseases, collectively known as ciliopathies, result from defective cilium function has expanded interest in these structures. Among the many properties of cilia, motility and intraflagellar transport have been most extensively studied. The latter is the process by which multiprotein complexes associate with microtubule motors to transport structural subunits along the axoneme to and from the ciliary tip. By contrast, the mechanisms by which membrane proteins and lipids are specifically targeted to the cilium are still largely unknown. In this Commentary, we review the current knowledge of protein and lipid targeting to ciliary membranes and outline important issues for future study. We also integrate this information into a proposed model of how the cell specifically targets proteins and lipids to the specialized membrane of this unique organelle. PMID:20145001

  8. TNNI3K, a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease

    PubMed Central

    Lal, Hind; Ahmad, Firdos; Parikh, Shan; Force, Thomas

    2014-01-01

    Coronary heart disease (AHD) is the leading cause of death and disability worldwide. In patients with acute coronary syndromes (ACS), timely and effective myocardial reperfusion by percutaneous coronary intervention (PCI) is the primary treatment of choice to minimize the ischemic injury and limit MI size. However, reperfusion can itself promote cardiomyocyte death which leads to cardiac dysfunction via reperfusion injury. The molecular mechanisms of ischemia/reperfusion (I/R) injury are not completely understood and new drug targets are needed. Recently we reported that cardiac troponin I-interacting protein kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes I/R injury via profound oxidative stress, thereby promoting cardiomyocyte death. By using novel genetic animal models and newly developed small-molecule TNNI3K inhibitors, we demonstrate that TNNI3K-mediated I/R injury occurs through impaired mitochondrial function and is in part dependent on p38 MAPK. Herein we discuss the emerging role of TNNI3K as a promising new drug target to limit the I/R-induced myocardial injury. We will also examine the underlying mechanisms that drive the profoundly reduced infarct size in mice in which TNNI3K is specifically deleted in cardiomyocytes. Since TNNI3K is a cardiac-specific kinase, it could be an ideal molecular target since inhibiting it would have little or no effect on other organ systems, a serious problem associated with the use of kinase inhibitors targeting kinases that are more widely expressed. PMID:24899531

  9. Size-exclusion chromatography of ultrahigh molecular weight methylcellulose ethers and hydroxypropyl methylcellulose ethers for reliable molecular weight distribution characterization.

    PubMed

    Li, Yongfu; Shen, Hongwei; Lyons, John W; Sammler, Robert L; Brackhagen, Meinolf; Meunier, David M

    2016-03-15

    Size-exclusion chromatography (SEC) coupled with multi-angle laser light scattering (MALLS) and differential refractive index (DRI) detectors was employed for determination of the molecular weight distributions (MWD) of methylcellulose ethers (MC) and hydroxypropyl methylcellulose ethers (HPMC) having weight-average molecular weights (Mw) ranging from 20 to more than 1,000kg/mol. In comparison to previous work involving right-angle light scattering (RALS) and a viscometer for MWD characterization of MC and HPMC, MALLS yields more reliable molecular weight for materials having weight-average molecular weights (Mw) exceeding about 300kg/mol. A non-ideal SEC separation was observed for cellulose ethers with Mw>800kg/mol, and was manifested by upward divergence of logM vs. elution volume (EV) at larger elution volume at typical SEC flow rate such as 1.0mL/min. As such, the number-average molecular weight (Mn) determined for the sample was erroneously large and polydispersity (Mw/Mn) was erroneously small. This non-ideality resulting in the late elution of high molecular weight chains could be due to the elongation of polymer chains when experimental conditions yield Deborah numbers (De) exceeding 0.5. Non-idealities were eliminated when sufficiently low flow rates were used. Thus, using carefully selected experimental conditions, SEC coupled with MALLS and DRI can provide reliable MWD characterization of MC and HPMC covering the entire ranges of compositions and molecular weights of commercial interest. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Indium-111 labeled gold nanoparticles for in-vivo molecular targeting.

    PubMed

    Ng, Quinn K T; Olariu, Cristina I; Yaffee, Marcus; Taelman, Vincent F; Marincek, Nicolas; Krause, Thomas; Meier, Lorenz; Walter, Martin A

    2014-08-01

    The present report describes the synthesis and biological evaluation of a molecular imaging platform based on gold nanoparticles directly labeled with indium-111. The direct labeling approach facilitated radiolabeling with high activities while maintaining excellent stability within the biological environment. The resulting imaging platform exhibited low interference of the radiolabel with targeting molecules, which is highly desirable for in-vivo probe tracking and molecular targeted tumor imaging. The indium-111 labeled gold nanoparticles were synthesized using a simple procedure that allowed stable labeling of the nanoparticle core with various indium-111 activities. Subsequent surface modification of the particle cores with RGD-based ligands at various densities allowed for molecular targeting of the αvß3 integrin in-vitro and for molecular targeted imaging in human melanoma and glioblastoma models in-vivo. The results demonstrate the vast potential of direct labeling with radioisotopes for tracking gold nanoparticles within biological systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Dynamic modulation of illusory and physical target size on separate and coordinated eye and hand movements

    PubMed Central

    Gamble, Christine M.; Song, Joo-Hyun

    2017-01-01

    In everyday behavior, two of the most common visually guided actions—eye and hand movements—can be performed independently, but are often synergistically coupled. In this study, we examine whether the same visual representation is used for different stages of saccades and pointing, namely movement preparation and execution, and whether this usage is consistent between independent and naturalistic coordinated eye and hand movements. To address these questions, we used the Ponzo illusion to dissociate the perceived and physical sizes of visual targets and measured the effects on movement preparation and execution for independent and coordinated saccades and pointing. During independent movements, we demonstrated that both physically and perceptually larger targets produced faster preparation for both effectors. Furthermore, participants who showed a greater influence of the illusion on saccade preparation also showed a greater influence on pointing preparation, suggesting that a shared mechanism involved in preparation across effectors is influenced by illusions. However, only physical but not perceptual target sizes influenced saccade and pointing execution. When pointing was coordinated with saccades, we observed different dynamics: pointing no longer showed modulation from illusory size, while saccades showed illusion modulation for both preparation and execution. Interestingly, in independent and coordinated movements, the illusion modulated saccade preparation more than pointing preparation, with this effect more pronounced during coordination. These results suggest a shared mechanism, dominated by the eyes, may underlie visually guided action preparation across effectors. Furthermore, the influence of illusions on action may operate within such a mechanism, leading to dynamic interactions between action modalities based on task demands. PMID:28362898

  12. Molecular pathways: targeting ETS gene fusions in cancer.

    PubMed

    Feng, Felix Y; Brenner, J Chad; Hussain, Maha; Chinnaiyan, Arul M

    2014-09-01

    Rearrangements, or gene fusions, involving the ETS family of transcription factors are common driving events in both prostate cancer and Ewing sarcoma. These rearrangements result in pathogenic expression of the ETS genes and trigger activation of transcriptional programs enriched for invasion and other oncogenic features. Although ETS gene fusions represent intriguing therapeutic targets, transcription factors, such as those comprising the ETS family, have been notoriously difficult to target. Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as PARP1, the catalytic subunit of DNA protein kinase (DNAPK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins. In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions. ©2014 American Association for Cancer Research.

  13. Diverse Molecular Targets for Therapeutic Strategies in Alzheimer's Disease

    PubMed Central

    Han, Sun-Ho

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development. PMID:25045220

  14. Diverse molecular targets for therapeutic strategies in Alzheimer's disease.

    PubMed

    Han, Sun-Ho; Mook-Jung, Inhee

    2014-07-01

    Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.

  15. Clipped speckle autocorrelation metric for spot size characterization of focused beam on a diffuse target.

    PubMed

    Li, Yuanyang; Guo, Jin; Liu, Lisheng; Wang, Tingfeng; Tang, Wei; Jiang, Zhenhua

    2015-03-23

    The clipped speckle autocorrelation (CSA) metric is proposed for estimating the laser beam energy concentration on a remote diffuse target in a laser beam projection system with feedback information. Using the second order statistics of the intensity distribution of the fully developed speckle and the relation of the autocorrelation functions for the clipped and unclipped speckles, we present the theoretical expression of this metric as a function of the normalized CSA function. The simulation technique based on the equivalence of the spatial average and the ensemble time average is provided. Based on this simulation technique, we analyze the influence of the surface roughness of the target on this metric and then show the influencing factors of the metric performance, for example the finite sample effect and aperture size of the observation system. Experimental results are illustrated to examine the capability of this metric and the correctness of the discussion about the metric performance.

  16. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter.

    PubMed

    Gilbert, Ian H

    2014-01-01

    Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.

  17. Predicting the size-dependent tissue accumulation of agents released from vascular targeted nanoconstructs

    NASA Astrophysics Data System (ADS)

    de Tullio, Marco D.; Singh, Jaykrishna; Pascazio, Giuseppe; Decuzzi, Paolo

    2014-03-01

    Vascular targeted nanoparticles have been developed for the delivery of therapeutic and imaging agents in cancer and cardiovascular diseases. However, at authors' knowledge, a comprehensive systematic analysis on their delivery efficiency is still missing. Here, a computational model is developed to predict the vessel wall accumulation of agents released from vascular targeted nanoconstructs. The transport problem for the released agent is solved using a finite volume scheme in terms of three governing parameters: the local wall shear rate , ranging from to ; the wall filtration velocity , varying from to ; and the agent diffusion coefficient , ranging from to . It is shown that the percentage of released agent adsorbing on the vessel walls in the vicinity of the vascular targeted nanoconstructs reduces with an increase in shear rate , and with a decrease in filtration velocity and agent diffusivity . In particular, in tumor microvessels, characterized by lower shear rates () and higher filtration velocities (), an agent with a diffusivity (i.e. a 50 nm particle) is predicted to deposit on the vessel wall up to of the total released dose. Differently, drug molecules, exhibiting a smaller size and much higher diffusion coefficient (), are predicted to accumulate up to . In healthy vessels, characterized by higher and lower , the largest majority of the released agent is redistributed directly in the circulation. These data suggest that drug molecules and small nanoparticles only can be efficiently released from vascular targeted nanoconstructs towards the diseased vessel walls and tissue.

  18. Development of hierarchical, tunable pore size polymer foams for ICF targets

    SciTech Connect

    Hamilton, Christopher E.; Lee, Matthew Nicholson; Parra-Vasquez, A. Nicholas Gerardo

    2016-08-01

    In this study, one of the great challenges of inertial confinement fusion experiments is poor understanding of the effects of reactant heterogeneity on fusion reactions. The Marble campaign, conceived at Los Alamos National Laboratory, aims to gather new insights into this issue by utilizing target capsules containing polymer foams of variable pore sizes, tunable over an order of magnitude. Here, we describe recent and ongoing progress in the development of CH and CH/CD polymer foams in support of Marble. Hierarchical and tunable pore sizes have been achieved by utilizing a sacrificial porogen template within an open-celled poly(divinylbenzene) or poly(divinylbenzene-co-styrene) aerogel matrix, resulting in low-density foams (~30 mg/ml) with continuous multimodal pore networks.

  19. Particle size, magnetic field, and blood velocity effects on particle retention in magnetic drug targeting.

    PubMed

    Cherry, Erica M; Maxim, Peter G; Eaton, John K

    2010-01-01

    A physics-based model of a general magnetic drug targeting (MDT) system was developed with the goal of realizing the practical limitations of MDT when electromagnets are the source of the magnetic field. The simulation tracks magnetic particles subject to gravity, drag force, magnetic force, and hydrodynamic lift in specified flow fields and external magnetic field distributions. A model problem was analyzed to determine the effect of drug particle size, blood flow velocity, and magnetic field gradient strength on efficiency in holding particles stationary in a laminar Poiseuille flow modeling blood flow in a medium-sized artery. It was found that particle retention rate increased with increasing particle diameter and magnetic field gradient strength and decreased with increasing bulk flow velocity. The results suggest that MDT systems with electromagnets are unsuitable for use in small arteries because it is difficult to control particles smaller than about 20 microm in diameter.

  20. Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle

    PubMed Central

    Zhang, Li; Varma, Nadimpalli RS; Gang, Zhang Z.; Ewing, James R.; Arbab, Ali S; Ali, Meser M

    2016-01-01

    There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs. PMID:28018751

  1. Effects of window size and shape on accuracy of subpixel centroid estimation of target images

    NASA Technical Reports Server (NTRS)

    Welch, Sharon S.

    1993-01-01

    A new algorithm is presented for increasing the accuracy of subpixel centroid estimation of (nearly) point target images in cases where the signal-to-noise ratio is low and the signal amplitude and shape vary from frame to frame. In the algorithm, the centroid is calculated over a data window that is matched in width to the image distribution. Fourier analysis is used to explain the dependency of the centroid estimate on the size of the data window, and simulation and experimental results are presented which demonstrate the effects of window size for two different noise models. The effects of window shape were also investigated for uniform and Gaussian-shaped windows. The new algorithm was developed to improve the dynamic range of a close-range photogrammetric tracking system that provides feedback for control of a large gap magnetic suspension system (LGMSS).

  2. Development of hierarchical, tunable pore size polymer foams for ICF targets

    SciTech Connect

    Hamilton, Christopher E.; Lee, Matthew Nicholson; Parra-Vasquez, A. Nicholas Gerardo

    2016-08-01

    In this study, one of the great challenges of inertial confinement fusion experiments is poor understanding of the effects of reactant heterogeneity on fusion reactions. The Marble campaign, conceived at Los Alamos National Laboratory, aims to gather new insights into this issue by utilizing target capsules containing polymer foams of variable pore sizes, tunable over an order of magnitude. Here, we describe recent and ongoing progress in the development of CH and CH/CD polymer foams in support of Marble. Hierarchical and tunable pore sizes have been achieved by utilizing a sacrificial porogen template within an open-celled poly(divinylbenzene) or poly(divinylbenzene-co-styrene) aerogel matrix, resulting in low-density foams (~30 mg/ml) with continuous multimodal pore networks.

  3. Development of hierarchical, tunable pore size polymer foams for ICF targets

    DOE PAGES

    Hamilton, Christopher E.; Lee, Matthew Nicholson; Parra-Vasquez, A. Nicholas Gerardo

    2016-08-01

    In this study, one of the great challenges of inertial confinement fusion experiments is poor understanding of the effects of reactant heterogeneity on fusion reactions. The Marble campaign, conceived at Los Alamos National Laboratory, aims to gather new insights into this issue by utilizing target capsules containing polymer foams of variable pore sizes, tunable over an order of magnitude. Here, we describe recent and ongoing progress in the development of CH and CH/CD polymer foams in support of Marble. Hierarchical and tunable pore sizes have been achieved by utilizing a sacrificial porogen template within an open-celled poly(divinylbenzene) or poly(divinylbenzene-co-styrene) aerogelmore » matrix, resulting in low-density foams (~30 mg/ml) with continuous multimodal pore networks.« less

  4. Targeting cancer with small-molecular-weight kinase inhibitors.

    PubMed

    Fabbro, Doriano; Cowan-Jacob, Sandra W; Möbitz, Henrik; Martiny-Baron, Georg

    2012-01-01

    Protein and lipid kinases fulfill essential roles in many signaling pathways that regulate normal cell functions. Deregulation of these kinase activities lead to a variety of pathologies ranging from cancer to inflammatory diseases, diabetes, infectious diseases, cardiovascular disorders, cell growth and survival. 518 protein kinases and about 20 lipid-modifying kinases are encoded by the human genome, and a much larger proportion of additional kinases are present in parasite, bacterial, fungal, and viral genomes that are susceptible to exploitation as drug targets. Since many human diseases result from overactivation of protein and lipid kinases due to mutations and/or overexpression, this enzyme class represents an important target for the pharmaceutical industry. Approximately one third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases.The kinase inhibitors that have been launched, thus far, are mainly in oncology indications and are directed against a handful of protein and lipid kinases. With one exception, all of these registered kinase inhibitors are directed toward the ATP-site and display different selectivities, potencies, and pharmacokinetic properties. At present, about 150 kinase-targeted drugs are in clinical development and many more in various stages of preclinical development. Kinase inhibitor drugs that are in clinical trials target all stages of signal transduction from the receptor protein tyrosine kinases that initiate intracellular signaling, through second-messenger-dependent lipid and protein kinases, and protein kinases that regulate the cell cycle.This review provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.

  5. Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting

    NASA Astrophysics Data System (ADS)

    Sykes, Edward Alexander

    Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. . Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano

  6. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity.

    PubMed

    Esfandyari-Manesh, Mehdi; Darvishi, Behrad; Ishkuh, Fatemeh Azizi; Shahmoradi, Elnaz; Mohammadi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul; Atyabi, Fatemeh

    2016-05-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC50) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells.

  7. Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration

    PubMed Central

    MacKrell, James G.; Yaden, Benjamin C.; Bullock, Heather; Chen, Keyue; Shetler, Pamela; Bryant, Henry U.; Krishnan, Venkatesh

    2015-01-01

    The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.Therefore, the aim of this study was to examine coinciding androgen-mediated genetic changes in an in vitro MSC model and clinically relevant in vivo models. A gene signature was established via microarray analysis for androgen-mediated MSC engagement and highlighted several markers including follistatin (FST), IGF-1, C-X-C chemokine receptor 4 (CXCR4), hepatocyte growth factor (HGF) and glucocorticoid receptor (GR). In an in vivo muscle atrophy model, androgen re-supplementation significantly increased muscle size and expression of IGF-1, FST, and HGF, while significantly decreasing expression of GR. Biphasic gene expression profiles over the 7-day re-supplementation period identifed temporal androgen regulation of molecular targets involved in satellite cell engagement into myogenesis. In a muscle injury model, removal of androgens resulted in delayed muscle recovery and regeneration. Modifications in the androgen signaling gene signature, along with reduced Pax7 and MyoD expression, suggested that limited MSC activation and increased inflammation contributed to the delayed regeneration. However, enhanced MSC activation in the androgen-deplete mouse injury model was driven by an androgen receptor (AR) agonist. These results provide novel in vitro and in vivo evidence describing molecular targets of androgen signaling, while also increasing support for translational use of AR agonists in skeletal muscle recovery and regeneration. PMID:26457071

  8. Molecular approaches to target discovery:--evaluating targets for anti-tuberculosis drug discovery programmes.

    PubMed

    Balganesh, T S; Furr, B J A

    2007-06-01

    Selection of appropriate targets for launching antituberculosis drug discovery programmes is challenging. This challenge is magnified by the limited repertoire of 'validated targets' and the paucity of clinically successful drugs. However, continued understanding of the biology of the microbe and its interaction with the host has enabled detailed evaluation of several interesting pathways and novel targets. The value of a target that is suitable for antituberculosis drug discovery needs to be defined not only in the context of its 'essentiality' for survival in vitro but also against a variety of properties relevant to activities in the drug discovery process, e.g.; selectivity, vulnerability, suitability for structural studies, ability to monitor inhibition in whole cells etc. It is also rarely feasible to obtain all the relevant information on the target prior to the launch of a discovery programme. Thus, there is a continuous confidence-building exercise on the validity of a target. Several novel approaches have enabled exploitation of the mycobacterial genome and prioritisation of putative targets; the concept of 'sterilisation' is now being evaluated not only through the availability of structurally diverse probe compounds but also by the ability to characterise metabolic pathways in vivo. The impact of the current knowledge base on the different facets of 'target validation' relevant to antituberculosis drug discovery is discussed in this article with emphasis on developing appropriate matrix systems to prioritise them. The article also discusses the influence of lead generation approaches with specific reference to antibacterial drug discovery.

  9. New molecular targets for the treatment of sarcoidosis.

    PubMed

    Chiarchiaro, Jared; Chen, Bill B; Gibson, Kevin F

    2016-09-01

    Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease.

  10. New molecular targets for the treatment of sarcoidosis

    PubMed Central

    Chiarchiaro, Jared; Chen, Bill B.; Gibson, Kevin F.

    2016-01-01

    Purpose of review Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn’s disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. Recent findings Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. Summary Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease. PMID:27454074

  11. Molecular targeting of liposomal nanoparticles to tumor microenvironment

    PubMed Central

    Zhao, Gang; Rodriguez, B Leticia

    2013-01-01

    Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment. PMID:23293520

  12. Molecular Size and Weight of Asphaltene and Asphaltene Solubility Fractions from Coals, Crude Oils and Bitumen

    SciTech Connect

    Badre,S.; Goncalves, C.; Norinaga, K.; Gustavson, G.; Mullins, O.

    2005-01-01

    The molecular weight of asphaltenes has been a controversy for several decades. In recent years, several techniques have converged on the size of the fused ring system; indicating that chromophores in virgin crude oil asphaltenes typically have 4-10 fused rings. Consequently, the molecular weight debate is equivalent to determining whether asphaltenes are monomeric (one fused-ring system per molecule) or whether they are polymeric. Time-resolved fluorescence depolarization (FD) is employed here to interrogate the absolute size of asphaltene molecules and to determine the relation of the size of the fused ring system to that of the corresponding molecule. Coal, petroleum and bitumen asphaltenes are compared. Molecular size of coal asphaltenes obtained here by FD-determined rotational diffusion match closely with Taylor-dispersion-derived translational diffusion measurements with UV absorption. Coal asphaltenes are smaller than petroleum asphaltenes. N-methyl pyrrolidinone (NMP) soluble and insoluble fractions are examined. NMP soluble and insoluble fractions of asphaltenes are monomeric. It is suggested that the 'giant' asphaltene molecules reported from SEC studies using NMP as the eluting solvent may actually be the expected flocs of asphaltene which are not soluble in NMP. Data is presented that intramolecular electronic relaxation in asphaltenes does not perturb FD results.

  13. Changes in Molecular Size Distribution of Cellulose during Attack by White Rot and Brown Rot Fungi

    PubMed Central

    Kleman-Leyer, Karen; Agosin, Eduardo; Conner, Anthony H.; Kirk, T. Kent

    1992-01-01

    The kinetics of cotton cellulose depolymerization by the brown rot fungus Postia placenta and the white rot fungus Phanerochaete chrysosporium were investigated with solid-state cultures. The degree of polymerization (DP; the average number of glucosyl residues per cellulose molecule) of cellulose removed from soil-block cultures during degradation by P. placenta was first determined viscosimetrically. Changes in molecular size distribution of cellulose attacked by either fungus were then determined by size exclusion chromatography as the tricarbanilate derivative. The first study with P. placenta revealed two phases of depolymerization: a rapid decrease to a DP of approximately 800 and then a slower decrease to a DP of approximately 250. Almost all depolymerization occurred before weight loss. Determination of the molecular size distribution of cellulose during attack by the brown rot fungus revealed single major peaks centered over progressively lower DPs. Cellulose attacked by P. chrysosporium was continuously consumed and showed a different pattern of change in molecular size distribution than cellulose attacked by P. placenta. At first, a broad peak which shifted at a slightly lower average DP appeared, but as attack progressed the peak narrowed and the average DP increased slightly. From these results, it is apparent that the mechanism of cellulose degradation differs fundamentally between brown and white rot fungi, as represented by the species studied here. We conclude that the brown rot fungus cleaved completely through the amorphous regions of the cellulose microfibrils, whereas the white rot fungus attacked the surfaces of the microfibrils, resulting in a progressive erosion. PMID:16348694

  14. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms.

    PubMed

    Mooney, Michael A; Simon, Elias D; Little, Andrew S

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  15. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms

    PubMed Central

    Mooney, Michael A.; Simon, Elias D.; Little, Andrew S.

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment. PMID:27517036

  16. Effects of molecular size and chemical factor on plasma gene transfection

    NASA Astrophysics Data System (ADS)

    Ikeda, Yoshihisa; Motomura, Hideki; Kido, Yugo; Satoh, Susumu; Jinno, Masafumi

    2016-07-01

    In order to clarify the mechanism of plasma gene transfection, the relationship between transfection efficiency and transferred molecular size was investigated. Molecules with low molecular mass (less than 50 kDa; dye or dye-labeled oligonucleotide) and high molecular mass (more than 1 MDa; plasmid DNA or fragment of plasmid DNA) were transferred to L-929 cells. It was found that the transfection efficiency decreases with increasing in transferred molecular size and also depends on the tertiary structure of transferred molecules. Moreover, it was suggested the transfection mechanism is different between the molecules with low (less than 50 kDa) and high molecular mass (higher than 1 MDa). For the amount of gene transfection after plasma irradiation, which is comparable to that during plasma irradiation, it is shown that H2O2 molecules are the main contributor. The transfection efficiency decreased to 0.40 ± 0.22 upon scavenging the H2O2 generated by plasma irradiation using the catalase. On the other hand, when the H2O2 solution is dropped into the cell suspension without plasma irradiation, the transfection efficiency is almost 0%. In these results, it is also suggested that there is a synergetic effect of H2O2 with electrical factors or other reactive species generated by plasma irradiation.

  17. Size and shape of soil humic acids estimated by viscosity and molecular weight.

    PubMed

    Kawahigashi, Masayuki; Sumida, Hiroaki; Yamamoto, Kazuhiko

    2005-04-15

    Ultrafiltration fractions of three soil humic acids were characterized by viscometry and high performance size-exclusion chromatography (HPSEC) in order to estimate shapes and hydrodynamic sizes. Intrinsic viscosities under given solute/solvent/temperature conditions were obtained by extrapolating the concentration dependence of reduced viscosities to zero concentration. Molecular mass (weight average molecular weight (M (w)) and number average molecular weight (M (n))) and hydrodynamic radius (R(H)) were determined by HPSEC using pullulan as calibrant. Values of M (w) and M (n) ranged from 15 to 118 x 10(3) and from 9 to 50 x 10(3) (g mol(-1)), respectively. Polydispersity, as indicated by M (w)/M (n), increased with increasing filter size from 1.5 to 2.4. The hydrodynamic radii (R(H)) ranged between 2.2 and 6.4 nm. For each humic acid, M (w) and [eta] were related. Mark-Houwink coefficients calculated on the basis of the M (w)-[eta] relationships suggested restricted flexible chains for two of the humic acids and a branched structure for the third humic acid. Those structures probably behave as hydrated sphere colloids in a good solvent. Hydrodynamic radii of fractions calculated from [eta] using Einstein's equation, which is applicable to hydrated sphere colloids, ranged from 2.2 to 7.1 nm. These dimensions are fit to the size of nanospaces on and between clay minerals and micropores in soil particle aggregates. On the other hand, the good agreement of R(H) values obtained by applying Einstein's equation with those directly determined by HPSEC suggests that pullulan is a suitable calibrant for estimation of molecular mass and size of humic acids by HPSEC.

  18. From Guide to Target: Molecular Insights into Eukaryotic RNAi Machinery

    PubMed Central

    Ipsaro, Jonathan J.; Joshua-Tor, Leemor

    2015-01-01

    Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. PMID:25565029

  19. Testing and improving experimental parameters for the use of low molecular weight targets in array-CGH experiments.

    PubMed

    Stef, Marianne; Simon, Delphine; Burgelin, Ingrid; Guisle, Isabelle; Chevalier, Catherine; Delrue, Marie-Ange; Lacombe, Didier; Léger, Jean; Arveiler, Benoît

    2006-11-01

    Array-comparative genomic hybridization (CGH) has evolved as a useful technique for the detection and characterization of deletions, and, to a lesser extent, of duplications. The resolution of the technique is dictated by the genomic distance between targets spotted on the microarray, and by the targets' sizes. The use of region-specific, high-resolution microarrays is a specific goal when studying regions that are prone to rearrangements, such as those involved in deletion syndromes. The aim of the present study was to evaluate the best experimental conditions to be used for array-CGH analysis using low molecular weight (LMW) targets. The parameters tested were: the target concentration, the way LMW targets are prepared (either as linearized plasmids or as purified PCR products), and the way the targets are attached to the array-CGH slide (in a random fashion on amino-silane coated slides, or by one amino-modified end on epoxysilane-coated slides). As a test case, we constructed a microarray harboring LMW targets located in the CREBBP gene, mutations of which cause the Rubinstein-Taybi syndrome (RTS). From 10 to 15% of RTS patients have a CREBBP deletion. We showed that aminosilane- and epoxysilane-coated slides were equally efficient with targets above 1,000 bp in size. On the other hand, with the smallest targets, especially those below 500 bp, epoxysilane-coated slides were superior to aminosilane-coated slides, which did not allow deletion detection. Use of the high resolution array allowed us to map intragenic breakpoints with precision and to identify a very small deletion and a duplication that were not detected by the currently available techniques for finding CREBBP deletions.

  20. Communication target object recognition for D2D connection with feature size limit

    NASA Astrophysics Data System (ADS)

    Ok, Jiheon; Kim, Soochang; Kim, Young-hoon; Lee, Chulhee

    2015-03-01

    Recently, a new concept of device-to-device (D2D) communication, which is called "point-and-link communication" has attracted great attentions due to its intuitive and simple operation. This approach enables user to communicate with target devices without any pre-identification information such as SSIDs, MAC addresses by selecting the target image displayed on the user's own device. In this paper, we present an efficient object matching algorithm that can be applied to look(point)-and-link communications for mobile services. Due to the limited channel bandwidth and low computational power of mobile terminals, the matching algorithm should satisfy low-complexity, low-memory and realtime requirements. To meet these requirements, we propose fast and robust feature extraction by considering the descriptor size and processing time. The proposed algorithm utilizes a HSV color histogram, SIFT (Scale Invariant Feature Transform) features and object aspect ratios. To reduce the descriptor size under 300 bytes, a limited number of SIFT key points were chosen as feature points and histograms were binarized while maintaining required performance. Experimental results show the robustness and the efficiency of the proposed algorithm.

  1. Targeting molecular interactions essential for Plasmodium sexual reproduction

    PubMed Central

    Vega-Rodriguez, Joel; Perez-Barreto, Davinia; Ruiz-Reyes, Antonio; Jacobs-Lorena, Marcelo

    2015-01-01

    Summary Malaria remains one of the most devastating infectious diseases, killing up to a million people every year. Whereas much progress has been made in understanding the life cycle of the parasite in the human host and in the mosquito vector, significant gaps of knowledge remain. Fertilization of malaria parasites, a process that takes place in the lumen of the mosquito midgut, is poorly understood and the molecular interactions (receptor–ligand) required for Plasmodium fertilization remain elusive. By use of a phage display library, we identified FG1 (Female Gamete peptide 1), a peptide that binds specifically to the surface of female Plasmodium berghei gametes. Importantly, FG1 but not a scrambled version of the peptide, strongly reduces P. berghei oocyst formation by interfering with fertilization. In addition, FG1 also inhibits P. falciparum oocyst formation suggesting that the peptide binds to a molecule on the surface of the female gamete whose structure is conserved. Identification of the molecular interactions disrupted by the FG1 peptide may lead to the development of novel malaria transmission-blocking strategies. PMID:25944054

  2. The molecular basis of targeting protein kinases in cancer therapeutics.

    PubMed

    Tsai, Chung-Jung; Nussinov, Ruth

    2013-08-01

    In this paper, we provide an overview of targeted anticancer therapies with small molecule kinase inhibitors. First, we discuss why a single constitutively active kinase emanating from a variety of aberrant genetic alterations is capable of transforming a normal cell, leading it to acquire the hallmarks of a cancer cell. To draw attention to the fact that kinase inhibition in targeted cancer therapeutics differs from conventional cytotoxic chemotherapy, we exploit a conceptual framework explaining why suppressed kinase activity will selectively kill only the so-called oncogene 'addicted' cancer cell, while sparing the healthy cell. Second, we introduce the protein kinase superfamily in light of its common active conformation with precisely positioned structural elements, and the diversified auto-inhibitory conformations among the kinase families. Understanding the detailed activation mechanism of individual kinases is essential to relate the observed oncogenic alterations to the elevated constitutively active state, to identify the mechanism of consequent drug resistance, and to guide the development of the next-generation inhibitors. To clarify the vital importance of structural guidelines in studies of oncogenesis, we explain how somatic mutations in EGFR result in kinase constitutive activation. Third, in addition to the common theme of secondary (acquired) mutations that prevent drug binding from blocking a signaling pathway which is hijacked by the aberrant activated kinase, we discuss scenarios of drug resistance and relapse by compensating lesions that bypass the inactivated pathway in a vertical or horizontal fashion. Collectively, these suggest that the future challenge of cancer therapy with small molecule kinase inhibitors will rely on the discovery of distinct combinations of optimized drugs to target individual subtypes of different cancers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Molecular Chaperones in Pathogen Virulence: Emerging New Targets for Therapy

    PubMed Central

    Neckers, Len; Tatu, Utpal

    2009-01-01

    Summary Infectious organisms have to cope with demanding and rapidly changing environments during establishment in the host. This is particularly relevant for pathogens which utilize different hosts to complete their life cycle. In addition to homeotic environmental challenges, other stressful factors, such as oxidative bursts, are often triggered in response to infection. It is not surprising that many successful pathogens have developed robust chaperone systems to conquer the stressful environments in the host. In addition to discussing ingenious ways by which pathogens have utilized chaperones, the potential of exploiting pathogen chaperones as drug targets is also discussed. PMID:19064253

  4. [Molecular target therapy: a milestone on the road for curing cancer].

    PubMed

    Zeng, Yi-Xin; Zhang, Xiao-Shi; Liu, Quentin

    2008-08-01

    Molecular target therapy (MTT), using chemicals of low molecular weight, monoclonal antibodies, and/or polypeptides to interfere with specific signal pathways in cancer cells, causes inhibition of tumor progression. Clinical evidence has demonstrated that MTT has promising potential in not only killing tumors but also inducing tumor cells differentiate into normal cells, leading to cure of the patients. Furthermore, MTT leads to potent inhibition of oncogenic signals. The delay of tumor progression makes the patients "survival with tumor". Thus, in the future it is possible that cancer become a chronic disease much like diabetes and hypertension. This article reviewed the theory on molecular target therapy, its features and future direction.

  5. Condition for the formation of micron-sized dust grains in dense molecular cloud cores

    NASA Astrophysics Data System (ADS)

    Hirashita, Hiroyuki; Li, Zhi-Yun

    2013-07-01

    We investigate the condition for the formation of micron-sized grains in dense cores of molecular clouds. This is motivated by the detection of mid-infrared emission from deep inside a number of dense cores, the so-called `coreshine,' which is thought to come from scattering by micron (μm)-sized grains. Based on numerical calculations of coagulation starting from the typical grain-size distribution in the diffuse interstellar medium, we obtain a conservative lower limit to the time t to form μm-sized grains: t/tff > 3(5/S)(nH/105 cm-3)-1/4 (where tff is the free-fall time at hydrogen number density nH in the core and S the enhancement factor of the grain-grain collision cross-section to account for non-compact aggregates). At the typical core density nH = 105 cm-3, it takes at least a few free-fall times to form the μm-sized grains responsible for coreshine. The implication is that those dense cores observed in coreshine are relatively long-lived entities in molecular clouds, rather than dynamically transient objects that last for one free-fall time or less.

  6. Size-dependent Melting Behavior of Iron Nanoparticles by Replica Exchange Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Shu, Qiang; Yang, Yang; Zhai, Yingteng; Sun, Deyan; Xiang, Hongjun; Gong, Xingao

    2013-03-01

    Due to the finite size effect, nanoparticles own unique physical, chemical, and magnetic properties. Comparing with the bulk materials, the large surface/volume ratio of nanoparticles could lead to more complicate atomic and electronic behavior, thus the thermodynamical properties can be also very rich. In the last a few decades, as one of the fundamental problems in the nano science, the melting behavior of nanoparticles had been widely investigated by numerous experimental and theoretical studies. Using replica-exchange molecular dynamics method (REMD), we have investigated the size dependence of the melting behavior of iron nanoparticles. Comparing to the conventional molecular dynamics (MD), the REMD method is found to be very efficient to determine the melting point, by avoiding the superheating and undercooling phenomena. With accurate determination of the melting point, we find that the melting temperature does not follow linearly with the inverse of size. By incorporating the size dependent thickness of surface liquid layer which is observed in our simulation, we propose a revised liquid skin melting model to describe the size dependent melting temperature. Special Funds for Major State Basic Research, NSFC, MOE, Shanghai Municipality

  7. Size, Albedo, and Taxonomy of the Don Quijote Space Mission Target

    NASA Astrophysics Data System (ADS)

    Harris, Alan; Mueller, Michael; Fitzsimmons, Alan

    2006-03-01

    Rendezvous and lander missions are a very effective but very expensive way of investigating Solar-System bodies. The planning, optimization and success of space missions depends crucially on prior remotely-sensed knowledge of target bodies. Near-Earth asteroids (NEAs), which are mainly fragments of main-belt asteroids, are seen as important goals for investigation by space missions, mainly due to the role their forebears played in planet formation and the evolution of the Solar System, but also for the pragmatic reason that these objects can collide with the Earth with potentially devastating consequences. The European Space Agency is currently planning the Don Quijote mission to a NEA, which includes a rendezvous (and perhaps a lander) spacecraft and an impactor vehicle. The aim is to study the physical properties of the target asteroid and the effects of the impact on its dynamical state, as a first step in considering realistic mitigation measures against an eventual hazardous NEA. Two potential targets have been selected for the mission, the preferred one being (10302) 1989 ML, which is energetically easier to reach and is possibly a scientifically interesting primitive asteroid. However, due to the ambiguity of available spectral data, it is currently not possible to confidently determine the taxonomic type and mineralogy of this object. Crucially, the albedo is uncertain by a factor of 10, which leads to large uncertainties in the size and mass and hence the planned near-surface operations of Don Quijote. Thermal-infrared observations are urgently required for accurate size and albedo determination. These observations, which can only be carried out by Spitzer and would require only a modest amount of observing time, would enable an accurate diameter to be derived for the first time and the resulting albedo would remove the taxonomic ambiguity. The proposed Spitzer observations are critical for effective mission planning and would greatly increase our

  8. Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

    PubMed Central

    Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

    2014-01-01

    The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals. PMID:25140792

  9. Folate-targeted polymeric micelles loaded with ultrasmall superparamagnetic iron oxide: combined small size and high MRI sensitivity

    PubMed Central

    Hong, Guo-bin; Zhou, Jing-xing; Yuan, Ren-xu

    2012-01-01

    Targeted delivery of contrast agents is a highly desirable strategy for enhancing diagnostic efficiency and reducing side effects and toxicity. Water-soluble and tumor-targeting superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by loading hydrophobic SPIONs into micelles assembled from an amphiphilic block copolymer poly(ethylene glycol)- poly(ɛ-caprolactone) (PEG-PCL) bearing folate in the distal ends of PEG chains. Compared to the water-soluble SPIONs obtained by small molecular surfactant coating, ultrasmall SPION encapsulation with PEG-PCL micelles (PEG-PCL-SPIONs) simultaneously increases transverse (r2) and decreases longitudinal (r1) magnetic resonance (MR) relaxivities of water proton in micelle solution, leading to a notably high r2/r1 ratio up to 78, which makes the PEG-PCL-SPIONs a highly sensitive MR imaging (MRI) T2 contrast agent. The mean size of folate-attached SPION micelles (Fa-PEG-PCL-SPIONs) is 44 ± 3 nm on average, ideal for in vivo MRI applications in which long circulation is greatly determined by small particle size and is highly desirable. Prussian blue staining of BEL-7402 cells over-expressing folate receptors, after incubation with micelle-containing medium, demonstrated that folate functionalization of the magnetic particles significantly enhanced their cell uptake. The potential of Fa-PEG-PCL-SPIONs as a potent MRI probe for in vivo tumor detection was assessed. At 3 hours after intravenous injection of the Fa-PEG-PCL-SPION solution into mice bearing subcutaneous xenografts of human BEL-7402 hepatoma, a 41.2% signal intensity decrease was detected in the T2-weighted MR images of the tumor, indicating the efficient accumulation of Fa-PEG-PCL-SPIONs in the tumor tissue. PMID:22745549

  10. Communication: Kirkwood-Buff integrals in the thermodynamic limit from small-sized molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Cortes-Huerto, R.; Kremer, K.; Potestio, R.

    2016-10-01

    We present an accurate and efficient method to obtain Kirkwood-Buff (KB) integrals in the thermodynamic limit from small-sized molecular dynamics simulations. By introducing finite size effects into integral equations of statistical mechanics, we derive an analytical expression connecting the KB integrals of the bulk system with the fluctuations of the number of molecules in the corresponding closed system. We validate the method by calculating the activity coefficients of aqueous urea mixtures and the KB integrals of Lennard-Jones fluids. Moreover, our results demonstrate how to identify simulation conditions under which computer simulations reach the thermodynamic limit.

  11. Proteasome as a Molecular Target of Microcystin-LR

    PubMed Central

    Zhu, Zhu; Zhang, Li; Shi, Guoqing

    2015-01-01

    Proteasome degrades proteins in eukaryotic cells. As such, the proteasome is crucial in cell cycle and function. This study proved that microcystin-LR (MC-LR), which is a toxic by-product of algal bloom, can target cellular proteasome and selectively inhibit proteasome trypsin-like (TL) activity. MC-LR at 1 nM can inhibit up to 54% of the purified 20S proteasome TL activity and 43% of the proteasome TL activity in the liver of the cyprinid rare minnow (Gobiocypris rarus). Protein degradation was retarded in GFP-CL1-transfected PC-3 cells because MC-LR inhibited the proteasome TL activity. Docking studies indicated that MC-LR blocked the active site of the proteasome β2 subunit; thus, the proteasome TL activity was inhibited. In conclusion, MC-LR can target proteasome, selectively inhibit proteasome TL activity, and retard protein degradation. This study may be used as a reference of future research on the toxic mechanism of MC-LR. PMID:26090622

  12. Molecular pathways: targeting MALT1 paracaspase activity in lymphoma.

    PubMed

    Fontán, Lorena; Melnick, Ari

    2013-12-15

    MALT1 mediates the activation of NF-κB in response to antigen receptor signaling. MALT1, in association with BCL10 and CARD11, functions as a scaffolding protein to activate the inhibitor of IκB kinase (IKK) complex. In addition, MALT1 is a paracaspase that targets key proteins in a feedback loop mediating termination of the NF-κB response, thus promoting activation of NF-κB signaling. Activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL), which tend to be more resistant to chemotherapy, are often biologically dependent on MALT1 activity. Newly developed MALT1 small-molecule inhibitors suppress the growth of ABC-DLBCLs in vitro and in vivo. This review highlights the recent advances in the normal and disease-related functions of MALT1. Furthermore, recent progress targeting MALT1 proteolytic activity raises the possibility of deploying MALT1 inhibitors for the treatment of B-cell lymphomas and perhaps autoimmune diseases that involve increased B- or T-cell receptor signaling.

  13. Nuclear EGFR as a molecular target in cancer.

    PubMed

    Brand, Toni M; Iida, Mari; Luthar, Neha; Starr, Megan M; Huppert, Evan J; Wheeler, Deric L

    2013-09-01

    The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell's nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future.

  14. Radiosensitizers in Pancreatic Cancer – Preclinical and Clinical Exploits with Molecularly Targeted Agents

    PubMed Central

    Walker, Amanda J.; Alcorn, Sara; Narang, Amol; Nugent, Katriana; Wild, Aaron T.; Herman, Joseph M.; Tran, Phuoc T.

    2013-01-01

    There has been an explosion in the number of molecularly targeted agents engineered to inhibit specific molecular pathways driving the tumorigenic phenotype in cancer cells. Some of these molecularly targeted agents have demonstrated robust clinical effects, but few result in meaningful durable responses. Therapeutic radiation is used to treat a majority of cancer patients with recent technologic and pharmacologic enhancements, leading to improvements in the therapeutic ratio for cancer care. Radiotherapy has a very specific role in select cases of postoperative and locally advanced pancreatic cancer patients, but control of metastatic disease still appears to be the major limiting factor behind improvements in cure. Recent rapid autopsy pathologic findings suggest a sub-group of advanced pancreatic cancer patients where death is caused from local disease progression and who would thus benefit from improved local control. One promising approach is to combine molecularly targeted agents with radiotherapy to improve tumor response rates and likelihood of durable local control. We review suggested recommendations on the investigation of molecularly targeted agents as radiosensitizers from preclinical studies to implementation in phase I–II clinical trials. We then discuss a select set of molecularly targeted therapies that we believe show promise as radiosensitizers in the treatment of pancreatic cancer. PMID:24331186

  15. [Targeted molecular therapy based on advanced cancer stem cell model].

    PubMed

    Hirao, Atsushi

    2015-08-01

    Improvement of cell purification and transplantation techniques have contributed to the identification of cell populations known as tumor-initiating cells (TICs). Although it was hypothesized that tumors are organized as hierarchies of tumor cells that are sustained by rare TICs, like normal tissue stem cells, there are several controversies towards such cancer stem cell model, e.g. reversible change of stem cell like population based on epigenetic changes, clonal genetic evolution and problems in xenotransplantation system. Despite complexity in cancer stem cell models, studies in cancer stem cell field have revealed that there are close relationship between cancer malignancy and stem cell properties, called "stemness". Understanding molecular mechanisms for controlling stemness would contribute to establishment of novel diagnostics or therapeutics for cancer.

  16. Molecular targets of epigenetic regulation and effectors of environmental influences

    SciTech Connect

    Choudhuri, Supratim; Cui Yue; Klaassen, Curtis D.

    2010-06-15

    The true understanding of what we currently define as epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current explosion of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses the molecular mechanisms of epigenetic regulation and expands the discussion with examples on the role of environment, such as the immediate environment during development, in inducing epigenetic changes and modulating gene expression.

  17. MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

    PubMed Central

    Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

    2015-01-01

    Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

  18. Phase behavior and molecular mobility of n-octylcyanobiphenyl confined to molecular sieves: dependence on the pore size.

    PubMed

    Frunza, Ligia; Frunza, Stefan; Kosslick, Hendrik; Schönhals, Andreas

    2008-11-01

    The molecular dynamics of 4-n-octyl-4'-cyanobiphenyl (8CB) confined inside the pores of a series of AlMCM-41 samples with the same structure, constant composition (SiAl=14.7) but different pore sizes (diameter between 2.3 and 4.6 nm) was investigated by broadband dielectric spectroscopy (10(-2)-10(9) Hz) in a large temperature interval. Two relaxation processes are observed: one has a bulklike behavior and is assigned to the 8CB in the pore center. The relaxation time of the second relaxation process is essentially slower than that of the former one and this process is related to the dynamics of molecules in a surface layer with a paranematic order. Both relaxation processes are specifically influenced by the interaction of the molecules with the surface and by the confinement. Above the clearing temperature the temperature dependence of the relaxation rate of the bulklike process obeys the Vogel-Fulcher-Tammann (VFT) law. The Vogel temperature increases with decreasing pore size. This is explained by increasing influence of paranematic potential of the surface layer with decreasing pore size. The temperature dependence of the relaxation rate of the surface layer follows also the VFT formula and the Vogel temperature decreases with decreasing pore size. This temperature dependence is controlled by both the interaction of the 8CB molecules with the surface via hydrogen bonding and by spatial confinement effects. To discriminate between both effects the data for the surface layer of 8CB confined to the molecular sieves are compared with results concerning 8CB adsorbed as a quasimonolayer on the surface of silica spheres of aerosil. On this basis a confinement parameter is defined and discussed.

  19. Improving the accuracy of hyaluronic acid molecular weight estimation by conventional size exclusion chromatography.

    PubMed

    Shanmuga Doss, Sreeja; Bhatt, Nirav Pravinbhai; Jayaraman, Guhan

    2017-08-15

    There is an unreasonably high variation in the literature reports on molecular weight of hyaluronic acid (HA) estimated using conventional size exclusion chromatography (SEC). This variation is most likely due to errors in estimation. Working with commercially available HA molecular weight standards, this work examines the extent of error in molecular weight estimation due to two factors: use of non-HA based calibration and concentration of sample injected into the SEC column. We develop a multivariate regression correlation to correct for concentration effect. Our analysis showed that, SEC calibration based on non-HA standards like polyethylene oxide and pullulan led to approximately 2 and 10 times overestimation, respectively, when compared to HA-based calibration. Further, we found that injected sample concentration has an effect on molecular weight estimation. Even at 1g/l injected sample concentration, HA molecular weight standards of 0.7 and 1.64MDa showed appreciable underestimation of 11-24%. The multivariate correlation developed was found to reduce error in estimations at 1g/l to <4%. The correlation was also successfully applied to accurately estimate the molecular weight of HA produced by a recombinant Lactococcus lactis fermentation. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Molecular targeted therapy in the treatment of advanced stage non-small cell lung cancer (NSCLC).

    PubMed

    Kumarakulasinghe, Nesaretnam Barr; van Zanwijk, Nico; Soo, Ross A

    2015-04-01

    Historically, patients with advanced stage non-small cell lung cancer (NSCLC) were treated with chemotherapy alone, but a therapeutic plateau has been reached. Advances in the understanding of molecular genetics have led to the recognition of multiple molecularly distinct subsets of NSCLC. This in turn has led to the development of rationally directed molecular targeted therapy, leading to improved clinical outcomes. Tumour genotyping for EGFR mutations and ALK rearrangement has meant chemotherapy is no longer given automatically as first-line treatment but reserved for when patients do not have a 'druggable' driver oncogene. In this review, we will address the current status of clinically relevant driver mutations and emerging new molecular subsets in lung adenocarcinoma and squamous cell carcinoma, and the role of targeted therapy and mechanisms of acquired resistance to targeted therapy.

  1. Molecularly imprinted polymeric micro- and nano-particles for the targeted delivery of active molecules.

    PubMed

    Gagliardi, Mariacristina; Mazzolai, Barbara

    2015-01-01

    Molecular imprinting (MI) represents a strategy to introduce a 'molecular memory' in a polymeric system obtaining materials with specific recognition properties. MI particles can be used as drug delivery systems providing a targeted release and thus reducing the side effects. The introduction of molecular recognition properties on a polymeric drug carrier represents a challenge in the development of targeted delivery systems to increase their efficiency. This review will summarize the limited number of drug delivery MI particles described in the literature along with an overview of potential solutions for a larger exploitation of MI particles as targeted drug delivery carriers. Molecularly imprinted drug carriers can be considered interesting candidates to significantly improve the efficiency of a controlled drug treatment.

  2. Potential nanotechnologies and molecular targets in the quest for efficient chemotherapy in ovarian cancer.

    PubMed

    Rhoda, Khadija; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Pillay, Viness

    2015-04-01

    Ovarian cancer, considered one of the most fatal gynecological cancers, goes largely undiagnosed until metastasis presents itself, usually once the patient is in the final stages and thus, too late for worthwhile therapy. Targeting this elusive disease in its early stages would improve the outcome for most patients, while the information generated thereof would increase the possibility of preventative mechanisms of therapy. This review discusses various molecular targets as possible moieties to be incorporated in a holistic drug delivery system or the more aptly termed 'theranostic' system. These molecular targets can be used for targeting, visualizing, diagnosing, and ultimately, treating ovarian cancer in its entirety. Currently implemented nanoframeworks, such as nanomicelles and nanoliposomes, are described and the effectiveness of nanostructures in tumor targeting, treatment functions, and overcoming the drug resistance challenge is discussed. Novel nanotechnology strategies such as the development of nanoframeworks decorated with targeted ligands of a molecular nature may provide an efficient chemotherapy, especially when instituted in combination with imaging, diagnostic, and ultimately, therapeutic moieties. An imperative aspect of utilizing nanotechnology in the treatment of ovarian cancer is the flexibility of the drug delivery system and its ability to overcome standard obstacles such as: i) successfully treating the desired cells through direct targeting; ii) reducing toxicity levels of treatment by achieving direct targeting; and iii) delivery of targeted therapy using an efficient vehicle that is exceptionally degradable in response to a particular stimulus. The targeting of ovarian cancer in its early stages using imaging and diagnostic nanotechnology is an area that can be improved upon by combining therapeutic moieties with molecular biomarkers. The nanotechnology and molecular markers mentioned in this review have generally been used for either

  3. Polydiacetylene chromism towards toxic chemical detection via molecular size-dependent selectivity

    NASA Astrophysics Data System (ADS)

    Seo, Donghwan

    Polydiacetylene (PDA) is a pi-conjugated polymer that has unique optical properties. PDA changes color from blue to red when subjected to various stimuli such as mechanical stress, heat, photoirradiation, pH change, and binding of specific ligands. The steric effect induced by those stimuli on PDA headgroup has been investigated to understand the mechanism of PDA chromism and to apply those optical properties to the development of various sensors. In this work, pH chromism of PDA was examined in terms of the effects of the molecular size and acidity of acid analytes with the consideration of the molecular design aspect of diacetylene lipids. The pH level is an important parameter, since a low pH will produce a charge on the amine headgroup of PDA, but this does not necessarily result in PDA chromatic transition from 'blue phase' to 'red phase.' The molecular size of the counter anion was identified as another determinant condition to ensure the perturbation of the ene-yne conjugated backbone of PDA, which produces the chromatic transition. In the molecular design of the sensory diacetylene lipids, the alkyl spacer length between the amine as a receptor and the amide linker was found to strongly affect the degree of PDA chromatic transition. The longer alkyl spacer showed the less chromatic transition. The length of alkyl spacer seems to promote the flexibility of the molecule diminishing the extent of the transfer of the steric effect at PDA headgroup to the conjugated backbone. Finally, PDA chromism dependent on the molecular size of acid analytes was applied to develop the colorimetric detection of diethyl phosphate (DEP), a degraded nerve agent simulant. PDA liposome sensors successfully showed selective chromatic transition with fluorescent emission upon binding of DEP compared to other acid analytes. The molecular size and acidity of acid analytes, and alkyl spacer length have proven to be correlated with PDA chromism. These new findings provide further

  4. Tyrosine kinase receptors as molecular targets In pheochromocytomas and paragangliomas

    PubMed Central

    Cassol, Clarissa A.; Winer, Daniel; Liu, Wei; Guo, Miao; Ezzat, Shereen; Asa, Sylvia L.

    2016-01-01

    Pheochromocytomas and paragangliomas are neuroendocrine tumors shown to be responsive to multi-targeted tyrosine kinase inhibitor treatment. Despite growing knowledge regarding their genetic basis, the ability to predict behavior in these tumors remains challenging. There is also limited knowledge of their tyrosine kinase receptor expression and whether the clinical response observed to the tyrosine kinase inhibitor Sunitinib relates only to its anti-angiogenic properties or also due to a direct effect on tumor cells. To answer these questions, an in vitro model of sunitinib treatment of a pheochromocytoma cell line was created. Sunitinib targets (VEGFRs, PDGFRs, C-KIT), FGFRs and cell cycle regulatory proteins were investigated in human tissue microarrays. SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations. The FGFR4 G388R SNP was also investigated. Sunitinib treatment in vitro decreases cell proliferation mainly by targeting cell cycle, DNA metabolism, and cell organization genes. FGFR1, -2 and -4, VEGFR2, PDGFRα and p16 were overexpressed in primary human pheochromocytomas and paragangliomas. Discordant results were observed for VEGFR1, p27 and p21 (overexpressed in paragangliomas but underexpressed in pheochromoctyomas); PDGFRβ, Rb and Cyclin D1 (overexpressed in paragangliomas only) and FGFR3 (overexpressed in pheochromocytomas and underexpressed in paragangliomas). Low expression of C-KIT, p53, Aurora Kinase A and B was observed. Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio [OR]=7.61; p=0.008), as was membranous PDGFRα (OR= 13.71, p=0.015), membranous VEGFR1 (OR=8.01; p=0.037), nuclear MIB1 (OR=1.26, p=0.008) and cytoplasmic p27 (OR=1.037, p=0.030). FGFR3, VEGFR2 and C-KIT levels were associated with decreased risk of metastasis. We provide new insights into the mechanistic actions of sunitinib in pheochromoctyomas and paragangliomas and support current

  5. Convenient Molecular Approach of Size and Shape Controlled ZnSe and ZnTe Nanocrystals

    DTIC Science & Technology

    2001-01-01

    Materials Research Society Symposium Proceedings Volume 635. Anisotropic Nanoparticles - Synthesis , Characterization and Applications To order the...diffraction patterns were measured on a Rigaku Miniflex instrument (0.5 kW) operating with a Cu K,(X, 0.1541 nm) X-ray source. ZnSc Nanocrystals. Zn ...one-pot synthesis of size and shape controlled zinc chalcogenide nanocrystals using a monomeric molecular precursor, [ Zn (EPh)2][TMEDA]. By varying

  6. Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicides.

    PubMed Central

    Matringe, M; Camadro, J M; Labbe, P; Scalla, R

    1989-01-01

    Diphenyl ether herbicides induce an accumulation of protoporphyrin IX in plant tissues. By analogy to human porphyria, the accumulation could be attributed to decreased (Mg or Fe)-chelatase or protoporphyrinogen oxidase activities. Possible effects of acifluorfen-methyl on these enzymes were investigated in isolated corn (maize, Zea mays) etioplasts, potato (Solanum tuberosum) and mouse mitochondria, and yeast mitochondrial membranes. Acifluorfen-methyl was strongly inhibitory to protoporphyrinogen oxidase activities whatever their origins [concn. causing 50% inhibition (IC50) = 4 nM for the corn etioplast enzyme]. By contrast, it was roughly 100,000 times less active on (Mg or Fe)-chelatase activities (IC50 = 80-100 microM). Our results lead us to propose protoporphyrinogen oxidase as a cellular target for diphenyl ether herbicides. PMID:2775186

  7. [Depression and addiction comorbidity: towards a common molecular target?].

    PubMed

    Arango-Lievano, Margarita; Kaplitt, Michael G

    2015-05-01

    The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans.

  8. Promising Molecular Targets and Biomarkers for Male BPH and LUTS

    PubMed Central

    Gharaee-Kermani, Mehrnaz; Macoska, Jill A.

    2013-01-01

    Benign prostatic hyperplasia (BPH) is a major health concern for aging men. BPH is associated with urinary voiding dysfunction and lower urinary tract symptoms (LUTS), which negatively affects quality of life. Surgical resection and medical approaches have proven effective for improving urinary flow and relieving LUTS, but are not effective for all men and can produce adverse effects that require termination of the therapeutic regimen. Thus, there is a need to explore other therapeutic targets to treat BPH/LUTS. Complicating the treatment of BPH/LUTS is the lack of biomarkers to effectively identify pathobiologies contributing to BPH/LUTS or to gauge successful response to therapy. This review will briefly discuss current knowledge and will highlight new studies that illuminate the pathobiologies contributing to BPH/LUTS; potential new therapeutic strategies for successfully treating BPH/LUTS; and new approaches for better defining these pathobiologies and response to therapeutics through the development of biomarkers and phenotyping strategies. PMID:23913202

  9. Molecular diversity patterns among various phytoplankton size-fractions in West Greenland in late summer

    NASA Astrophysics Data System (ADS)

    Elferink, Stephanie; Neuhaus, Stefan; Wohlrab, Sylke; Toebe, Kerstin; Voß, Daniela; Gottschling, Marc; Lundholm, Nina; Krock, Bernd; Koch, Boris P.; Zielinski, Oliver; Cembella, Allan; John, Uwe

    2017-03-01

    Arctic regions have experienced pronounced biological and biophysical transformations as a result of global change processes over the last several decades. Current hypotheses propose an elevated impact of those environmental changes on the biodiversity, community composition and metabolic processes of species. The effects on ecosystem function and services, particularly when invasive or toxigenic harmful species become dominant, can be expressed over a wide range of temporal and spatial scales in plankton communities. Our study focused on the comparison of molecular biodiversity of three size-fractions (micro-, nano-, picoplankton) in the coastal pelagic zone of West Greenland and their association with environmental parameters. Molecular diversity was assessed via parallel amplicon sequencing the 28S rRNA hypervariable D1/D2 region. We showed that biodiversity distribution within the area of Uummannaq Fjord, Vaigat Strait and Disko Bay differed markedly within and among size-fractions. In general, we observed a higher diversity within the picoplankton size fraction compared to the nano- and microplankton. In multidimensional scaling analysis, community composition of all three size fractions correlated with cell size, silicate and phosphate, chlorophyll a (chl a) and dinophysistoxin (DTX). Individually, each size fraction community composition also correlated with other different environmental parameters, i.e. temperature and nitrate. We observed a more homogeneous community of the picoplankton across all stations compared to the larger size classes, despite different prevailing environmental conditions of the sampling areas. This suggests that habitat niche occupation for larger-celled species may lead to higher functional trait plasticity expressed as an enhanced range of phenotypes, whereas smaller organisms may compensate for lower potential plasticity with higher diversity. The presence of recently identified toxigenic harmful algal bloom (HAB) species (such

  10. Biomimetic supercontainers for size-selective electrochemical sensing of molecular ions

    PubMed Central

    Netzer, Nathan L.; Must, Indrek; Qiao, Yupu; Zhang, Shi-Li; Wang, Zhenqiang; Zhang, Zhen

    2017-01-01

    New ionophores are essential for advancing the art of selective ion sensing. Metal-organic supercontainers (MOSCs), a new family of biomimetic coordination capsules designed using sulfonylcalix[4]arenes as container precursors, are known for their tunable molecular recognition capabilities towards an array of guests. Herein, we demonstrate the use of MOSCs as a new class of size-selective ionophores dedicated to electrochemical sensing of molecular ions. Specifically, a MOSC molecule with its cavities matching the size of methylene blue (MB+), a versatile organic molecule used for bio-recognition, was incorporated into a polymeric mixed-matrix membrane and used as an ion-selective electrode. This MOSC-incorporated electrode showed a near-Nernstian potentiometric response to MB+ in the nano- to micro-molar range. The exceptional size-selectivity was also evident through contrast studies. To demonstrate the practical utility of our approach, a simulated wastewater experiment was conducted using water from the Fyris River (Sweden). It not only showed a near-Nernstian response to MB+ but also revealed a possible method for potentiometric titration of the redox indicator. Our study thus represents a new paradigm for the rational design of ionophores that can rapidly and precisely monitor molecular ions relevant to environmental, biomedical, and other related areas. PMID:28393841

  11. Biomimetic supercontainers for size-selective electrochemical sensing of molecular ions

    NASA Astrophysics Data System (ADS)

    Netzer, Nathan L.; Must, Indrek; Qiao, Yupu; Zhang, Shi-Li; Wang, Zhenqiang; Zhang, Zhen

    2017-04-01

    New ionophores are essential for advancing the art of selective ion sensing. Metal-organic supercontainers (MOSCs), a new family of biomimetic coordination capsules designed using sulfonylcalix[4]arenes as container precursors, are known for their tunable molecular recognition capabilities towards an array of guests. Herein, we demonstrate the use of MOSCs as a new class of size-selective ionophores dedicated to electrochemical sensing of molecular ions. Specifically, a MOSC molecule with its cavities matching the size of methylene blue (MB+), a versatile organic molecule used for bio-recognition, was incorporated into a polymeric mixed-matrix membrane and used as an ion-selective electrode. This MOSC-incorporated electrode showed a near-Nernstian potentiometric response to MB+ in the nano- to micro-molar range. The exceptional size-selectivity was also evident through contrast studies. To demonstrate the practical utility of our approach, a simulated wastewater experiment was conducted using water from the Fyris River (Sweden). It not only showed a near-Nernstian response to MB+ but also revealed a possible method for potentiometric titration of the redox indicator. Our study thus represents a new paradigm for the rational design of ionophores that can rapidly and precisely monitor molecular ions relevant to environmental, biomedical, and other related areas.

  12. Using solvents with different molecular sizes to investigate the structure of Antheraea pernyi silk.

    PubMed

    Wang, Yu; Porter, David; Shao, Zhengzhong

    2013-11-11

    The interaction between silk and polar solvents of different molecular size can be an important tool for understanding the structural features of natural silk; in particular, the disordered regions associated with the key property of mechanical toughness. In this work, we investigate the transitions induced in the tensile performance and structure of as-reeled Antheraea pernyi silks from different silkworms by a range of solvents that can only soften the protein chains in the amorphous regions. The results indicate that polar solvents with different molecular sizes affect the silk to different degrees, and silks with slightly different structures display significantly different tensile performance in the same solvent. The solvent molecular size is quantitatively correlated with the accessible volume in the amorphous regions before and after the yield point, which suggests that the volume accessible to the solvent molecules decreases as the solvent radius increases. Moreover, silks with more ordered structure (less free volume) in the amorphous regions are less sensitive to solvents than those with more disordered structures. However, silks with higher free volume have higher toughness due to the greater strain to failure.

  13. Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats

    PubMed Central

    Matsuzaki, Takashi; Araki, Ryo; Tsuchida, Shota; Thanikachalam, Punniyakoti V.; Fukuta, Tatsuya; Asai, Tomohiro; Yamato, Masaki; Sanada, Shoji; Asanuma, Hiroshi; Asano, Yoshihiro; Asakura, Masanori; Hanawa, Haruo; Hao, Hiroyuki; Oku, Naoto; Takashima, Seiji; Kitakaze, Masafumi; Sakata, Yasushi; Minamino, Tetsuo

    2016-01-01

    Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug’s effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents. PMID:27501378

  14. Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update.

    PubMed

    Khan, Fazlullah; Niaz, Kamal; Maqbool, Faheem; Ismail Hassan, Fatima; Abdollahi, Mohammad; Nagulapalli Venkata, Kalyan C; Nabavi, Seyed Mohammad; Bishayee, Anupam

    2016-08-29

    Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods-including fruits, vegetables, tea, wine, as well as other dietary supplements-and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed.

  15. Molecular targets in pulmonary fibrosis: the myofibroblast in focus.

    PubMed

    Scotton, Chris J; Chambers, Rachel C

    2007-10-01

    Idiopathic pulmonary fibrosis (IPF) is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, IPF has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of IPF. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells (fibrocytes). From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of IPF. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.

  16. Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update

    PubMed Central

    Khan, Fazlullah; Niaz, Kamal; Maqbool, Faheem; Ismail Hassan, Fatima; Abdollahi, Mohammad; Nagulapalli Venkata, Kalyan C.; Nabavi, Seyed Mohammad; Bishayee, Anupam

    2016-01-01

    Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods—including fruits, vegetables, tea, wine, as well as other dietary supplements—and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed. PMID:27589790

  17. Exploring the molecular targets of dietary flavonoid fisetin in cancer.

    PubMed

    Syed, Deeba N; Adhami, Vaqar Mustafa; Khan, Naghma; Khan, Mohammad Imran; Mukhtar, Hasan

    2016-10-01

    The last few decades have seen a resurgence of interest among the scientific community in exploring the efficacy of natural compounds against various human cancers. Compounds of plant origin belonging to different groups such as alkaloids, flavonoids and polyphenols evaluated for their cancer preventive effects have yielded promising data, thereby offering a potential therapeutic alternative against this deadly disease. The flavonol fisetin (3,3',4',7-tetrahydroxyflavone), present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant and more significantly anti-carcinogenic activity when assessed in diverse cell culture and animal model systems. The purpose of this review is to update and discuss key findings obtained till date from in vitro and in vivo studies on fisetin, with special focus on its anti-cancer role. The molecular mechanism(s) described in the observed growth inhibitory effects of fisetin in different cancer cell types is also summarized. Moreover, an attempt is made to delineate the direction of future studies that could lead to the development of fisetin as a potent chemopreventive/chemotherapeutic agent against cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. [The quality practice of molecular-genetic testing in the era of molecular target therapy in chronic myelogenous leukemia].

    PubMed

    Miyachi, Hayato; Matsushita, Hiromichi; Masukawa, Atsuko; Asai, Satomi

    2012-10-01

    The advent of tyrosine kinase inhibitors as molecular target therapy has resulted in a marked change in the laboratory process for the diagnosis and therapeutic monitoring of chronic myelogenous leukemia. This includes defining the molecular typing of BCR-ABL1 to establish the diagnosis, a quantitative and/or high quality assay for minimal residual disease to evaluate the molecular response, and mutation analysis and chromosomal examination to assess its resistance to inhibitors. These processes should be used where appropriate for each patient. In the ongoing development and clinical use of novel agents for treatment of the leukemia, the quality assurance of each process of molecular-genetic testing, such as specimen handling, measurement, and reporting, has become increasingly important in the quality care of patients.

  19. Molecular targeted therapy for pancreatic adenocarcinoma: A review of completed and ongoing late phase clinical trials.

    PubMed

    Mosquera, Catalina; Maglic, Dino; Zervos, Emmanuel E

    2016-12-01

    Molecular targeted therapy is widely utilized and effective in a number of solid tumors. In pancreatic adenocarcinoma, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. The purpose of this study is to review therapeutic molecular targets in completed and ongoing later phase (II and III) clinical trials to have a better understanding of the rationale and progress towards targeted molecular therapies for pancreatic cancer. The PubMed database and the NCDI clinical trial website (www.clinicaltrials.gov) were queried to identify phase II and III completed and published (PubMed) and ongoing (clinicaltrials.gov) trials using the keywords: pancreatic cancer and molecular targeted therapy. The search engines were further limited by adding Phase II or III, active enrollment and North American. A total of 14 completed and published phase II/III clinical trials and 17 ongoing trials were identified. Evaluated strategies included inhibition of growth factor receptors (EGFR, PDGFR, VGFR, IGF-1R), tyrosine kinase inhibitors, MEK1/2, mTOR blockade and PI3K and HER2-neu pathway inhibitors. Only one trial conducted by the National Cancer Institute of Canada and the PANTAR trial have demonstrated a survival improvement from EGFR inhibition using erlotinib. These trials ultimately led to FDA approval of erlotinib/Tarceva in advanced stage disease. It remains unclear whether new combinations of cytotoxic chemotherapy or immunotherapy plus molecular targeted therapy will be beneficial in management of pancreatic adenocarcinoma. Despite a number of phase II and III trials, to date, only erlotinib has emerged as an approved targeted therapy in pancreatic adenocarcinoma. There are several ongoing late phase trials evaluating a number of targets, the results of which will become available over the next 1 to 2 years. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Molecular behavior of DNA in a cell-sized compartment coated by lipids

    NASA Astrophysics Data System (ADS)

    Hamada, Tsutomu; Fujimoto, Rie; Shimobayashi, Shunsuke F.; Ichikawa, Masatoshi; Takagi, Masahiro

    2015-06-01

    The behavior of long DNA molecules in a cell-sized confined space was investigated. We prepared water-in-oil droplets covered by phospholipids, which mimic the inner space of a cell, following the encapsulation of DNA molecules with unfolded coil and folded globule conformations. Microscopic observation revealed that the adsorption of coiled DNA onto the membrane surface depended on the size of the vesicular space. Globular DNA showed a cell-size-dependent unfolding transition after adsorption on the membrane. Furthermore, when DNA interacted with a two-phase membrane surface, DNA selectively adsorbed on the membrane phase, such as an ordered or disordered phase, depending on its conformation. We discuss the mechanism of these trends by considering the free energy of DNA together with a polyamine in the solution. The free energy of our model was consistent with the present experimental data. The cooperative interaction of DNA and polyamines with a membrane surface leads to the size-dependent behavior of molecular systems in a small space. These findings may contribute to a better understanding of the physical mechanism of molecular events and reactions inside a cell.

  1. Molecular Targets of Opiate Drug Abuse in NeuroAIDS

    PubMed Central

    Hauser, Kurt F.; El-Hage, Nazira; Buch, Shreya; Berger, Joseph R.; Tyor, William R.; Nath, Avindra; Bruce-Keller, Annadora J.; Knapp, Pamela E.

    2015-01-01

    Opiate drug abuse, through selective actions at μ opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiate drugs have some affinity for κ (KOR) and/or δ (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS. PMID:16260386

  2. Molecular profiling of biliary tract cancer: a target rich disease

    PubMed Central

    Jain, Apurva

    2016-01-01

    Biliary tract cancers (BTCs) are relatively uncommon orphan tumors that have an aggressive disease course and a poor clinical outcome. Surgery is the only curative treatment, but most patients present with advanced disease and therefore have a limited survival. Gemcitabine and cisplatin based chemotherapy has been the only widely accepted standard systemic therapy regimen in these patients but these tumors can be chemoresistant, further complicating their management. In recent times, there has been considerable research in the genetics of BTC and with the advent of new, advanced technologies like next-generation sequencing (NGS) we are achieving a greater understanding of its disease biology. With the help of NGS, we have now been able to identify actionable mutations such as in the isocitrate dehydrogenase 1 (IDH1), FGFR2, BRAF and HER2/neu genes for targeted therapeutics and correlate the genetic variations with distinct clinical prognoses. This recent genetic information has the potential to make precision medicine a part of routine clinical practice for the management of BTC patients. PMID:27747093

  3. Study of molecular behavior in a water nanocluster: size and temperature effect.

    PubMed

    Ju, Shin-Pon; Yang, Sheng-Hui; Liao, Ming-Liang

    2006-05-11

    Temperature and size effects on the behavior of nanoscale water molecule clusters are investigated by molecular dynamics simulations. The flexible three-centered (F3C) water potential is used to model the inter- and intramolecular interactions of the water molecule. The differences between the structural properties for the surface region and those for the interior region of the cluster are also investigated. It is found that as the temperature rises, the average number of hydrogen bonds per water molecule decreases, but the ratio of surface water molecules increases. After comparing the water densities in interior regions and the average number of hydrogen bonds in those regions, we find there is no apparent size effect on water molecules in the interior region, whereas the size of the water cluster has a significant influence on the behavior of water molecules at the surface region.

  4. Molecular targets of diabetic vascular complications and potential new drugs.

    PubMed

    Da Ros, Roberto; Assaloni, Roberta; Ceriello, Antonio

    2005-06-01

    In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.

  5. Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da

    SciTech Connect

    Bellinger-Kawahara, C.G.; Kempner, E.; Groth, D.; Gabizon, R.; Prusiner, S.B.

    1988-06-01

    Scrapie is a degenerative neurologic disease in sheep and goats which can be experimentally transmitted to laboratory rodents. Considerable evidence suggests that the scrapie agent is composed largely, if not entirely, of an abnormal isoform of the prion protein (PrPSc). Inactivation of scrapie prions by ionizing radiation exhibited single-hit kinetics and gave a target size of 55,000 +/- 9000 mol wt. The inactivation profile was independent of the form of the prion. Scrapie agent infectivity in brain homogenates, microsomal fractions, detergent-extracted microsomes, purified amyloid rods, and liposomes exhibited the same inactivation profile. Our data are consistent with the hypothesis that the infectious particle causing scrapie contains approximately 2 PrPSc molecules.

  6. [Targeted magnetic nanoparticles used as probe for magnetic resonance molecular imaging of tumor].

    PubMed

    Lu, Jing-Jing; Wang, Fang; Jin, Zheng-Yu; Zhong, Ding-Rong

    2009-04-01

    To investigate the feasibility of in vivo tumor detection using magnetic resonance (MR) molecular imaging with targeted magnetic nanoparticles as imaging probe. Targeted probe was synthesized by covalently linking the recombinant human gonadotropin releasing hormone analog (the targeting portion) with the ultrasmall superparamagnetic iron oxide nanoparticles (the imaging portion). The imaging portion served as the control material. The in vitro tumor cell experiment and the in vivo experiment using nude mice bearing tumors were carried out to test the targeting ability of the probe. In the in vitro experiment, the targeting probe and control materials were incubated separately with A549 cells which had high affinity to gonadotropin releasing hormone. Then the cells were taken out and lysed. The resultant solution was then subjected to MR imaging. The T2 value of the solutions was measured and compared. In the in vivo experiment, the targeting probe was administered into nude mice bearing A549 tumors. Dynamic MR imaging was carried out to measure the signal and T2 value of the tumor. The control material was also administered into control group of nude mice, and dynamic magnetic resonance imaging was performed. The T2 value of the tumor in both groups were recorded and compared. Both the in vitro and in vivo experiments proved the targeting ability of targeted probe. Compared with control material, the targeting probe had higher combining ability with tumor cells. MR molecular imaging of tumor can be realized by using targeting magnetic nanoparticles.

  7. Variation of LTR size in molecular clones of the BALB/c endogenous ecotropic molecular leukemia virus

    SciTech Connect

    Boone, L.R.; Myer, F.E.; Yang, D.M.; Kiggans, J.O.; Koh, C.; Tennant, R.W.; Yang, W.K.

    1982-01-01

    Retrovirus replication involves the synthesis of a DNA intermediate which integrates into the host cell genome. Structure analysis has revealed that the viral DNA contains a nucleotide sequence on both ends, termed long terminal repeat (LTR) which is derived from terminal sequences of the genomic RNA and consists of three portions: U3, R, and U5, representing respectively the 3' end, a short terminal repeated sequence, and the 5' end of the RNA. Each species of retrovirus has a characteristic length LTR; however, within a species different strains and isolates have variations in LTR size. The evolution of viral genomes during replication as an exogenous agent may involve changes which occur in the LTR. A population of molecular clones of an endogenous ecotropic virus was analyzed to identify possible changes which occur in the LTR region. Thirteen of fifteen plaque purified isolates examined have an insert which appears to be a typical viral genome with no major rearrangement or deletion. Six of these have an insert which contains a single LTR, and seven have an insert which contains two LTRs. Approximately half of the isolates, including single and double LTR clones, are infectious. More detailed analysis of plasmid subclones all containing double LTRs, revealed that the variation resided in the U3 region rather than the left LTR/right LTR junction region. Thus, the size variation of LTR in the WN1802N MuLV recombinant DNA clones appears to be different from the situation which is responsible for LTR size variability in some molecular clones of avian retrovirus. The mechanism which generates this diversity in the U3 region is not known. Perhaps there is a selective advantage for duplication/insertions in this region of the LTR. The SV40 repeat has an important activator role and it was postulated that repeats in retrovirus LTR have a similar role. (ERB)

  8. Screening for low aquatic bioaccumulation. 1. Lipinski's 'Rule of 5' and molecular size.

    PubMed

    Nendza, M; Müller, M

    2010-07-01

    Aquatic bioconcentration factors are critical in PBT assessment of industrial chemicals under REACH. Reliable indicators based on physico-chemical properties and molecular attributes of chemicals with low bioconcentration potential have been searched to de-prioritize non-accumulative chemicals in order to avoid unnecessary biotests that do not produce risk-relevant information. Developed to screen drug candidates, Lipinski's 'Rule of 5' identifies chemicals with poor oral absorption based on criteria in partitioning, molecular weight and hydrogen bonding. This parameter ensemble has been supplemented with molecular diameter and tested for its adequacy to filter chemicals with low bioconcentration potential. Perhaps (not) surprisingly, the application of the 'Rule of 5' fails to protectively identify non-accumulative compounds because other processes dominate the uptake in aquatic environments as compared with oral absorption. No robust evidence was found for cut-offs in bioconcentration related to molecular size. However, pragmatic thresholds in molecular weight (>650 g mol(-1)) and lipophilicity (log K(OW) < 3 or > 10) have been verified to securely de-prioritize 30-40% of chemicals of low concern with regard to the B criterion.

  9. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma.

    PubMed

    Shaikh, Atik Badshah; Li, Fangfei; Li, Min; He, Bing; He, Xiaojuan; Chen, Guofen; Guo, Baosheng; Li, Defang; Jiang, Feng; Dang, Lei; Zheng, Shaowei; Liang, Chao; Liu, Jin; Lu, Cheng; Liu, Biao; Lu, Jun; Wang, Luyao; Lu, Aiping; Zhang, Ge

    2016-04-06

    Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%-75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma.

  10. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma

    PubMed Central

    Shaikh, Atik Badshah; Li, Fangfei; Li, Min; He, Bing; He, Xiaojuan; Chen, Guofen; Guo, Baosheng; Li, Defang; Jiang, Feng; Dang, Lei; Zheng, Shaowei; Liang, Chao; Liu, Jin; Lu, Cheng; Liu, Biao; Lu, Jun; Wang, Luyao; Lu, Aiping; Zhang, Ge

    2016-01-01

    Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%–75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma. PMID:27058531

  11. Molecular Characterization of Head and Neck Cancer: How Close to Personalized Targeted Therapy?

    PubMed Central

    Worsham, Maria J.; Ali, Haythem; Dragovic, Jadranka; Schweitzer, Vanessa P.

    2013-01-01

    Molecular targeted therapy in squamous head and neck cancer (HNSCC) continues to make strides and holds much promise. Cetuximab remains the sole FDA-approved molecular targeted therapy available for HNSCC, though there are several new biological agents targeting the epidermal growth factor receptor (EGFR) and other pathways in the regulatory approval pipeline. While targeted therapies have the potential to be personalized, their current use in HNSCC is not personalized. This is illustrated for EGFR targeted drugs, where EGFR as a molecular target has yet to be individualized for HNSCC. Future research needs to identify factors that correlate with response (or lack of one) and the underlying genotype-phenotype relationship that dictates this response. Comprehensive exploration of genetic and epigenetic landscapes in HNSCC is opening new frontiers to further enlighten, mechanistically inform, and set a course for eventually translating these discoveries into therapies for patients. This opinion offers a snap shot of the evolution of molecular subytping in HNSCC, its current clinical applicability, as well as new emergent paradigms with implications for controlling this disease in the future. PMID:22873739

  12. Heat Shock Protein 70s as Potential Molecular Targets for Colon Cancer Therapeutics.

    PubMed

    Black, Jennifer D; Rezvani, Khosrow

    2016-01-01

    Targeted drugs modulate selective pathways activated or repressed only in cancer cells, resulting in a higher response to chemotherapy with less severe side effects. The use of a selected member of the heat shock protein 70 family (HSP70) as an effective therapeutic target in the treatment of colorectal cancer (CRC) will be the focus of this review. We generated two main questions for this study: 1) What are the current and potential future molecular therapies in CRC? 2) Can selective members of the HSP70 family advance drug design and drug discovery for treatment of CRC patients? We discuss related articles based on their significance and translational contributions to the existing literature. The first part of this review discusses molecularly targeted agents that are currently used successfully in the clinic for the treatment of patients with CRC and highlights several novel targeted agents that are being investigated in ongoing trials. The second part of this review focuses on the unique tumorigenic functions of heat shock proteins, particularly mortalin-2, an essential heat shock protein for mitochondrial biogenesis in normal cells and a dominant oncoprotein in colon cancer cells. Basic and clinical studies have justified mortalin-2 as a potential molecular target, and its inhibition could dramatically improve patients' responses to standard chemotherapies. Further understanding of the contributions of HSP70 family members to CRC at the molecular level, combined with translation of new concepts into effective targeted therapies, are anticipated to improve clinical outcomes and increase the therapeutic synergy with combination treatment with cytotoxic agents.

  13. Targeted Capture and High-Throughput Sequencing Using Molecular Inversion Probes (MIPs).

    PubMed

    Cantsilieris, Stuart; Stessman, Holly A; Shendure, Jay; Eichler, Evan E

    2017-01-01

    Molecular inversion probes (MIPs) in combination with massively parallel DNA sequencing represent a versatile, yet economical tool for targeted sequencing of genomic DNA. Several thousand genomic targets can be selectively captured using long oligonucleotides containing unique targeting arms and universal linkers. The ability to append sequencing adaptors and sample-specific barcodes allows large-scale pooling and subsequent high-throughput sequencing at relatively low cost per sample. Here, we describe a "wet bench" protocol detailing the capture and subsequent sequencing of >2000 genomic targets from 192 samples, representative of a single lane on the Illumina HiSeq 2000 platform.

  14. Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging.

    PubMed

    DeNardo, Gerald L; Natarajan, Arutselvan; Hok, Saphon; Mirick, Gary; DeNardo, Sally J; Corzett, Michele; Sysko, Vladimir; Lehmann, Joerg; Beckett, Laurel; Balhorn, Rod

    2008-12-01

    To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.

  15. Control of Endothelial Targeting and Intracellular Delivery of Therapeutic Enzymes by Modulating the Size and Shape of ICAM-1-targeted Carriers

    PubMed Central

    Muro, Silvia; Garnacho, Carmen; Champion, Julie A; Leferovich, John; Gajewski, Christine; Schuchman, Edward H; Mitragotri, Samir; Muzykantov, Vladimir R

    2009-01-01

    Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1–10 μm) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule–mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics. PMID:18560419

  16. The kinetic mechanism of Human Thymidine Phosphorylase - a molecular target for cancer drug development.

    PubMed

    Deves, Candida; Rostirolla, Diana Carolina; Martinelli, Leonardo Kras Borges; Bizarro, Cristiano Valim; Santos, Diogenes Santiago; Basso, Luiz Augusto

    2014-03-04

    Human Thymidine Phosphorylase (HTP), also known as the platelet-derived endothelial cell growth factor (PD-ECGF) or gliostatin, catalyzes the reversible phosphorolysis of thymidine (dThd) to thymine and 2-deoxy-α-d-ribose-1-phosphate (2dR1P). HTP is a key enzyme in the pyrimidine salvage pathway involved in dThd homeostasis in cells. HTP is a target for anticancer drug development as its enzymatic activity promotes angiogenesis. Here, we describe cloning, expression, and purification to homogeneity of recombinant TYMP-encoded HTP. Peptide fingerprinting and the molecular mass value of the homogenous protein confirmed its identity as HTP assessed by mass spectrometry. Size exclusion chromatography showed that HTP is a dimer in solution. Kinetic studies revealed that HTP displayed substrate inhibition for dThd. Initial velocity and isothermal titration calorimetry (ITC) studies suggest that HTP catalysis follows a rapid-equilibrium random bi-bi kinetic mechanism. ITC measurements also showed that dThd and Pi binding are favorable processes. The pH-rate profiles indicated that maximal enzyme activity was achieved at low pH values. Functional groups with apparent pK values of 5.2 and 9.0 are involved in dThd binding and groups with pK values of 6.1 and 7.8 are involved in phosphate binding.

  17. All-atom molecular dynamics of virus capsids as drug targets

    DOE PAGES

    Perilla, Juan R.; Hadden, Jodi A.; Goh, Boon Chong; ...

    2016-04-29

    Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways.more » When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Finally, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets.« less

  18. Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin

    PubMed Central

    Dai, Shao-Xing; Li, Wen-Xing

    2016-01-01

    Besides its anti-inflammatory, analgesic and anti-pyretic properties, aspirin is used for the prevention of cardiovascular disease and various types of cancer. The multiple activities of aspirin likely involve several molecular targets and pathways rather than a single target. Therefore, systematic identification of these targets of aspirin can help us understand the underlying mechanisms of the activities. In this study, we identified 23 putative targets of aspirin in the human proteome by using binding pocket similarity detecting tool combination with molecular docking, free energy calculation and pathway analysis. These targets have diverse folds and are derived from different protein family. However, they have similar aspirin-binding pockets. The binding free energy with aspirin for newly identified targets is comparable to that for the primary targets. Pathway analysis revealed that the targets were enriched in several pathways such as vascular endothelial growth factor (VEGF) signaling, Fc epsilon RI signaling and arachidonic acid metabolism, which are strongly involved in inflammation, cardiovascular disease and cancer. Therefore, the predicted target profile of aspirin suggests a new explanation for the disease prevention ability of aspirin. Our findings provide a new insight of aspirin and its efficacy of disease prevention in a systematic and global view. PMID:26989626

  19. Radiation Oncology In Vitro: Trends to Improve Radiotherapy through Molecular Targets

    PubMed Central

    Feofanova, Natália; Geraldo, Jony Marques; de Andrade, Lídia Maria

    2014-01-01

    Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements. PMID:25302298

  20. Radiation oncology in vitro: trends to improve radiotherapy through molecular targets.

    PubMed

    Feofanova, Natália; Geraldo, Jony Marques; de Andrade, Lídia Maria

    2014-01-01

    Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements.

  1. Shapes and sizes of molecular anions via topographical analysis of electrostatic potential

    NASA Astrophysics Data System (ADS)

    Gadre, Shridhar R.; Shrivastava, Indira H.

    1991-03-01

    The theorem proposed by Pathak and Gadre [J. Chem. Phys. 93, 1770 (1990)], that the electrostatic potential (ESP) of negative ions must exhibit a directional negative valued minimum along any arbitrary direction has been verified for some small negative molecular ions, viz., OH-, CN-, N-3, NO-3, and NH-2. Also, as predicted by Gadre and Pathak [Proc. Ind. Acad. Sci. (Chem. Sci.) 102, 18 (1989)], the molecular ESP (MESP) maps are found to be devoid of local maxima. As a consequence, these maps reveal rich topographical details in the form of several saddle points as well as point minima. From the location of these critical points, estimates of the sizes and shapes of the negatively charged molecular ions are obtained. For anions, there exists a surface on which ■VṡdS=0 and which passes through all the negative valued critical points (∇V=0). The ionic size estimates from the location of the critical points of the MESP are found to be in good agreement with the corresponding (spherically averaged) literature values.

  2. Size-dependent mechanical behavior of nanoscale polymer particles through coarse-grained molecular dynamics simulation.

    PubMed

    Zhao, Junhua; Nagao, Shijo; Odegard, Gregory M; Zhang, Zhiliang; Kristiansen, Helge; He, Jianying

    2013-12-21

    Anisotropic conductive adhesives (ACAs) are promising materials used for producing ultra-thin liquid-crystal displays. Because the mechanical response of polymer particles can have a significant impact in the performance of ACAs, understanding of this apparent size effect is of fundamental importance in the electronics industry. The objective of this research is to use a coarse-grained molecular dynamics model to verify and gain physical insight into the observed size dependence effect in polymer particles. In agreement with experimental studies, the results of this study clearly indicate that there is a strong size effect in spherical polymer particles with diameters approaching the nanometer length scale. The results of the simulations also clearly indicate that the source for the increases in modulus is the increase in relative surface energy for decreasing particle sizes. Finally, the actual contact conditions at the surface of the polymer nanoparticles are shown to be similar to those predicted using Hertz and perfectly plastic contact theory. As ACA thicknesses are reduced in response to reductions in polymer particle size, it is expected that the overall compressive stiffness of the ACA will increase, thus influencing the manufacturing process.

  3. Size-dependent mechanical behavior of nanoscale polymer particles through coarse-grained molecular dynamics simulation

    PubMed Central

    2013-01-01

    Anisotropic conductive adhesives (ACAs) are promising materials used for producing ultra-thin liquid-crystal displays. Because the mechanical response of polymer particles can have a significant impact in the performance of ACAs, understanding of this apparent size effect is of fundamental importance in the electronics industry. The objective of this research is to use a coarse-grained molecular dynamics model to verify and gain physical insight into the observed size dependence effect in polymer particles. In agreement with experimental studies, the results of this study clearly indicate that there is a strong size effect in spherical polymer particles with diameters approaching the nanometer length scale. The results of the simulations also clearly indicate that the source for the increases in modulus is the increase in relative surface energy for decreasing particle sizes. Finally, the actual contact conditions at the surface of the polymer nanoparticles are shown to be similar to those predicted using Hertz and perfectly plastic contact theory. As ACA thicknesses are reduced in response to reductions in polymer particle size, it is expected that the overall compressive stiffness of the ACA will increase, thus influencing the manufacturing process. PMID:24359191

  4. Target-to-background enhancement in multispectral endoscopy with background autofluorescence mitigation for quantitative molecular imaging

    NASA Astrophysics Data System (ADS)

    Yang, Chenying; Hou, Vivian W.; Girard, Emily J.; Nelson, Leonard Y.; Seibel, Eric J.

    2014-07-01

    Fluorescence molecular imaging with exogenous probes improves specificity for the detection of diseased tissues by targeting unambiguous molecular signatures. Additionally, increased diagnostic sensitivity is expected with the application of multiple molecular probes. We developed a real-time multispectral fluorescence-reflectance scanning fiber endoscope (SFE) for wide-field molecular imaging of fluorescent dye-labeled molecular probes at nanomolar detection levels. Concurrent multichannel imaging with the wide-field SFE also allows for real-time mitigation of the background autofluorescence (AF) signal, especially when fluorescein, a U.S. Food and Drug Administration approved dye, is used as the target fluorophore. Quantitative tissue AF was measured for the ex vivo porcine esophagus and murine brain tissues across the visible and near-infrared spectra. AF signals were then transferred to the unit of targeted fluorophore concentration to evaluate the SFE detection sensitivity for sodium fluorescein and cyanine. Next, we demonstrated a real-time AF mitigation algorithm on a tissue phantom, which featured molecular probe targeted cells of high-grade dysplasia on a substrate containing AF species. The target-to-background ratio was enhanced by more than one order of magnitude when applying the real-time AF mitigation algorithm. Furthermore, a quantitative estimate of the fluorescein photodegradation (photobleaching) rate was evaluated and shown to be insignificant under the illumination conditions of SFE. In summary, the multichannel laser-based flexible SFE has demonstrated the capability to provide sufficient detection sensitivity, image contrast, and quantitative target intensity information for detecting small precancerous lesions in vivo.

  5. Target-to-background enhancement in multispectral endoscopy with background autofluorescence mitigation for quantitative molecular imaging

    PubMed Central

    Yang, Chenying; Hou, Vivian W.; Girard, Emily J.; Nelson, Leonard Y.; Seibel, Eric J.

    2014-01-01

    Abstract. Fluorescence molecular imaging with exogenous probes improves specificity for the detection of diseased tissues by targeting unambiguous molecular signatures. Additionally, increased diagnostic sensitivity is expected with the application of multiple molecular probes. We developed a real-time multispectral fluorescence-reflectance scanning fiber endoscope (SFE) for wide-field molecular imaging of fluorescent dye-labeled molecular probes at nanomolar detection levels. Concurrent multichannel imaging with the wide-field SFE also allows for real-time mitigation of the background autofluorescence (AF) signal, especially when fluorescein, a U.S. Food and Drug Administration approved dye, is used as the target fluorophore. Quantitative tissue AF was measured for the ex vivo porcine esophagus and murine brain tissues across the visible and near-infrared spectra. AF signals were then transferred to the unit of targeted fluorophore concentration to evaluate the SFE detection sensitivity for sodium fluorescein and cyanine. Next, we demonstrated a real-time AF mitigation algorithm on a tissue phantom, which featured molecular probe targeted cells of high-grade dysplasia on a substrate containing AF species. The target-to-background ratio was enhanced by more than one order of magnitude when applying the real-time AF mitigation algorithm. Furthermore, a quantitative estimate of the fluorescein photodegradation (photobleaching) rate was evaluated and shown to be insignificant under the illumination conditions of SFE. In summary, the multichannel laser-based flexible SFE has demonstrated the capability to provide sufficient detection sensitivity, image contrast, and quantitative target intensity information for detecting small precancerous lesions in vivo. PMID:25027002

  6. Accurate and molecular-size-tolerant NMR quantitation of diverse components in solution

    PubMed Central

    Okamura, Hideyasu; Nishimura, Hiroshi; Nagata, Takashi; Kigawa, Takanori; Watanabe, Takashi; Katahira, Masato

    2016-01-01

    Determining the amount of each component of interest in a mixture is a fundamental first step in characterizing the nature of the solution and to develop possible means of utilization of its components. Similarly, determining the composition of units in complex polymers, or polymer mixtures, is crucial. Although NMR is recognized as one of the most powerful methods to achieve this and is widely used in many fields, variation in the molecular sizes or the relative mobilities of components skews quantitation due to the size-dependent decay of magnetization. Here, a method to accurately determine the amount of each component by NMR was developed. This method was validated using a solution that contains biomass-related components in which the molecular sizes greatly differ. The method is also tolerant of other factors that skew quantitation such as variation in the one-bond C–H coupling constant. The developed method is the first and only way to reliably overcome the skewed quantitation caused by several different factors to provide basic information on the correct amount of each component in a solution. PMID:26883279

  7. Effects of organic acids of different molecular size on phosphate removal by HZO-201 nanocomposite.

    PubMed

    Lin, Bin; Hua, Ming; Zhang, Yanyang; Zhang, Weiming; Lv, Lu; Pan, Bingcai

    2017-01-01

    Various organic acids in wastewater effluent could significantly influence the performance of phosphate adsorbent. This study focused on the effects of organic acids of different-molecular-size on phosphate adsorption by a novel nanocomposite HZO-201. Three organic acids (gallic acid (GA), tannic acid (TA) and humic acid (HA)) with distinct molecular size (HA > TA > GA) were chosen for this purpose. Both isotherm and kinetic tests of phosphate adsorption were conducted in the single-phosphate and binary system, and a series of microscopic techniques (i.e., XPS, FT-IR and SEM-EDX) and N2 adsorption-desorption test were employed to explore the underlying mechanism. It was found that GA could greatly weaken phosphate adsorption capability of HZO-201 by directly competing for ammonium group on the nanocomposite, TA exhibited significant inhibition on phosphate adsorption rate mainly through pore constriction/blockage, while HA posed negligible impact on phosphate adsorption because of the size exclusion effect. It was also observed that although GA, TA and HA showed substantial influence on bulky HZO due to complexation, their impact on the nano-HZO loaded inside HZO-201 was little. The covalently bounded ammonium group and the networking pore structure of HZO-201 may play important roles in it. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The Size, Shape, and Albedo of Deep Impact Target 9P/Tempel 1

    NASA Astrophysics Data System (ADS)

    A'Hearn, Michael; Lisse, Carey; Lisse, C.; Fernandez, Y.; Belton, M.; Groussin, O.; Meech, K.; van Cleve, J.

    2004-02-01

    The Deep Impact mission, the eighth mission in NASA's Discovery Program, will launch on 30 Dec 2004 and will impact the nucleus of comet 9P/Tempel 1 on 4 July 2005. Delivering an impactor to a cometary nucleus and observing the results of the impact is a challenging task. Mission success depends critically on the ability of the DI spacecraft to navigate to the comet. Despite robust targeting algorithms, large uncertainties in size, shape, albedo distribution, and rotational state significantly degrade the probability that the impactor will land in a sunlit portion of the surface that is observable from the flyby. The uncertainties in the size, axial ratio, and rotational state further jeopardize the ability of the flyby spacecraft to point its High Resolution Instrument at the actual impact site with sufficient precision to ensure it is in the field of view. Current estimate of the comet's size using Keck LWS observations are uncertain by 50% and they have provided no information on the distribution of albedo. Although uncertainty in the phasing of the optical lightcurve represents a large part of that error, there is also a significant uncertainty due to the combination of low SNR in the data from Keck and the limited spectral range over which data could be obtained. In order to improve our estimate of the size and shape of the nucleus of Tempel 1, we must obtain data with much higher SNR and with one-hour time resolution over a significant portion of the rotation light curve when the comet is inactive. We must determine whether or not there are large variations in albedo across the surface to order to ensure that the rotational lightcurve from optical data can be used to predict the convex hull of the actual shape. Tempel 1 is available in only one Spitzer viewing widow before it is expected to be close enough to the sun to become active, namely the window from 27 Feb through 29 April 2004, before the first GO observing period, at 3.7 AU from the Sun. The expect

  9. Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

    PubMed

    Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura

    2017-01-04

    In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.

  10. Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

    PubMed Central

    Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura

    2017-01-01

    In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer. PMID:28054957

  11. Quencher-free molecular beacon tethering 7-hydroxycoumarin detects targets through protonation/deprotonation.

    PubMed

    Kashida, Hiromu; Yamaguchi, Kyohei; Hara, Yuichi; Asanuma, Hiroyuki

    2012-07-15

    In this study, we synthesized a simple but efficient quencher-free molecular beacon tethering 7-hydroxycoumarin on D-threoninol based on its pK(a) change. The pK(a) of 7-hydroxycoumarin in a single strand was determined as 8.8, whereas that intercalated in the duplex was over 10. This large pK(a) shift (more than 1.2) upon hybridization could be attributed to the anionic and hydrophobic microenvironment inside the DNA duplex. Because 7-hydroxycoumarin quenches its fluorescence upon protonation, the emission intensity of the duplex at pH 8.5 was 1/15 that of the single strand. We applied this quenching mechanism to the preparation of a quencher-free molecular beacon by introducing the dye into the middle of the stem part. In the absence of the target, the stem region formed a duplex and fluorescence was quenched. However, when the target was added, the molecular beacon opened and the dye was deprotonated. As a result, the emission intensity of the molecular beacon with the target was 10 times higher than that without the target. Accordingly, a quencher-free molecular beacon utilizing the pK(a) change was successfully developed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Molecular Size and Separability Features of Pea Cell Wall Polysaccharides 1

    PubMed Central

    Talbott, Lawrence D.; Ray, Peter M.

    1992-01-01

    Relative molecular size distributions of pectic and hemicellulosic polysaccharides of pea (Pisum sativum cv Alaska) third internode primary walls were determined by gel filtration chromatography. Pectic polyuronides have a peak molecular mass of about 1100 kilodaltons, relative to dextran standards. This peak may be partly an aggregate of smaller molecular units, because demonstrable aggregation occurred when samples were concentrated by evaporation. About 86% of the neutral sugars (mostly arabinose and galactose) in the pectin cofractionate with polyuronide in gel filtration chromatography and diethylaminoethyl-cellulose chromatography and appear to be attached covalently to polyuronide chains, probably as constituents of rhamnogalacturonans. However, at least 60% of the wall's arabinan/galactan is not linked covalently to the bulk of its rhamnogalacturonan, either glycosidically or by ester links, but occurs in the hemicellulose fraction, accompanied by negligible uronic acid, and has a peak molecular mass of about 1000 kilodaltons. Xyloglucan, the other principal hemicellulosic polymer, has a peak molecular mass of about 30 kilodaltons (with a secondary, usually minor, peak of approximately 300 kilodaltons) and is mostly not linked glycosidically either to pectic polyuronides or to arabinogalactan. The relatively narrow molecular mass distributions of these polymers suggest mechanisms of co- or postsynthetic control of hemicellulose chain length by the cell. Although the macromolecular features of the mentioned polymers individually agree generally with those shown in the widely disseminated sycamore cell primary wall model, the matrix polymers seem to be associated mostly noncovalently rather than in the covalently interlinked meshwork postulated by that model. Xyloglucan and arabinan/galactan may form tightly and more loosely bound layers, respectively, around the cellulose microfibrils, the outer layer interacting with pectic rhamnogalacturonans that occupy

  13. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies

    PubMed Central

    Matsuoka, Tasuku; Yashiro, Masakazu

    2016-01-01

    Pancreatic cancer is the fourth most common cause of cancer deaths worldwide. Although recent therapeutic developments for patients with pancreatic cancer have provided survival benefits, the outcomes for patients with pancreatic cancer remain unsatisfactory. Molecularly targeted cancer therapy has advanced in the past decade with the use of a number of pathways as candidates of therapeutic targets. This review summarizes the molecular features of this refractory disease while focusing on the recent clinical and experimental findings on pancreatic cancer. It also discusses the data supporting current standard clinical outcomes, and offers conclusions that may improve the management of pancreatic cancer in the future. PMID:26811624

  14. Molecular Targets of Omega 3 and Conjugated Linoleic Fatty Acids – “Micromanaging” Cellular Response

    PubMed Central

    Visioli, Francesco; Giordano, Elena; Nicod, Nathalie Marie; Dávalos, Alberto

    2012-01-01

    Essential fatty acids cannot be synthesized de novo by mammals and need to be ingested either with the diet or through the use of supplements/functional foods to ameliorate cardiovascular prognosis. This review focus on the molecular targets of omega 3 fatty acids and conjugated linoleic acid, as paradigmatic molecules that can be exploited both as nutrients and as pharmacological agents, especially as related to cardioprotection. In addition, we indicate novel molecular targets, namely microRNAs that might contribute to the observed biological activities of such essential fatty acids. PMID:22393325

  15. Toxicity assessment of arsenic and cobalt in the presence of aquatic humic substances of different molecular sizes.

    PubMed

    Watanabe, Cláudia Hitomi; Monteiro, Adnivia Santos Costa; Gontijo, Erik Sartori Jeunon; Lira, Vivian Silva; Bueno, Carolina de Castro; Kumar, Nirmal Tej; Fracácio, Renata; Rosa, André Henrique

    2017-05-01

    The release of contaminants in aquatic ecosystems can be influenced by humic acids. In this study, toxicity tests using environmentally relevant concentrations of arsenic and cobalt were conducted both in the presence and absence of aquatic humic substances (AHS) and the fractions of different molecular sizes in the range of (<5, 5-10;10-30; 30-100 and >100kDa) using the microcrustacean Ceriodaphnia dubia. AHS together with arsenic reduced the toxicity, and the toxicity decreased in fractions of larger molecular size AHS. Despite the presence of cobalt, the reduction in toxicity was not observed and that depended on the molecular size of AHS. There was a trend of enhanced toxicity for Co in fractions of larger molecular sizes, opposed to that found for arsenic. Thus, the humic substances alter toxicity of trace elements, and this effect varies depending on the size of the humic substances. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome.

    PubMed

    Burkhart, Keith K; Abernethy, Darrell; Jackson, David

    2015-06-01

    Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with drug-induced adverse events. The information gained may contribute to systems biology disease models.

  17. Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

    PubMed Central

    Alcorn, Sara; Walker, Amanda J.; Gandhi, Nishant; Narang, Amol; Wild, Aaron T.; Hales, Russell K.; Herman, Joseph M.; Song, Danny Y.; DeWeese, Theodore L.; Antonarakis, Emmanuel S.; Tran, Phuoc T.

    2013-01-01

    As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer. PMID:23863691

  18. Bounds on the Number and Size of Extra Dimensions from Molecular Spectroscopy

    NASA Astrophysics Data System (ADS)

    Salumbides, Edcel John; Schellekens, Bert; Gato-Rivera, Beatriz; Ubachs, Wim

    2015-06-01

    Modern string theories, which seek to produce a consistent description of physics beyond the Standard Model that also includes the gravitational interaction, appear to be most consistent if a large number of dimensions are postulated. For example the mysterious M-theory, which generalizes all consistent versions of superstring theories, require 11 dimensions. We demonstrate that investigations of quantum level energies in simple molecular systems provide a testing ground to constrain the size of compactified extra dimensions, for example those proposed in the ADD [1] and RS scenarios [2]. This is made possible by the recent progress in precision metrology with ultrastable lasers on energy levels in neutral molecular hydrogen (H_2, HD and D_2) [3] and the molecular hydrogen ions (H_2^+, HD^+ and D_2^+) [4]. Comparisons between experiment and quantum electrodynamics calculations for these molecular systems can be interpreted in terms of probing large extra dimensions, under which conditions gravity will become much stronger. Molecules are a probe of space-time geometry at typical distances where chemical bonds are effective, i.e. at length scales of an Å. [1] N. Arkani-Hamed, S. Dimopoulos and G. Dvali, Phys. Lett. B 429, 263 (1998) [2] L. Randall and R. Sundrum, Phys. Rev. Lett. 83, 3370 (1999). [3] G. Dickenson et al., Phys. Rev. Lett. 110, 193601 (2013). [4] J. C. J. Koelemeij et al., Phys. Rev. Lett. 98, 173002 (2007).

  19. Molecular characterization of multivalent bioconjugates by size-exclusion chromatography with multiangle laser light scattering.

    PubMed

    Pollock, Jacob F; Ashton, Randolph S; Rode, Nikhil A; Schaffer, David V; Healy, Kevin E

    2012-09-19

    The degree of substitution and valency of bioconjugate reaction products are often poorly judged or require multiple time- and product-consuming chemical characterization methods. These aspects become critical when analyzing and optimizing the potency of costly polyvalent bioactive conjugates. In this study, size-exclusion chromatography with multiangle laser light scattering was paired with refractive index detection and ultraviolet spectroscopy (SEC-MALS-RI-UV) to characterize the reaction efficiency, degree of substitution, and valency of the products of conjugation of either peptides or proteins to a biopolymer scaffold, i.e., hyaluronic acid (HyA). Molecular characterization was more complete compared to estimates from a protein quantification assay, and exploitation of this method led to more accurate deduction of the molecular structures of polymer bioconjugates. Information obtained using this technique can improve macromolecular engineering design principles and help to better understand multivalent macromolecular interactions in biological systems.

  20. [Molecular-Genetic Diagnosis and Molecular-Targeted Therapy in Cancer: Challenges in the Era of Precision Medicine].

    PubMed

    Miyachi, Hayato

    2015-10-01

    Elucidation of the molecular pathogenesis of neoplasms and application of emerging technologies for testing and therapy have resulted in a series of paradigm shifts in patient care, from conventional to personalized medicine. This has been promoted by companion diagnostics and molecular targeted therapy, tailoring the treatment to the individual characteristics of each patient. Precision oncology has been accelerated by integrating the enhanced resolution of molecular analysis, mechanism clarity, and therapeutic relevance through genomic knowledge. In its clinical implementation, there are laboratory challenges concerning accurate measurement using stored samples, differentiation between driver and passenger mutations as well as between germline and somatic mutations, bioinformatics availability, practical decision-making algorithms, and ethical issues regarding incidental findings. The medical laboratory has a new role in providing not only testing services but also an instructive approach to users to ensure the sample quality and privacy protection of personal genome information, supporting the quality of patient practice based on laboratory diagnosis.

  1. Drug-Target Binding Investigated by Quantum Mechanical/Molecular Mechanical (QM/MM) Methods

    NASA Astrophysics Data System (ADS)

    Rothlisberger, U.; Carloni, P.

    Many important drugs, also used in the clinics, exert their function by binding covalently to their targets. Understanding their action requires quantum mechanical simulations. Here, after briefly reviewing few basic concepts of thermodynamics and kinetics of drug-target binding, we summarize principles and applications of Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. From this discussion, this approach emerges as a computational methodology particularly well suited to investigate covalent binding in systems of pharmacological relevance.

  2. Size distribution of particle-phase molecular markers during a severe winter pollution episode.

    PubMed

    Kleeman, Michael J; Riddle, Sarah G; Jakober, Chris A

    2008-09-01

    Airborne particulate matter was collected using filter samplers and cascade impactors in six size fractions below 1.8 microm during a severe winter air pollution event at three sites in the Central Valley of California. The smallest size fraction analyzed was 0.056 < Dp <0.1 microm particle diameter, which accounts for the majority of the mass in the ultrafine (PM0.1) size range. Separate samples were collected during the daytime (10 a.m. to 6 p.m. PST) and nighttime (8 p.m. to 8 a.m. PST) to characterize diurnal patterns. Each sample was extracted with organic solvents and analyzed using gas chromatography mass spectrometry for molecular markers that can be used for size-resolved source apportionment calculations. Colocated impactor and filter measurements were highly correlated (R8 > 0.8) for retene, benzo[ghi]flouranthene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[e]pyrene, benzo[a]pyrene, perylene, indeno[1,2,3-cd]pyrene, benzo[ghi]perylene, coronene, MW302 polycyclic aromatic hydrocarbon (PAHs), 17beta(H)-21alpha(H)-30-norhopane, 17alpha(H)-21beta(H)-hopane, alphabetabeta-20R-C29-ethylcholestane, levoglucosan, and cholesterol. Of these compounds, levoglucosan was present in the highest concentration (60-2080 ng m(-3)) followed by cholesterol (6-35 ng m(-3)), PAHs (2-38 ng m(-3)), and hopanes and steranes (0-2 ng m(-3)). Nighttime concentrations were higher than daytime concentrations in all cases. Organic compound size distributions were generally similar to the total carbon size distributions during the nighttime but showed greater variability during the daytime. This may reflect the dominance of fresh emission in the stagnant surface layer during the evening hours and the presence of aged organic aerosol at the surface during the daytime when the atmosphere is better mixed. All of the measured organic compound particle size distributions had a single mode that peaked somewhere between 0.18 and 0.56 microm, but the width of each distribution

  3. Molecular and cellular alterations in Down syndrome: toward the identification of targets for therapeutics.

    PubMed

    Créau, Nicole

    2012-01-01

    Down syndrome is a complex disease that has challenged molecular and cellular research for more than 50 years. Understanding the molecular bases of morphological, cellular, and functional alterations resulting from the presence of an additional complete chromosome 21 would aid in targeting specific genes and pathways for rescuing some phenotypes. Recently, progress has been made by characterization of brain alterations in mouse models of Down syndrome. This review will highlight the main molecular and cellular findings recently described for these models, particularly with respect to their relationship to Down syndrome phenotypes.

  4. Endothelial cell targeted molecular imaging in tumor angiogenesis: strategies and current status.

    PubMed

    Xu, Ye; Zeng, Yun; Liu, Yanhong; Liu, Gang; Ai, Hua

    2013-01-01

    Angiogenesis plays crucial roles in tumor growth, progression and metastasis. Non-invasive in vivo imaging of tumor neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly anti-angiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of cellular/molecular processes before gross pathological changes, leading to better understanding of fundamental biological processes of tumor angiogenesis. In this review, we will summarize recent progresses on molecular imaging of attractive biochemical epitopes in tumor angiogenesis, especially the endothelial cell targets-based imaging probes.

  5. Communication: Molecular simulation study of kaolinite intercalation with realistic layer size

    SciTech Connect

    Ható, Zoltán; Kristóf, Tamás; Rutkai, Gábor; Vrabec, Jadran

    2014-09-07

    Intercalation phenomena of kaolinite in aqueous potassium acetate and in hexyl-amine solutions are studied by large scale molecular dynamics simulations. The simulated kaolinite particle is constructed from ∼6.5 × 10{sup 6} atoms, producing a particle size of ∼100 nm × 100 nm × 10 nm. The simulation with potassium acetate results in a stable kaolinite-potassium acetate complex, with a basal spacing that is in close agreement with experimental data. The simulation with hexyl-amine shows signs of the experimentally observed delamination of kaolinite (the initial phase of the formation of nanoscrolls from the external layers)

  6. Quality of epitaxial InAs nanowires controlled by catalyst size in molecular beam epitaxy

    NASA Astrophysics Data System (ADS)

    Zhang, Zhi; Lu, Zhen-Yu; Chen, Ping-Ping; Xu, Hong-Yi; Guo, Ya-Nan; Liao, Zhi-Ming; Shi, Sui-Xing; Lu, Wei; Zou, Jin

    2013-08-01

    In this study, the structural quality of Au-catalyzed InAs nanowires grown by molecular beam epitaxy is investigated. Through detailed electron microscopy characterizations and analysis of binary Au-In phase diagram, it is found that defect-free InAs nanowires can be induced by smaller catalysts with a high In concentration, while comparatively larger catalysts containing less In induce defected InAs nanowires. This study indicates that the structural quality of InAs nanowires can be controlled by the size of Au catalysts when other growth conditions remain as constants.

  7. Molecular size of different neurotoxin receptors on the voltage-sensitive Na+ channel.

    PubMed

    Barhanin, J; Schmid, A; Lombet, A; Wheeler, K P; Lazdunski, M; Ellory, J C

    1983-01-25

    Measurements were made of the molecular sizes of two distinct receptors on the Na+ channel in rat brain synaptosomes that are specific for different neurotoxins. Radiation inactivation of the binding of radiolabeled derivatives of the toxins was consistent with Mr = 260,000 for the tetrodotoxin receptor and Mr = 266,000 for the receptor specific for two scorpion toxins, toxin II from Centruroides suffusus suffusus and toxin gamma from Tityus serrulatus serrulatus. Covalent cross-linking of the latter to its receptor similarly indicated Mr = 270,000. It seems most likely that these two distinct receptors reside on the same molecule.

  8. Effects of Atomistic Domain Size on Hybrid Lattice Boltzmann-Molecular Dynamics Simulations of Dense Fluids

    NASA Astrophysics Data System (ADS)

    Dupuis, A.; Koumoutsakos, P.

    We present a convergence study for a hybrid Lattice Boltzmann-Molecular Dynamics model for the simulation of dense liquids. Time and length scales are decoupled by using an iterative Schwarz domain decomposition algorithm. The velocity field from the atomistic domain is introduced as forcing terms to the Lattice Boltzmann model of the continuum while the mean field of the continuum imposes mean field conditions for the atomistic domain. In the present paper we investigate the effect of varying the size of the atomistic subdomain in simulations of two dimensional flows of liquid argon past carbon nanotubes and assess the efficiency of the method.

  9. Determination of molecular weight of heparin by size exclusion chromatography with universal calibration.

    PubMed

    Guo, X; Condra, M; Kimura, K; Berth, G; Dautzenberg, H; Dubin, P L

    2003-01-01

    The molecular weight (MW) of heparin can be accurately determined by size exclusion chromatography using "universal calibration." A universal calibration curve was constructed for Superose 12 with standard pullulan samples and verified using characterized ficoll fractions. This calibration yielded the correct MW of heparin as determined by light scattering, when the ionic strength of the mobile phase was maintained over 1.0M. Sodium poly(styrenesulfonate) samples were not suitable standards because of adsorption at high salt concentration and repulsion from the packing material at low ionic strength. The extraordinarily high charge density of heparin leads to the need for high salt concentration to screen such repulsions.

  10. Photofragmentation and vibrational relaxation of size-selected clusters ions : Non-adiabatic molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Douady, J.; Gervais, B.; Jacquet, E.; Zanuttini, D.; Giglio, E.

    2009-11-01

    We present non-adiabatic molecular dynamics simulations of size-selected Na2+ Arn (n=6-11-17) cluster. Their electronic structure is obtained from an accurate 1-electron model using core polarization pseudopotentials. We follow the dynamics of two specific photoexcitation processes (X2 Σ+g → A2Σ+u) and (X2 Σ+g → B2 Πu) during the first 10 ps. We identify a variety of processes in these clusters, such as dissociation of the Na2+ chromophore, solvation of the Na+ fragment as Na+ Arp and the recombination to the ground state of the Na2+ Arp with an important solvent evaporation. These processes depend significantly on the transition and on the isomer. We discuss these processes as a function of the cluster size.

  11. Determination of nanoparticle size distribution together with density or molecular weight by 2D analytical ultracentrifugation

    PubMed Central

    Carney, Randy P.; Kim, Jin Young; Qian, Huifeng; Jin, Rongchao; Mehenni, Hakim; Stellacci, Francesco; Bakr, Osman M.

    2011-01-01

    Nanoparticles are finding many research and industrial applications, yet their characterization remains a challenge. Their cores are often polydisperse and coated by a stabilizing shell that varies in size and composition. No single technique can characterize both the size distribution and the nature of the shell. Advances in analytical ultracentrifugation allow for the extraction of the sedimentation (s) and diffusion coefficients (D). Here we report an approach to transform the s and D distributions of nanoparticles in solution into precise molecular weight (M), density (ρP) and particle diameter (dp) distributions. M for mixtures of discrete nanocrystals is found within 4% of the known quantities. The accuracy and the density information we achieve on nanoparticles are unparalleled. A single experimental run is sufficient for full nanoparticle characterization, without the need for standards or other auxiliary measurements. We believe that our method is of general applicability and we discuss its limitations. PMID:21654635

  12. Finite-size dependence of the bridge function extracted from molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Baumketner, A.; Hiwatari, Y.

    2001-06-01

    The bridge function for liquid sodium at T=373 K is obtained by using the mean spherical approximation to extrapolate the pair distribution function (PDF), calculated in molecular dynamics (MD) simulations, beyond the half simulation box length for two sizes of the MD system. The bridge function is found to strongly depend on the total number of particles used in the simulation cell. This dependency leads to a spurious maximum of the static structure factor at long wavelengths, obtained from the reference hypernetted-chain approximation (RHNC) with the MD system used as a reference system (RHNC-MD). A simple self-consistent procedure, proposed to account for the finite-size effects in the bridge function, allows one to efficiently correct the RHNC-MD static structure factor for all unphysical manifestations.

  13. Finite-size effects on the lattice dynamics in spin crossover nanomaterials. II. Molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Mikolasek, Mirko; Nicolazzi, William; Terki, Férial; Molnár, Gábor; Bousseksou, Azzedine

    2017-07-01

    In the first part of this work, an experimental study of the lattice dynamics of spin crossover nanoparticles was performed using the nuclear inelastic scattering (NIS). A size dependence of low energy phonon modes appears under 10 nm, but its origin is not well understood. In this paper, we investigate the phonon confinement effects in the framework of molecular dynamics simulations by modeling three-dimensional nanoparticles considering a cubic lattice with an octahedral pattern. The vibrational density of states is computed and compared to the experiment. The simulations allow one to highlight both the role of the phonon quantification and the role of the size and shape distributions of particles on the extracted parameters leading to a better understanding of the experimental results.

  14. Melting Properties of Medium-Sized Silicon Nanoclusters: A Molecular Dynamics Study

    NASA Astrophysics Data System (ADS)

    Li, Haipeng; Xu, Runfeng; Bi, Zetong; Shen, Xiaopeng; Han, Kui

    2017-07-01

    The structures and melting properties of the medium-sized silicon nanoclusters have been comparatively studied using the molecular dynamics method. Structural and thermodynamic parameters are used to characterize the melting properties of the clusters. The size dependence of the melting temperature of silicon nanoclusters is determined using the computation results. Different from the homogeneous melting of bulk silicon, melting of silicon nanoparticles proceeds over a finite temperature range due to surface effects, which shows the heterogeneous melting of nanoclusters. We found that the melting starts at the cluster surface and progressively shifts into the core region. This study provides a fundamental perspective on the melting behaviors of semiconductor silicon nanoclusters at the atomistic level.

  15. Melting Properties of Medium-Sized Silicon Nanoclusters: A Molecular Dynamics Study

    NASA Astrophysics Data System (ADS)

    Li, Haipeng; Xu, Runfeng; Bi, Zetong; Shen, Xiaopeng; Han, Kui

    2016-11-01

    The structures and melting properties of the medium-sized silicon nanoclusters have been comparatively studied using the molecular dynamics method. Structural and thermodynamic parameters are used to characterize the melting properties of the clusters. The size dependence of the melting temperature of silicon nanoclusters is determined using the computation results. Different from the homogeneous melting of bulk silicon, melting of silicon nanoparticles proceeds over a finite temperature range due to surface effects, which shows the heterogeneous melting of nanoclusters. We found that the melting starts at the cluster surface and progressively shifts into the core region. This study provides a fundamental perspective on the melting behaviors of semiconductor silicon nanoclusters at the atomistic level.

  16. Attenuating the size and molecular carrier capabilities of polyacrylate nanoparticles by a hydrophobic fluorine effect.

    PubMed

    Labruère, Raphaël; Turos, Edward

    2012-08-15

    This study investigates the effect of introducing alkyl chain fluorination on the properties of polyacrylate nanoparticles prepared in aqueous solution by emulsion polymerization. For this, 2,2,3,3,4,4,4-heptafluorobutyl acrylate (1) and methyl trifluoroacrylate (2) were tested as monomers as a means to prepare fluorinated polyacrylate nanoparticles to evaluate how side chain fluorination may affect nanoparticle size and drug carrier properties. Our results show that as fluorine content within the polyacrylate matrix increases, the size of the nanoparticle systematically diminishes, from 45 nm (for nanoparticles containing no fluoroacrylate) to ~7 nm (for nanoparticles constructed solely of fluoroacrylate). We also observe that as fluoroacrylate content and hydrophobicity increases, the nanoparticles decrease their ability to incorporate lipophilic molecules during the process of emulsification. These findings have meaningful implications in the implementation of fluorinated nanoparticles in molecular delivery.

  17. Determination of nanoparticle size distribution together with density or molecular weight by 2D analytical ultracentrifugation.

    PubMed

    Carney, Randy P; Kim, Jin Young; Qian, Huifeng; Jin, Rongchao; Mehenni, Hakim; Stellacci, Francesco; Bakr, Osman M

    2011-06-07

    Nanoparticles are finding many research and industrial applications, yet their characterization remains a challenge. Their cores are often polydisperse and coated by a stabilizing shell that varies in size and composition. No single technique can characterize both the size distribution and the nature of the shell. Advances in analytical ultracentrifugation allow for the extraction of the sedimentation (s) and diffusion coefficients (D). Here we report an approach to transform the s and D distributions of nanoparticles in solution into precise molecular weight (M), density (ρ(P)) and particle diameter (d(p)) distributions. M for mixtures of discrete nanocrystals is found within 4% of the known quantities. The accuracy and the density information we achieve on nanoparticles are unparalleled. A single experimental run is sufficient for full nanoparticle characterization, without the need for standards or other auxiliary measurements. We believe that our method is of general applicability and we discuss its limitations.

  18. Fault diagnosis engineering in molecular signaling networks: an overview and applications in target discovery.

    PubMed

    Abdi, Ali; Emamian, Effat S

    2010-05-01

    Fault diagnosis engineering is a key component of modern industrial facilities and complex systems, and has gone through considerable developments in the past few decades. In this paper, the principles and concepts of molecular fault diagnosis engineering are reviewed. In this area, molecular intracellular networks are considered as complex systems that may fail to function, due to the presence of some faulty molecules. Dysfunction of the system due to the presence of a single or multiple molecules can ultimately lead to the transition from the normal state to the disease state. It is the goal of molecular fault diagnosis engineering to identify the critical components of molecular networks, i.e., those whose dysfunction can interrupt the function of the entire network. The results of the fault analysis of several signaling networks are discussed, and possible connections of the findings with some complex human diseases are examined. Implications of molecular fault diagnosis engineering for target discovery and drug development are outlined as well.

  19. Continuously adjustable, molecular-sieving “gate” on 5A zeolite for distinguishing small organic molecules by size

    SciTech Connect

    Song, Zhuonan; Huang, Yi; Xu, Weiwei L.; Wang, Lei; Bao, Yu; Li, Shiguang; Yu, Miao

    2015-09-11

    Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving “gate” at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences were effectively distinguished via appropriate misalignment. Lastly, this novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation.

  20. Continuously adjustable, molecular-sieving “gate” on 5A zeolite for distinguishing small organic molecules by size

    DOE PAGES

    Song, Zhuonan; Huang, Yi; Xu, Weiwei L.; ...

    2015-09-11

    Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving “gate” at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences weremore » effectively distinguished via appropriate misalignment. Lastly, this novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation.« less

  1. Continuously Adjustable, Molecular-Sieving “Gate” on 5A Zeolite for Distinguishing Small Organic Molecules by Size

    PubMed Central

    Song, Zhuonan; Huang, Yi; Xu, Weiwei L.; Wang, Lei; Bao, Yu; Li, Shiguang; Yu, Miao

    2015-01-01

    Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving “gate” at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences were effectively distinguished via appropriate misalignment. This novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation. PMID:26358480

  2. Continuously Adjustable, Molecular-Sieving “Gate” on 5A Zeolite for Distinguishing Small Organic Molecules by Size

    NASA Astrophysics Data System (ADS)

    Song, Zhuonan; Huang, Yi; Xu, Weiwei L.; Wang, Lei; Bao, Yu; Li, Shiguang; Yu, Miao

    2015-09-01

    Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving “gate” at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences were effectively distinguished via appropriate misalignment. This novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation.

  3. Correlation of early PET findings with tumor response to molecular targeted agents in patients with advanced driver-mutated non-small cell lung cancer.

    PubMed

    Koizumi, Tomonobu; Fukushima, Toshirou; Gomi, Daisuke; Kobayashi, Takashi; Sekiguchi, Nodoka; Mamiya, Keiko; Tateishi, Kazunari; Katou, Akane; Oguchi, Kazuhiro

    2017-09-01

    Recent advances in positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) have facilitated not only the diagnosis and staging of lung cancer, but also the prediction of treatment outcome. The present study was designed to assess the usefulness of early FDG-PET examination for predicting subsequent tumor size reduction in response to molecular targeted agents in metastatic non-small cell lung cancer (NSCLC) with sensitive gene anomalies. I. In 29 targeted lesions of 10 NSCLC patients, changes in FDG uptake before and on day 7 after the initiation of molecular targeted therapy (gefitinib, n = 7; crizotinib, n = 3) were compared with subsequent radiographic tumor size reduction by RECIST. FDG uptake was evaluated as the maximum standardized uptake value (SUVmax) of each targeted lesion. SUVmax decreased in all lesions after therapy (mean SUVmax 8.3 ± 3.4 before to 3.7 ± 1.8 after therapy, p < 0.05). The % decrease in SUVmax of each lesion was significantly correlated with the % tumor size reduction (r = 0.44). In addition, the reduction rate of SUVmax in metastatic bone lesions after initiation of molecular targeted therapy was significantly lower than that in targeted organs (27.1 ± 27.5 vs. 51.2 ± 21.3%, respectively, p < 0.05). Early reduction in FDG-PET uptake after initiation of molecular targeted agents was able to predict subsequent tumor reduction in patients harboring EGFR-mutated or ALK-positive NSCLC. In addition, nontargeted bone metastasis may have different glucose metabolism after TKI treatment compared with other involved organs.

  4. Finite-size effects on molecular dynamics interfacial thermal-resistance predictions

    NASA Astrophysics Data System (ADS)

    Liang, Zhi; Keblinski, Pawel

    2014-08-01

    Using molecular dynamics simulations, we study the role of finite size effects on the determination of interfacial thermal resistance between two solids characterized by high phonon mean free paths. In particular, we will show that a direct, heat source-sink method leads to strong size effect, associated with ballistic phonon transport to and from, and specular reflections at the simulation domain boundary. Lack of proper account for these effects can lead to incorrect predictions about the role of interfacial bonding and structure on interfacial thermal resistance. We also show that the finite size effect can be dramatically reduced by introduction of rough external boundaries leading to diffuse phonon scattering, as explicitly demonstrated by phonon wave-packet simulations. Finally, we demonstrate that when careful considerations are given to the effects associated with the finite heat capacity of the simulation domains and phonon scattering from the external surfaces, a size-independent interfacial resistance can be properly extracted from the time integral of the correlation function of heat power across the interface. Our work demonstrates that reliable and consistent values of the interfacial thermal resistance can be obtained by equilibrium and nonequilibrium methods with a relatively small computational cost.

  5. Molecular configuration and glomerular size selectivity in healthy and nephrotic humans.

    PubMed

    Blouch, K; Deen, W M; Fauvel, J P; Bialek, J; Derby, G; Myers, B D

    1997-09-01

    We studied eight healthy volunteers and eight nephrotic subjects to compare the glomerular sieving coefficients (theta) of dextran, a linear polymer of glucopyranose, with those of Ficoll, a spherical polysucrose. Over a molecular radius (rs) interval of 20-70 A, theta for a given Ficoll was uniformly lower than corresponding theta for a dextran of equivalent rs. For each macromolecular species, the theta of molecules with rs > 50 A was selectively enhanced in nephrotic vs. healthy subjects. Analysis of either dextran or Ficoll sieving curves with pore theory revealed the glomerular barrier to have a bimodal pore size distribution: a lower mode of restrictive pores with a lognormal distribution of radii and an upper mode of large shuntlike pores. Nephrotics differed from controls in that the lower mode was broadened and shifted to pores of smaller mean size, but the prominence of shuntlike pores was enhanced by an order of magnitude. Both the mean radius of restrictive pores and the magnitude of the shunt pathway were substantially smaller when estimated from Ficoll than dextran sieving. We interpret the more realistic values for pore parameters derived from Ficoll than dextran sieving to indicate 1) that the normal glomerular barrier prevents albuminuria by virtue of a combination of both charge- and size-selective properties and 2) that a combined impairment of both barrier charge selectivity and size selectively are required to account for the observed level and composition of proteinuria in our nephrotic subjects.

  6. Effect of xylose on the molecular and particle size distribution of peanut hydrolysate in Maillard reaction system.

    PubMed

    Su, Guowan; Cui, Chun; Ren, Jiaoyan; Yang, Bao; Zhao, Mouming

    2011-10-01

    The Maillard reaction is a complex series of reactions between reducing sugars and amino groups. Changing any of reaction parameters would alter the reaction pathway. This study investigated the effect of xylose concentration on the molecular and particle size distribution of Maillard reaction products (MRPs) derived from peanut hydrolysate and xylose to discuss their formation mechanism. Molecular weight and particle size distribution analyses indicated that both peptide degradation and peptide cross-linking occurred during the Maillard reaction. Heat treatment would make the high-molecular-weight peptides degrade into low-molecular-weight peptides and free amino acids. Maillard reaction increased the molecular weight and particle sizes of products as the xylose concentration increased from 1% to 4%. The study shows that both peptide degradation and peptide cross-linking occurred during the Maillard reaction. The thermal degradation product (TDP) and MRPs had significantly different molecular size distribution, and the particle size distribution of TDPs and MRPs had similar change tendency to that of the molecular size distribution. These would provide an insight into the formation mechanism of MRPs. Copyright © 2011 Society of Chemical Industry.

  7. Apparent target size of rat brain benzodiazepine receptor, acetylcholinesterase, and pyruvate kinase is highly influenced by experimental conditions

    SciTech Connect

    Nielsen, M.; Braestrup, C.

    1988-08-25

    Radiation inactivation is a method to determine the apparent target size of molecules. In this report we examined whether radiation inactivation of various enzymes and brain receptors is influenced by the preparation of samples preceding irradiation. The apparent target sizes of endogenous acetylcholinesterase and pyruvate kinase from rat brain and from rabbit muscle and benzodiazepine receptor from rat brain were investigated in some detail. In addition the target sizes of alcohol dehydrogenase (from yeast and horse liver), beta-galactosidase (from Escherichia coli), lactate dehydrogenase (endogenous from rat brain), and 5-HT2 receptors, acetylcholine muscarine receptors, and (/sup 35/S) butyl bicyclophosphorothionate tertiary binding sites from rat brain were determined. The results show that apparent target sizes are highly influenced by the procedure applied for sample preparation before irradiation. The data indicate that irradiation of frozen whole tissue as opposed to lyophilized tissue or frozen tissue homogenates will estimate the smallest and most relevant functional target size of a receptor or an enzyme.

  8. Molecular approach to find target(s) for oligoclonal bands in multiple sclerosis

    PubMed Central

    Rand, K.; Houck, H.; Denslow, N.; Heilman, K.

    1998-01-01

    OBJECTIVES—Oligoclonal bands are a characteristic finding in the CSF of patients with multiple sclerosis, yet their target antigen(s) remain unknown. The objective was to determine whether a filamentous phage peptide library could be employed to allow the oligoclonal bands to select their own target epitopes.
METHODS—CSF IgG antibody from 14 patients with multiple sclerosis and 14 controls was used to select individual phage clones from a bacteriophage library containing≈4 × 107 different hexamers expressed on its surface pIII protein. The amino acid sequence selected was deduced by sequencing the DNA of the genetically engineered insert.
RESULTS—In general, after three rounds of selection, CSF from both patients with multiple sclerosis and controls selected one to two consistent peptide motifs. Five out of 14 patients with multiple sclerosis, and one control, selected the amino acid sequence motif, RRPFF. Given 20 possible amino acids per position, the likelihood of five patients selecting the same linear five amino acid sequence is at most 1.6 × 10-13, corrected for the number of clones sequenced. A GenBank computer search showed that this sequence is found in the Epstein-Barr Virus nuclear antigen (EBNA-1), and a heat shock protein αB crystallin. Human serum antibodies to a synthetic peptide containing RRPFF were virtually exclusively found in patients with prior infection by Epstein-Barr virus. Other studies have suggested a relation between Epstein-Barr virus infection and multiple sclerosis, including nearly 100% Epstein-Barr virus seropositivity among patients with multiple sclerosis and increased concentrations of antibody to EBNA in CSF of patients with multiple sclerosis. By antigen specific immunoblotting, antibodies to the RRPFF motif in the CSF were shown to correspond to a subset of oligoclonal bands in the CSF from the same patient.
CONCLUSION—This study shows that phage epitope display libraries may be used to select amino acid

  9. Innovative molecular targeted agents in hepatocellular carcinoma: new gladiators on the arena.

    PubMed

    Ferri, Jose; Dockx, Yanina; Vonghia, Luisa; Papadimitriou, Konstantinos; Rasschaert, Marika; Francque, Sven; Peeters, Marc; Rolfo, Christian

    2017-02-14

    Treatment of advanced hepatocellular carcinoma remains a challenge, with discouraging results in terms of survival. Following the approval of the multikinase inhibitor sorafenib, a large number of molecular targeted agents have been tested, but many have failed to demonstrate significant efficacy in clinical trials. However, the deeper knowledge in HCC pathogenesis achieved through the years has enabled us to explore new targetable pathways as well as biomarkers that could lead to treatment personalization. In this review, we provide a comprehensive update of the most recent data regarding new drugs under investigation -some like regorafenib, very close to its approval- and new possible targets for future treatments.

  10. Exploration of Molecular Targets in the Development of New Therapeutics Aimed at Overcoming Multidrug Resistance.

    PubMed

    Nishida, Shozo; Tsubaki, Masanobu

    2017-01-01

     Multidrug resistance (MDR) in cancer is a major problem in clinical settings: MDR correlates with a patient's poor prognosis and decreased quality of life. Recently, MDR was found to be involved in various signal pathways, so the inhibition of signal molecules by molecular targeting drugs may help overcome MDR. In addition, the acquisition of MDR is shown to be associated with the overexpression of drug efflux pumps such as P-glycoprotein (MDR1), which in turn affects the regulation of the expression of cell survival factors, B-cell leukemia protein 2 (Bcl-2) family proteins, etc. We analyzed the mechanisms of MDR in hematopoietic malignancies, and showed that the activation of signaling molecules regulated the expression of drug efflux pumps and cell survival factors, thus suggesting that molecular targeting drugs are potentially useful as anti-MDR agents. In this review, I focus on recent advancements in understanding the mechanisms of MDR with respect to hematopoietic malignancies: (1) exploration of molecular targets for overcoming MDR in anti-cancer drug-resistant cell lines, (2) the mechanism of drug resistance through the cytokine autocrine loop, and (3) cell-cell interaction with bone marrow stromal cells, along with the application of molecular targeting drugs for overcoming MDR.

  11. Targeting Cell Surface Proteins in Molecular Photoacoustic Imaging to Detect Ovarian Cancer Early

    DTIC Science & Technology

    2012-07-01

    resolution required to detect ovarian cancer in an early curable stage, specific imaging probes are not currently available and are urgently needed...resolution required to detect ovarian cancer in an early, curable stage, specific imaging probes are not currently available and are urgently needed...10-1-0422 TITLE: Targeting Cell Surface Proteins in Molecular Photoacoustic Imaging to Detect Ovarian Cancer Early PRINCIPAL

  12. RYP1 gene as a target for molecular diagnosis of histoplasmosis.

    PubMed

    Brilhante, Raimunda Sâmia Nogueira; Guedes, Glaucia Morgana de Melo; Riello, Giovanna Barbosa; Ribeiro, Joyce Fonteles; Alencar, Lucas Pereira; Bandeira, Silviane Praciano; Castelo-Branco, Débora Souza Collares Maia; Oliveira, Jonathas Sales; Freire, Janaína Maria Maia; Mesquita, Jacó Ricarte Lima de; Camargo, Zoilo Pires de; Cordeiro, Rossana de Aguiar; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2016-11-01

    This study analyzed the RYP1 gene as a target for the molecular diagnosis of histoplasmosis. This assay detected fungal DNA in 13/13 blood samples from HIV/AIDS-patients with histoplasmosis. Therefore, the detection of RYP1 gene in whole blood sample is a quick and sensitive test to diagnose histoplasmosis.

  13. Preparation of actinide targets by molecular plating for Coulomb excitation studies at ATLAS.

    SciTech Connect

    Greene, J. P.

    1998-11-18

    Molecular plating is now routinely used to prepare sources and targets of actinide elements. Although the technique is simple and fairly reproducible, because of the radioactive nature of the target it is very useful to record various parameters in the preparation of such targets. At Argonne, {approximately}200 {micro}g/cm{sup 2} thick targets of Pu and Cm were required for Coulomb Excitation (COULEX) Studies with the Argonne-Notre Dame BGO gamma ray facility and later with the GAMMASPHERE. These targets were plated on 50 mg/cm{sup 2} Au backing and were covered with 150 {micro}g/cm{sup 2} Au foil. Targets of {sup 239}Pu, {sup 240}Pu, {sup 242}Pu, {sup 244}Pu and {sup 248}Cm were prepared by dissolving the material in isopropyl alcohol and electroplating the actinide ions by applying 600 volts. The amount of these materials on the target was determined by alpha particle counting and gamma ray counting. Details of the molecular plating and counting will be discussed.

  14. Multispectral excitation based multiple fluorescent targets resolving in fluorescence molecular tomography

    NASA Astrophysics Data System (ADS)

    Zhou, Yuan; Guang, Huizhi; Pu, Huangsheng; Zhang, Jiulou; Bai, Jing; Luo, Jianwen

    2016-04-01

    Fluorescence molecular tomography (FMT) can visualize biological activities at cellular and molecular levels in vivo, and has been extensively used in drug delivery and tumor detection research of small animals. The ill-posedness of the FMT inverse problem makes it difficult to reconstruct and resolve multiple adjacent fluorescent targets that have different functional features but are labeled with the same fluorochrome. An algorithm based on independent component analysis (ICA) for multispectral excited FMT is proposed to resolve multiple fluorescent targets in this study. Fluorescent targets are excited by multispectral excitation, and the three-dimensional distribution of fluorescent yields under the excitation spectrum is reconstructed by an iterative Tikhonov regularization algorithm. Subsequently, multiple fluorescent targets are resolved from mixed fluorescence signals by employing ICA. Simulations were performed and the results demonstrate that multiple adjacent fluorescent targets can be resolved if the number of excitation wavelengths is not smaller than that of fluorescent targets with different concentrations. The algorithm obtains both independent components that provide spatial information of different fluorescent targets and spectral courses that reflect variation trends of fluorescent yields along with the excitation spectrum. By using this method, it is possible to visualize the metabolism status of drugs in different structure organs, and quantitatively depict the variation trends of fluorescent yields of each functional organ under the excitation spectrum. This method may provide a pattern for tumor detection, drug delivery and treatment monitoring in vivo.

  15. A combined molecular docking-based and pharmacophore-based target prediction strategy with a probabilistic fusion method for target ranking.

    PubMed

    Li, Guo-Bo; Yang, Ling-Ling; Xu, Yong; Wang, Wen-Jing; Li, Lin-Li; Yang, Sheng-Yong

    2013-07-01

    Herein, a combined molecular docking-based and pharmacophore-based target prediction strategy is presented, in which a probabilistic fusion method is suggested for target ranking. Establishment and validation of the combined strategy are described. A target database, termed TargetDB, was firstly constructed, which contains 1105 drug targets. Based on TargetDB, the molecular docking-based target prediction and pharmacophore-based target prediction protocols were established. A probabilistic fusion method was then developed by constructing probability assignment curves (PACs) against a set of selected targets. Finally the workflow for the combined molecular docking-based and pharmacophore-based target prediction strategy was established. Evaluations of the performance of the combined strategy were carried out against a set of structurally different single-target compounds and a well-known multi-target drug, 4H-tamoxifen, which results showed that the combined strategy consistently outperformed the sole use of docking-based and pharmacophore-based methods. Overall, this investigation provides a possible way for improving the accuracy of in silico target prediction and a method for target ranking.

  16. Applications of Multi-Target Computer-Aided Methodologies in Molecular Design of CNS Drugs.

    PubMed

    Raevsky, Oleg A; Mukhametov, Azat; Grigorev, Veniamin Y; Ustyugov, Alexey; Tsay, Shwu-Chen; Jih-Ru Hwu, Reuben; Yarla, Nagendra Sastry; Barreto, George E; Aliev, Gjumrakch; Bachurin, Sergey O

    2017-09-20

    : Discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bio-informatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of development of multi-target approaches in quantitative structure-activity relationships (mt-QSAR) for CNS drug discovery; and describe applications of multi-target approaches in molecular modelling (which can be called mt-MM) as well as perspectives for multi-target approaches in bio-informatics in relation to Alzheimer&apos's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Biogeography of soil organic matter molecular structure across multiple soil size fractions

    NASA Astrophysics Data System (ADS)

    Meier, C. L.; Neff, J.

    2009-12-01

    Recent work suggests that there is a common soil decomposition sequence whereby plant inputs are metabolized into a physiologically constrained set of compounds originating from microbes that may persist in soil over relatively long time-scales. Plant inputs tend to be found in coarse particulate fractions (>180 μm) with relatively fast turnover times, while microbially derived compounds tend to accrue in the finer silt + clay fractions (<53 μm) with relatively long turnover times. To investigate whether a common decomposition sequence exists, we used pyrolysis gas chromatography/mass spectrometry (py-GC/MS) to characterize the molecular structure of soil organic matter (SOM) in three size fractions (590-180 μm, 180-53 μm, and <53 μm), using soils sampled from multiple biomes (alpine tundra, sub-alpine forest, boreal forest, temperate coniferous, temperate deciduous, dry desert/savannah, and tropical forest). We hypothesized that: 1) regardless of biome, fractions >180 μm would be chemically similar, and would be characterized by lignin and other plant-derived compounds; and 2) fractions <53 μm would also be similar across biomes but would be dominated by microbially-derived compounds like polysaccharides. Across all biomes, we found that there was significantly less lignin in <53 μm fractions compared to >180 μm fractions (p<0.0001), providing some support for the idea that plant material is not incorporated into soil C pools with relatively long turnover times. However, a principal components analysis (PCA) showed that the >180 μm coarse particulate fractions also contained compounds associated with microbial origins, indicating that microbial C is not limited to <53 μm size fractions. The PCA also revealed that samples within each of the three size fractions did not cluster together (i.e. they did not share a common molecular structure), but we did note that: 1) cold alpine and sub-alpine sites were unique and chemically similar; and 2) tropical

  18. Targeting CYP51 for drug design by the contributions of molecular modeling.

    PubMed

    Rabelo, Vitor W; Santos, Taísa F; Terra, Luciana; Santana, Marcos V; Castro, Helena C; Rodrigues, Carlos R; Abreu, Paula A

    2017-02-01

    CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.

  19. Targeting the molecular chaperone SlyD to inhibit bacterial growth with a small molecule

    PubMed Central

    Kumar, Amit; Balbach, Jochen

    2017-01-01

    Molecular chaperones are essential molecules for cell growth, whereby they maintain protein homeostasis. Because of their central cellular function, bacterial chaperones might be potential candidates for drug targets. Antimicrobial resistance is currently one of the greatest threats to human health, with gram-negative bacteria being of major concern. We found that a Cu2+ complex readily crosses the bacterial cell wall and inhibits SlyD, which is a molecular chaperone, cis/trans peptidyl prolyl isomerise (PPIase) and involved in various other metabolic pathways. The Cu2+ complex binds to the active sites of SlyD, which suppresses its PPIase and chaperone activities. Significant cell growth retardation could be observed for pathogenic bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa). We anticipate that rational development of drugs targeting molecular chaperones might help in future control of pathogenic bacterial growth, in an era of rapidly increasing antibiotic resistance. PMID:28176839

  20. A Bayesian Target Predictor Method based on Molecular Pairing Energies estimation

    PubMed Central

    Oliver, Antoni; Canals, Vincent; Rosselló, Josep L.

    2017-01-01

    Virtual screening (VS) is applied in the early drug discovery phases for the quick inspection of huge molecular databases to identify those compounds that most likely bind to a given drug target. In this context, there is the necessity of the use of compact molecular models for database screening and precise target prediction in reasonable times. In this work we present a new compact energy-based model that is tested for its application to Virtual Screening and target prediction. The model can be used to quickly identify active compounds in huge databases based on the estimation of the molecule’s pairing energies. The greatest molecular polar regions along with its geometrical distribution are considered by using a short set of smart energy vectors. The model is tested using similarity searches within the Directory of Useful Decoys (DUD) database. The results obtained are considerably better than previously published models. As a Target prediction methodology we propose the use of a Bayesian Classifier that uses a combination of different active compounds to build an energy-dependent probability distribution function for each target. PMID:28263323

  1. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    PubMed Central

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-01-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents. PMID:27147293

  2. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    NASA Astrophysics Data System (ADS)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-05-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

  3. A Bayesian Target Predictor Method based on Molecular Pairing Energies estimation

    NASA Astrophysics Data System (ADS)

    Oliver, Antoni; Canals, Vincent; Rosselló, Josep L.

    2017-03-01

    Virtual screening (VS) is applied in the early drug discovery phases for the quick inspection of huge molecular databases to identify those compounds that most likely bind to a given drug target. In this context, there is the necessity of the use of compact molecular models for database screening and precise target prediction in reasonable times. In this work we present a new compact energy-based model that is tested for its application to Virtual Screening and target prediction. The model can be used to quickly identify active compounds in huge databases based on the estimation of the molecule’s pairing energies. The greatest molecular polar regions along with its geometrical distribution are considered by using a short set of smart energy vectors. The model is tested using similarity searches within the Directory of Useful Decoys (DUD) database. The results obtained are considerably better than previously published models. As a Target prediction methodology we propose the use of a Bayesian Classifier that uses a combination of different active compounds to build an energy-dependent probability distribution function for each target.

  4. Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

    PubMed Central

    Panaccione, Alexander; Chang, Michael T.; Ivanov, Sergey V.

    2016-01-01

    Objectives This review surveys trialed therapies and molecular defects in adenoid cystic carcinoma (ACC), with an emphasis on neural crest‐like stemness characteristics of newly discovered cancer stem cells (CSCs) and therapies that may target these CSCs. Data Sources Articles available on Pubmed or OVID MEDLINE databases and unpublished data. Review Methods Systematic review of articles pertaining to ACC and neural crest‐like stem cells. Results Adenoid cystic carcinoma of the salivary gland is a slowly growing but relentless cancer that is prone to nerve invasion and metastases. A lack of understanding of molecular etiology and absence of targetable drivers has limited therapy for patients with ACC to surgery and radiation. Currently, no curative treatments are available for patients with metastatic disease, which highlights the need for effective new therapies. Research in this area has been inhibited by the lack of validated cell lines and a paucity of clinically useful markers. The ACC research environment has recently improved, thanks to the introduction of novel tools, technologies, approaches, and models. Improved understanding of ACC suggests that neural crest‐like stemness is a major target in this rare tumor. New cell culture techniques and patient‐derived xenografts provide tools for preclinical testing. Conclusion Preclinical research has not identified effective targets in ACC, as confirmed by the large number of failed clinical trials. New molecular data suggest that drivers of neural crest‐like stemness may be required for maintenance of ACC; as such, CSCs are a target for therapy of ACC. PMID:28894804

  5. A Bayesian Target Predictor Method based on Molecular Pairing Energies estimation.

    PubMed

    Oliver, Antoni; Canals, Vincent; Rosselló, Josep L

    2017-03-06

    Virtual screening (VS) is applied in the early drug discovery phases for the quick inspection of huge molecular databases to identify those compounds that most likely bind to a given drug target. In this context, there is the necessity of the use of compact molecular models for database screening and precise target prediction in reasonable times. In this work we present a new compact energy-based model that is tested for its application to Virtual Screening and target prediction. The model can be used to quickly identify active compounds in huge databases based on the estimation of the molecule's pairing energies. The greatest molecular polar regions along with its geometrical distribution are considered by using a short set of smart energy vectors. The model is tested using similarity searches within the Directory of Useful Decoys (DUD) database. The results obtained are considerably better than previously published models. As a Target prediction methodology we propose the use of a Bayesian Classifier that uses a combination of different active compounds to build an energy-dependent probability distribution function for each target.

  6. Antibacterial effects of chitosan-tripolyphosphate nanoparticles: impact of particle size molecular weight

    NASA Astrophysics Data System (ADS)

    Sarwar, Atif; Katas, Haliza; Zin, Noraziah Mohamad

    2014-07-01

    This study revealed not only the antibacterial potential of smaller chitosan-tripolyphosphate nanoparticles (CS-TPP NPs) over larger ones, but also the attempt has been made to demonstrate antibacterial mechanism of action of CS-TPP NPs on the bacterial cell membrane. Several aspects of low-molecular-weight (LMW) and high-molecular-weight (HMW) CS-TPP NPs were evaluated by their interactions with selected Gram-positive and Gram-negative bacteria. The interaction of CS-TPP NPs with synthetic phospholipid membranes was also evaluated using Fourier transform infrared spectroscopy. The permeabilities of the bacterial outer and inner membranes were evaluated by determining the uptake of a fluorescent probe, 1- N-phenylnaphthylamine, and the release of cytoplasmic β-galactosidase. The morphology of the bacteria treated with LMW and HMW CS-TPP NPs was investigated using transmission electron microscopy. Flow cytometric analysis was also performed for the quantification of dead and surviving bacteria. These studies indicated that the antibacterial effects of LMW CS-TPP NPs (196 and 394 nm) were superior to those HMW CS-TPP NPs (598 and 872 nm). These data indicated that the antibacterial activity of CS-TPP NPs was negatively correlated with particle size and molecular weight, and that CS-TPP NPs represent a promising antimicrobial adjunct.

  7. Molecular Markers and Targeted Therapeutics in Metastatic Tumors of the Spine: Changing the Treatment Paradigms.

    PubMed

    Goodwin, C Rory; Abu-Bonsrah, Nancy; Rhines, Laurence D; Verlaan, Jorrit-Jan; Bilsky, Mark H; Laufer, Ilya; Boriani, Stefano; Sciubba, Daniel M; Bettegowda, Chetan

    2016-10-15

    A review of the literature. The aim of this study was to discuss the evolution of molecular signatures and the history and development of targeted therapeutics in metastatic tumor types affecting the spinal column. Molecular characterization of metastatic spine tumors is expected to usher in a revolution in diagnostic and treatment paradigms. Molecular characterization will provide critical information that can be used for initial diagnosis, prognosticating the ideal treatment strategy, assessment of treatment efficacy, surveillance and monitoring recurrence, and predicting complications, clinical outcome, and overall survival in patients diagnosed with metastatic cancers to the spinal column. A review of the literature was performed focusing on illustrative examples of the role that molecular-based therapeutics have played in clinical outcomes for patients diagnosed with metastatic tumor types affecting the spinal column. The impact of molecular therapeutics including receptor tyrosine kinases and immune checkpoint inhibitors and the ability of molecular signatures to provide prognostic information are discussed in metastatic breast cancer, lung cancer, prostate cancer, melanoma, and renal cell cancer affecting the spinal column. For the providers who will ultimately counsel patients diagnosed with metastases to the spinal column, molecular advancements will radically alter the management/surgical paradigms utilized. Ultimately, the translation of these molecular advancements into routine clinical care will greatly improve the quality and quantity of life for patients diagnosed with spinal malignancies and provide better overall outcomes and counseling for treating physicians. N/A.

  8. Development and validation of a molecular size distribution method for polysaccharide vaccines.

    PubMed

    Clément, G; Dierick, J-F; Lenfant, C; Giffroy, D

    2014-01-01

    Determination of the molecular size distribution of vaccine products by high performance size exclusion chromatography coupled to refractive index detection is important during the manufacturing process. Partial elution of high molecular weight compounds in the void volume of the chromatographic column is responsible for variation in the results obtained with a reference method using a TSK G5000PWXL chromatographic column. GlaxoSmithKline Vaccines has developed an alternative method relying on the selection of a different chromatographic column with a wider separation range and the generation of a dextran calibration curve to determine the optimal molecular weight cut-off values for all tested products. Validation of this method was performed according to The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The new method detected product degradation with the same sensitivity as that observed for the reference method. All validation parameters were within the pre-specified range. Precision (relative standard deviation (RSD) of mean values) was < 5 per cent (intra-assay) and < 10 per cent (inter-assay). Sample recovery was > 70 per cent for all polysaccharide conjugates and for the Haemophilus influenzae type B final container vaccine. All results obtained for robustness met the acceptance criteria defined in the validation protocol (≤ 2 times (RSD) or ≤ 2 per cent difference between the modified and the reference parameter value if RSD = 0 per cent). The new method was shown to be a suitable quality control method for the release and stability follow-up of polysaccharide-containing vaccines. The new method gave comparable results to the reference method, but with less intra- and inter-assay variability.

  9. Fast molecular beacon hybridization in organic solvents with improved target specificity.

    PubMed

    Dave, Neeshma; Liu, Juewen

    2010-12-02

    DNA hybridization is of tremendous importance in biology, bionanotechnology, and biophysics. Molecular beacons are engineered DNA hairpins with a fluorophore and a quencher labeled on each of the two ends. A target DNA can open the hairpin to give an increased fluorescence signal. To date, the majority of molecular beacon detections have been performed only in aqueous buffers. We describe herein DNA detection in nine different organic solvents, methanol, ethanol, isopropanol, acetonitrile, formamide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethylene glycol, and glycerol, varying each up to 75% (v/v). In comparison with detection in water, the detection in organic solvents showed several important features. First, the molecular beacon hybridizes to its target DNA in the presence of all nine solvents up to a certain percentage. Second, the rate of this hybridization was significantly faster in most organic solvents compared with water. For example, in 56% ethanol, the beacon showed a 70-fold rate enhancement. Third, the ability of the molecular beacon to discriminate single-base mismatch is still maintained. Lastly, the DNA melting temperature in the organic solvents showed a solvent concentration-dependent decrease. This study suggests that molecular beacons can be used for applications where organic solvents must be involved or organic solvents can be intentionally added to improve the molecular beacon performance.

  10. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors.

    PubMed

    Pincez, Thomas; Clément, Nathalie; Lapouble, Eve; Pierron, Gaëlle; Kamal, Maud; Bieche, Ivan; Bernard, Virginie; Fréneaux, Paul; Michon, Jean; Orbach, Daniel; Aerts, Isabelle; Pacquement, Hélène; Bourdeaut, Franck; Jiménez, Irene; Thébaud, Estelle; Oudot, Caroline; Vérité, Cécile; Taque, Sophie; Owens, Cormac; Doz, François; Le Tourneau, Christophe; Delattre, Olivier; Schleiermacher, Gudrun

    2017-06-01

    The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors. © 2016 Wiley Periodicals, Inc.

  11. Ultrasound molecular imaging of ovarian cancer with CA-125 targeted nanobubble contrast agents.

    PubMed

    Gao, Yong; Hernandez, Christopher; Yuan, Hai-Xia; Lilly, Jacob; Kota, Pavan; Zhou, Haoyan; Wu, Hanping; Exner, Agata A

    2017-06-09

    Ultrasound is frequently utilized in diagnosis of gynecologic malignancies such as ovarian cancer. Because epithelial ovarian cancer (EOC) is often characterized by overexpression of cancer antigen 125 (CA-125), ultrasound contrast agents able to target this molecular signature could be a promising complementary strategy. In this work, we demonstrate application of CA-125-targeted echogenic lipid and surfactant-stabilized nanobubbles imaged with standard clinical contrast harmonic ultrasound for imaging of CA-125 positive OVCAR-3 tumors in mice. Surface functionalization of the nanobubbles with a CA-125 antibody achieved rapid significantly (P < 0.05) enhanced tumor accumulation, higher peak ultrasound signal intensity and slower wash out rates in OVCAR-3 tumors compared to CA-125 negative SKOV-3 tumors. Targeted nanobubbles also exhibited increased tumor retention and prolonged echogenicity compared to untargeted nanobubbles. Data suggest that ultrasound molecular imaging using CA-125 antibody-conjugated nanobubbles may contribute to improved diagnosis of EOC. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Molecular docking of γ-sitosterol with some targets related to diabetes.

    PubMed

    Balamurugan, Rangachari; Stalin, Antony; Ignacimuthu, Savarimuthu

    2012-01-01

    γ-sitosterol isolated from Lippia nodiflora was taken as ligand for molecular docking. The molecular targets, glucokinase, Fructose 1, 6- bisphosphatase 1, Human multidrug resistance protein 1 and Cytochromes P450 whose crystallographic structures are available on the PDB database as 1V4S, 2JJK, 3LC4, 2CBZ respectively, were used for the docking analysis using the Autodock tool v 4.2 and ADT v1.5.4 programs. The docking studies of the ligand γ- sitosterol with four different target proteins showed that this is a good molecule which docks well with various targets related to diabetes mellitus. Hence γ-sitosterol can be considered for developing into a potent antidiabetic drug. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  13. Microbubble mediated sonoporation of cells in suspension: clonogenic viability and influence of molecular size on uptake.

    PubMed

    Karshafian, Raffi; Samac, Sanya; Bevan, Peter D; Burns, Peter N

    2010-06-01

    This work investigates whether the application of sonoporation is limited by the size of a macromolecule being delivered and by the ability of cells to proliferate following uptake. KHT-C cells in suspension were exposed to variations in ultrasound pressure (0-570 kPa) and microbubble shell-type (lipid and protein) at fixed settings of 500 kHz centre frequency, 32 micros pulse duration, 3 kHz pulse repetition frequency and 2 min insonation. Reversible permeability (P(R)), defined as the number of cells stained with FITC-dextran and unstained with propidium iodide (i.e., PI-viable), was measured with flow cytometry for marker molecules ranging from 10 kDa to 2 MDa in size. Viable permeability (P(V)) defined as the number of permeabilised cells that maintained their ability to proliferate, was measured by clonogenic assay. Comparable intracellular delivery of all sizes of molecules was achieved, indicating that intracellular delivery of common therapeutic drugs may not be limited by molecular size. Maximum P(R)'s of 80% (at 10 kDa) and 55% (at 10 kDa) were achieved with lipid coated bubbles at 3.3% v/v and protein coated bubbles at 6.7% v/v concentrations. The PI-viability was approximately 80% at 570 kPa in both cases. The maximum P(V) achieved with both agents was 22%, while inducing a lower overall clonogenic viability with the lipid (39%) compared to the protein (56%) shelled bubbles. This study demonstrates that large macromolecules, up to 2 MDa in size, can be delivered with high efficiency to cells which undergo reversible permeabilisation, maintaining long-term viability in approximately half of the cells.

  14. Molecular targeted enhanced ultrasound imaging of flk1 reveals diagnosis and prognosis potential in a genetically engineered mouse prostate cancer model.

    PubMed

    Xuan, Jim W; Bygrave, Michael; Valiyeva, Fatma; Moussa, Madeleine; Izawa, Jonathan I; Bauman, Glenn S; Klibanov, Alexander; Wang, Fen; Greenberg, Norman M; Fenster, Aaron

    2009-01-01

    Molecular imaging techniques used to detect the initiation of disease have the potential to provide the best opportunity for early treatment and cure. This report aimed at testing the possibility that Flk1+ (vascular endothelial growth factor receptor 2), a crucial angiogenesis factor of most tumor cells, could be a molecular targeted imaging marker for the diagnosis and prognosis of cancer. We performed Flk1-targeted microbubble-enhanced ultrasound (US) imaging of prostate cancer in a genetically engineered mouse model with normal-appearing intact US (negative) prostates and with three different tumor sizes (small, medium, and large). Higher levels of Flk1+ molecular signals were identified in the intact US (negative) prostate group by US-targeted imaging and immunohistochemical analysis. The increase in Flk1+ expression occurred prior to the angiogenesis switch-on phase and vascularity peak. After this peak accumulation stage of Flk1+ molecules, lower and stabilized levels of Flk1+ signals were maintained together with tumor growth from small, to medium, to large size. In a longitudinal observation in a subset (n = 5) of mice with established tumors, elevated Flk1+ signals were observed in tissues surrounding the prostate cancer, for example, the ipsilateral boundary zones between two developing tumor lobes, new tumor blood vessel recruits, the urethra border, and the pelvic node basin. The potential of Flk1-targeted US imaging as a predictive imaging tool was confirmed by correlation studies of three-dimensional US B-mode imaging, gross pathology, and histology analyses. The results of the application in a genetically engineered mouse model with prostate cancer of molecular Flk1-targeted US imaging support the contention that Flk1 can be used as a molecular imaging marker for small tumors undetectable by microimaging and as a molecular diagnostic and prognosis marker for tumor metastasis and progression.

  15. Phase and Size Controllable Synthesis of NaYbF4 Nanocrystals in Oleic Acid/ Ionic Liquid Two-Phase System for Targeted Fluorescent Imaging of Gastric Cancer

    PubMed Central

    Pan, Liyuan; He, Meng; Ma, Jiebing; Tang, Wei; Gao, Guo; He, Rong; Su, Haichuan; Cui, Daxiang

    2013-01-01

    Upconversion nanocrystals with small size and strong fluorescent signals own great potential in applications such as biomolecule-labeling, in vivo tracking and molecular imaging. Herein we reported that NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with small size and strong fluorescent signals were controllably synthesized by oleic acid (OA)/ ionic liquid (IL) two-phase system for targeted fluorescent imaging of gastric cancer in vivo. The optimal synthesis condition of NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals by OA/IL two-phase system was established, adding more metal ion such as Na+ ion could facilitate the size control and crystal-phase transition, more importantly, markedly enhancing fluorescent intensity of beta-phase nanocrystals compared with traditional methods. Alpha-phase NaYbF4, 2%Tm upconversion nanocrystals with less than 10nm in diameter and beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with 30 nm or so in diameter and strong fluorescent signals were obtained, these synthesized nanocrystals exhibited very low cytotoxicity. Folic acid-conjugated silica-modified beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals were prepared, could actively target gastric cancer tissues implanted into nude mice in vivo, and realized targeted fluorescent imaging. Folic acid-conjugated silica-modified NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals show great potential in applications such as targeted near infared radiation fluorescent imaging, magnetic resonance imaging and targeted therapy of gastric cancer in the near future. PMID:23471455

  16. Analysis of Molecular Diffusion by First-Passage Time Variance Identifies the Size of Confinement Zones

    PubMed Central

    Rajani, Vishaal; Carrero, Gustavo; Golan, David E.; de Vries, Gerda; Cairo, Christopher W.

    2011-01-01

    The diffusion of receptors within the two-dimensional environment of the plasma membrane is a complex process. Although certain components diffuse according to a random walk model (Brownian diffusion), an overwhelming body of work has found that membrane diffusion is nonideal (anomalous diffusion). One of the most powerful methods for studying membrane diffusion is single particle tracking (SPT), which records the trajectory of a label attached to a membrane component of interest. One of the outstanding problems in SPT is the analysis of data to identify the presence of heterogeneity. We have adapted a first-passage time (FPT) algorithm, originally developed for the interpretation of animal movement, for the analysis of SPT data. We discuss the general application of the FPT analysis to molecular diffusion, and use simulations to test the method against data containing known regions of confinement. We conclude that FPT can be used to identify the presence and size of confinement within trajectories of the receptor LFA-1, and these results are consistent with previous reports on the size of LFA-1 clusters. The analysis of trajectory data for cell surface receptors by FPT provides a robust method to determine the presence and size of confined regions of diffusion. PMID:21402028

  17. Molecular determinants of plaque size as an indicator of dengue virus attenuation

    PubMed Central

    Goh, Kenneth Choon Meng; Tang, Choon Kit; Norton, Diana Catherine; Gan, Esther Shuyi; Tan, Hwee Cheng; Sun, Bo; Syenina, Ayesa; Yousuf, Amjad; Ong, Xin Mei; Kamaraj, Uma Sangumathi; Cheung, Yin Bun; Gubler, Duane J; Davidson, Andrew; St John, Ashley Lauren; Sessions, October Michael; Ooi, Eng Eong

    2016-01-01

    The development of live viral vaccines relies on empirically derived phenotypic criteria, especially small plaque sizes, to indicate attenuation. However, while some candidate vaccines successfully translated into licensed applications, others have failed safety trials, placing vaccine development on a hit-or-miss trajectory. We examined the determinants of small plaque phenotype in two dengue virus (DENV) vaccine candidates, DENV-3 PGMK30FRhL3, which produced acute febrile illness in vaccine recipients, and DENV-2 PDK53, which has a good clinical safety profile. The reasons behind the failure of PGMK30FRhL3 during phase 1 clinical trial, despite meeting the empirically derived criteria of attenuation, have never been systematically investigated. Using in vitro, in vivo and functional genomics approaches, we examined infections by the vaccine and wild-type DENVs, in order to ascertain the different determinants of plaque size. We show that PGMK30FRhL3 produces small plaques on BHK-21 cells due to its slow in vitro growth rate. In contrast, PDK53 replicates rapidly, but is unable to evade antiviral responses that constrain its spread hence also giving rise to small plaques. Therefore, at least two different molecular mechanisms govern the plaque phenotype; determining which mechanism operates to constrain plaque size may be more informative on the safety of live-attenuated vaccines. PMID:27185466

  18. Characterization of macromolecular complexes in red wine: Composition, molecular mass distribution and particle size.

    PubMed

    Bindon, Keren A; Carew, Anna L; Mierczynska-Vasilev, Agnieszka; Kassara, Stella; Kerslake, Fiona; Smith, Paul A

    2016-05-15

    Precipitates were prepared from two compositionally different Pinot noir wines with addition of excess ethanol, and contained primarily polysaccharide, tannin and protein. The ethanol-soluble material was further fractionated into polymeric (tannin) and monomeric phenolics. Tannin associated with precipitates was of a higher molecular mass than that remaining in ethanolic solution. Wine fractions were reconstituted at the ratios of the original wine and analyzed using nanoparticle tracking analysis. The average particle size of the tannin fraction was 75-89 nm, and increased when combined with the precipitate (≅ 200 nm). Addition of the monomeric fraction to the tannin-precipitate complex increased both the incidence and concentration of smaller particles, reducing the average particle size. The formation of aggregates occurred in all fractions and only minor differences in particle size distribution were found between wines. Differences in particle concentration between wines appear to be due to differences in the total concentration of macromolecules rather than compositional differences. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides.

    PubMed

    Dharap, S S; Qiu, B; Williams, G C; Sinko, P; Stein, S; Minko, T

    2003-08-28

    Novel targeted proapoptotic anticancer drug delivery systems were developed and evaluated. Poly(ethyleneglycol) (PEG) conjugates were used as carriers. Camptothecin (CPT) was used as an anticancer agent-apoptosis inductor. Two types of molecular targets were investigated: (1) an extracellular membrane receptor specific to ovarian cancer and (2) intracellular controlling mechanisms of apoptosis. Synthetic peptides similar to luteinizing hormone-releasing hormone (LHRH) and BCL-2 homology 3 (BH3) peptide were used as a targeting moiety and a suppressor of cellular antiapoptotic defense, respectively. Three different conjugates (CPT-PEG, CPT-PEG-BH3 and CPT-PEG-LHRH) were synthesized and examined in A2780 human ovarian cancer cells. Cytotoxicity, expression of genes encoding BCL-2, BCL-XL, SMAC, APAF-1 proteins and caspases 3 and 9, the activity of caspases 3 and 9 and apoptosis induction were studied. Taken together the results indicate much higher cytotoxicity and apoptosis-inducing activity of PEG-CPT conjugates when compared to free CPT. Moreover, the effects of targeted CPT-PEG-BH3 and CPT-PEG-LHRH conjugates were more pronounced than the non-targeted PEG-CPT conjugate. The results confirmed the feasibility of this new two-tier molecular targeting strategy for enhancing the efficacy of cancer chemotherapy.

  20. The importance of molecular markers for diagnosis and selection of targeted treatments in patients with cancer.

    PubMed

    Tobin, N P; Foukakis, T; De Petris, L; Bergh, J

    2015-12-01

    The past 30 years have seen the introduction of a number of cancer therapies with the aim of restricting the growth and spread of primary and metastatic tumours. A shared commonality among these therapies is their targeting of various aspects of the cancer hallmarks, that is traits that are essential to successful tumour propagation and dissemination. The evolution of molecular-scale technology has been central to the identification of new cancer targets, and it is not a coincidence that improved therapies have emerged at the same time as gene expression arrays and DNA sequencing have enhanced our understanding of cancer genetics. Modern tumour pathology is now viewed at the molecular level ranging from IHC biomarkers, to gene signature classifiers and gene mutations, all of which provide crucial information about which patients will respond to targeted therapy regimens. In this review, we briefly discuss the general types of targeted therapies used in a clinical setting and provide a short background on immunohistochemical, gene expression and DNA sequencing technologies, before focusing on three tumour types: breast, lung and colorectal cancers. For each of these cancer types, we provide a background to the disease along with an overview of the current standard therapies and then focus on the relevant targeted therapies and the pathways they inhibit. Finally, we highlight several strategies that are pivotal to the successful development of targeted anti-cancer drugs.

  1. Molecular targeted therapies in all histologies of head and neck cancers: an update.

    PubMed

    Razak, Albiruni R A; Siu, Lillian L; Le Tourneau, Christophe

    2010-05-01

    This article reviewed the recent developments in molecular targeted therapy in head and neck cancers. A brief summary of other pathways of interest is also enclosed. The use of cetuximab in squamous cell head and neck cancer is associated with clinical benefit and, in some cases, survival. However, the use of targeted agents beyond cetuximab in this disease remains investigational. Combination therapy of molecular targeted agents with chemoradiation in the locally advanced setting of head and neck squamous cell carcinomas and nasopharyngeal cancer shows early promising results, but at the expense of increased toxicity. In malignant salivary gland tumors, the evaluation of targeted therapy has been disappointing. New therapeutic targets warrant further evaluation in these cancers. Despite the encouraging results achieved with antiepidermal growth factor receptor therapy, particularly with cetuximab, targeted therapy trials conducted in head and neck cancers to date have largely lacked efficacy or are associated with significant toxicity. Further research into modulation of other aberrant pathways is needed. The recent identification of improved prognosis among head and neck squamous cell carcinoma patients whose tumors harbor the human papilloma virus may allow better treatment selection for these patients, while the identification of a hallmark gene fusion transcript in adenocystic carcinoma may herald new treatment promise.

  2. Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer

    PubMed Central

    ANTONELLI, GIOVANNA; LIBRA, MASSIMO; PANEBIANCO, VINCENZO; RUSSO, ALESSIA ERIKA; VITALE, FELICE VITO; COLINA, PAOLO; D'ANGELO, ALESSANDRO; ROSSELLO, ROSALBA; FERRAÙ, FRANCESCO

    2016-01-01

    Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib. PMID:26870160

  3. Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer.

    PubMed

    Antonelli, Giovanna; Libra, Massimo; Panebianco, Vincenzo; Russo, Alessia Erika; Vitale, Felice Vito; Colina, Paolo; D'Angelo, Alessandro; Rossello, Rosalba; Ferraù, Francesco

    2016-01-01

    Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib.

  4. Molecular and Cellular Pathobiology of Ehrlichia Infection: Targets for New Therapeutics and Immunomodulation Strategies

    PubMed Central

    McBride, Jere W.; Walker, David H.

    2013-01-01

    Ehrlichia are small gram-negative obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. Ehrlichia are able to subvert both innate and adaptive host defenses, and advances in understanding molecular Ehrlichia-eukaryotic host cell interactions and the cellular and immunologic basis of disease are important for developing effective next generation therapies. New technologies for exploring host-pathogen interactions have yielded recent advances in understanding the molecular interactions between these intracellular pathogens and host cell components and identified new targets for therapeutic and vaccine development including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathologic mechanisms that contribute significantly to understanding severe disease manifestations that will lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology of Ehrlichia infection. We identify new molecular host-pathogen interactions that can be targets of new therapeutics and prospects for treating immunologic dysregulation that occurs during acute infection leading to life-threatening complications. PMID:21276277

  5. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.

    PubMed

    Lee, Hyukjin; Lytton-Jean, Abigail K R; Chen, Yi; Love, Kevin T; Park, Angela I; Karagiannis, Emmanouil D; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S; Jayaraman, Muthusamy; Peng, Chang G; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G

    2012-06-03

    Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t(1/2) ≈ 24.2 min) than the parent siRNA (t(1/2) ≈ 6 min).

  6. Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery

    PubMed Central

    Lee, Hyukjin; Lytton-Jean, Abigail K. R.; Chen, Yi; Love, Kevin T.; Park, Angela I.; Karagiannis, Emmanouil D.; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S.; Jayaraman, Muthusamy; Peng, Chang G.; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S.; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G.

    2013-01-01

    Nanoparticles are employed for delivering therapeutics into cells1,2. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell specific internalization, excretion, toxicity, and efficacy3-7. A variety of materials have been explored for delivering small interfering RNAs (siRNAs) - a therapeutic agent that suppresses the expression of targeted genes8,9. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, lack of tissue specificity and potential toxicity10-12. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer targeting ligands (such as peptides and folate) on the nanoparticle surface can be precisely controlled. We show that at least three folate molecules per nanoparticle is required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ∼ 24.2 min) than the parent siRNA (t1/2 ∼ 6 min). PMID:22659608

  7. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery

    NASA Astrophysics Data System (ADS)

    Lee, Hyukjin; Lytton-Jean, Abigail K. R.; Chen, Yi; Love, Kevin T.; Park, Angela I.; Karagiannis, Emmanouil D.; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S.; Jayaraman, Muthusamy; Peng, Chang G.; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S.; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G.

    2012-06-01

    Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ~ 24.2 min) than the parent siRNA (t1/2 ~ 6 min).

  8. Molecular clusters size of Puerariae thomsonii radix aqueous decoction and relevance to oral absorption.

    PubMed

    Wang, Gong; Yang, Caimei; Zhang, Kuan; Hu, Juan; Pang, Wensheng

    2015-07-07

    The multi-component system of traditional Chinese medicine (TCM) is very complicated. The clusters are dynamic aggregates whose molecules are held together by hydrogen-bonded, Van der Waals forces or the opposite charges of particles attract each other. In this paper, field emission scanning electron microscopy proved that molecules form clusters in Pueraria thomsonii Benth (Fenge) water decoction. Four kinds of Fenge water decoction, 0.07 g∙mL-1 (F-1), 0.1 g∙mL-1 (F-2), 0.17 g∙mL-1 (F-3), 0.35 g∙mL-1 (F-4); F-1, average diameter of molecular was about 120 nm; F-2, 195 nm; F-3, 256 nm; and F-4, 480 nm. The molecular size was shown to depend on concentration. Rabbits were given equal does of 2.8 g∙kg-1, to perfuse F-1, F-2, F-3, F-4 in volume of 80 mL, 56 mL, 33 mL, 17 mL, respectively. At 0-180 min to collect 2 mL blood from the rabbit ears middle arteries for metabolism fingerprints, the results show the particle size of molecular is smaller, the absorption of drugs is better instead. The acute blood stasis model rats were treatment with Fenge decoction of 1.5 g∙kg-1 for 14 days, the concentrations of Ang II in plasma were significantly lower in F-1 and F-2 groups than those in model group (p < 0.01 or p < 0.05), but there were no significantly difference in F-3 and F-4 groups than those in model group (p > 0.05). Despite the molecular aggregation is a common physical phenomenon, it influence on the kind and amount of molecule per unit volume. Molecules morphology influence on the absorption behavior of drugs in vivo therefore is to have an impact on pharmacological function.

  9. Molecular Pathways: Aspirin and Wnt Signaling—A Molecularly Targeted Approach to Cancer Prevention and Treatment

    PubMed Central

    Gala, Manish K.; Chan, Andrew T.

    2014-01-01

    The anti-inflammatory properties of aspirin have resulted in its widespread use as an analgesic, anti-pyretic, and cardioprotective agent. Beyond these applications, multiple observational studies and randomized controlled trials have demonstrated a chemopreventative role for aspirin, particularly in the development of colorectal neoplasia. Given the critical importance of Wnt dysregulation in colorectal carcinogenesis, the interplay between aspirin and canonical Wnt signaling has become a focus of investigation. These studies have illuminated our understanding of the anti-cancer mechanisms of aspirin, yielding the identification of potential biomarkers for which aspirin's chemopreventative efficacy can be safely optimized into routine clinical practice and providing leads into the discovery of novel preventive and therapeutic targets. In this review, we summarize key experimental and clinical studies of this interaction, as well as highlight future strategies to advance their clinical translation.