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

    PubMed

    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

  3. 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

  4. 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

  5. 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)

  6. Targeted molecular imaging in oncology.

    PubMed

    Yang, David J; Kim, E Edmund; Inoue, Tomio

    2006-01-01

    Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. Application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of ongoing research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. 99mTc- and 68Ga-labeled agents using ethylenedicysteine (EC) as a chelator were synthesized and their potential uses to assess tumor targets were evaluated. 99mTc (t1/2 = 6 hr, 140 keV) is used for SPECT and 68Ga (t1/2 = 68 min, 511 keV) for PET. Molecular targets labeled with Tc-99m and Ga-68 can be utilized for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics were demonstrated. PMID:16485568

  7. Hepatotoxicity of molecular targeted therapy

    PubMed Central

    Sałek-Zań, Agata

    2014-01-01

    A constant increase in occurrence of neoplasms is observed; hence new methods of therapy are being intensively researched. One of the methods of antineoplastic treatment is molecular targeted therapy, which aims to influence individual processes occurring in cells. Using this type of medications is associated with unwanted effects resulting from the treatment. Liver damage is a major adverse effect diagnosed during targeted therapy. Drug-induced liver damage can occur as necrosis of hepatocytes, cholestatic liver damage and cirrhosis. Hepatotoxicity is evaluated on the basis of International Consensus Criteria. Susceptibility of the liver to injury is connected not only with toxicity of the used medications but also with metastasis, coexistence of viral infections or other chronic diseases as well as the patient's age. It has been proven that in most cases the liver injury is caused by treatment with multikinase inhibitors, in particular tyrosine kinase inhibitors. The Food and Drug Administration (FDA) ordered the inclusion of additional labels – so-called “black box warnings” – indicating increased risk of liver injury when treating with pazopanib, sunitinib, lapatinib and regorafenib. A meta-analysis published in 2013 showed that treating neoplastic patients with tyrosine kinase inhibitors can increase the risk of drug-induced liver damage at least twofold. Below the mechanisms of drug-induced liver injury and hepatotoxic effects of molecular targeted therapy are described. PMID:26034384

  8. 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.

  9. 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

  10. Tamoxifen Resistance: Emerging Molecular Targets.

    PubMed

    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

  11. 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.

  12. Ovarian cancer: emerging molecular-targeted therapies

    PubMed Central

    Sourbier, Carole

    2012-01-01

    With about 22,000 new cases estimated in 2012 in the US and 15,500 related deaths, ovarian cancer is a heterogeneous and aggressive disease. Even though most of patients are sensitive to chemotherapy treatment following surgery, recurring disease is almost always lethal, and only about 30% of the women affected will be cured. Thanks to a better understanding of the molecular mechanisms underlying ovarian cancer malignancy, new therapeutic options with molecular-targeted agents have become available. This review discusses the rationale behind molecular-targeted therapies and examines how newly identified molecular targets may enhance personalized therapies for ovarian cancer patients. PMID:22807625

  13. Molecular targets of luteolin in cancer

    PubMed Central

    2016-01-01

    Many food-derived phytochemical compounds and their derivatives represent a cornucopia of new anticancer compounds. Despite extensive study of luteolin, the literature has no information on the exact mechanisms or molecular targets through which it deters cancer progression. This review discusses existing data on luteolin’s anticancer activities and then offers possible explanations for and molecular targets of its cancer-preventive action. Luteolin prevents tumor development largely by inactivating several signals and transcription pathways essential for cancer cells. This review also offers insights into the molecular mechanisms and targets through which luteolin either prevents cancer or mediates cancer cell death. PMID:25714651

  14. Presynaptic Molecular Determinants of Quantal Size

    PubMed Central

    Takamori, Shigeo

    2016-01-01

    The quantal hypothesis for the release of neurotransmitters at the chemical synapse has gained wide acceptance since it was first worked out at the motor endplate in frog skeletal muscle in the 1950’s. Considering the morphological identification of synaptic vesicles (SVs) at the nerve terminals that appeared to be homogeneous in size, the hypothesis proposed that signal transduction at synapses is mediated by the release of neurotransmitters packed in SVs that are individually uniform in size; the amount of transmitter in a synaptic vesicle is called a quantum. Although quantal size—the amplitude of the postsynaptic response elicited by the release of neurotransmitters from a single vesicle—clearly depends on the number and sensitivity of the postsynaptic receptors, accumulating evidence has also indicated that the amount of neurotransmitters stored in SVs can be altered by various presynaptic factors. Here, I provide an overview of the concepts and underlying presynaptic molecular underpinnings that may regulate quantal size. PMID:26903855

  15. 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.

  16. 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

  17. 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

  18. 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. PMID:25315298

  19. [Molecular based targets and endometrial cancer].

    PubMed

    Stoyanov, St; Ananiev, J; Ivanova, K; Velev, V; Todorova, M; Gulubova, M

    2015-01-01

    In recent years, increasing attention has been paid to the rate of spread of endometrial carcinoma, especially in the postmenopausal period. Along with routine diagnostic methods, giving information on the location and progression of the disease, there are some morphological methods determining very accurately the correlations in the development of this type of cancer and his prognosis. Moreover--in recent years, the accumulated information about the molecular profile of this type of cancer made it possible to implement a number of new drugs against the so-called molecular therapy -'targets' in the neoplastic process. Significant proportion of cases show response rates, it is more hope in the development of more successful formulas and target -based therapy. In this review, we present and discuss the role of certain molecular markers as potential indicators of prognosis and development, as well as determining the target treatment of endometrial carcinoma. PMID:25909140

  20. New strategy for monitoring targeted therapy: molecular imaging

    PubMed Central

    Teng, Fei-Fei; Meng, Xue; Sun, Xin-Dong; Yu, Jin-Ming

    2013-01-01

    Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future. PMID:24124361

  1. 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

  2. [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. PMID:26281687

  3. 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)

  4. 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

  5. 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. PMID:27173057

  6. 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.

  7. High Efficiency Diffusion Molecular Retention Tumor Targeting

    PubMed Central

    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 In3+), 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 IV methods was assessed by surface fluorescence, biodistribution of [111In] RGD and [111In] 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 [111In] 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 IV). 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. PMID:23505478

  8. 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

  9. [Molecular alterations in melanoma and targeted therapies].

    PubMed

    Mourah, Samia; Lebbé, Céleste

    2014-12-01

    Melanoma is a skin cancer whose incidence is increasing steadily. The recent discovery of frequent and recurrent genetic alterations in cutaneous melanoma allowed a molecular classification of tumors into distinct subgroups, and paved the way for targeted therapy. Several signaling pathways are involved in the progression of this disease with oncogenic mutations affecting signaling pathways: MAPK, PI3K, cAMP and cyclin D1/CDK4. In each of these pathways, several potential therapeutic targets have been identified and specific inhibitors have already been developed and have shown clinical efficacy. The use of these inhibitors is often conditioned by tumors genotyping. In France, melanomas genotyping is supported by the platforms of the National Cancer Institute (INCA), which implemented a national program ensuring access to innovation for personalized medicine. The identification of new targets in melanoma supplies a very active dynamic development of innovative molecules contributing to changing the therapeutic landscape of this pathology. PMID:25776766

  10. Radiation inactivation target size of rat adipocyte glucose transporter

    SciTech Connect

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

    1987-05-01

    In situ assembly states of rat adipocyte glucose transport protein in plasma membrane (PM) and in microsomal pool (MM) were assessed by measuring target size (TS) of D glucose-sensitive, cytochalasin B binding activity. High energy radiation inactivated the binding in both PM and MM by reducing the total capacity of the binding (B/sub T/) without affecting the dissociation constant (K/sub D/). The reduction in B/sub T/ as a function of radiation dose was analyzed based on classical target theory, from which TS was calculated. TS in the PM of insulin-treated adipocytes was 58 KDa. TS in the MM of noninsulin-treated and insulin-treated adipocytes were 112 and 109 KDa, respectively. With MM, however, inactivation data showed anomalously low radiation sensitivities at low radiation doses showing a shoulder in the semilog plots, which may be due to an interaction with a radiation sensitive inhibitor. With these results, they propose the following model: Adipocyte glucose transporter, while exists as a monomer (T) in PM, occurs in MM either as a homodimer (T/sub 2/) or as a heterodimer (TX) with a protein X of a similar size. These dimers (T/sub 2/ or TX) in MM, furthermore, may form a multi-molecular assembly with another, large (300-400 KDa) protein Y, and insulin increases this assembly formation. These putative, transporter-associated proteins X and Y may play an important role in control of transporter distribution between PM and MM, particularly in response to insulin.

  11. High-energy protons from submicron-sized targets

    SciTech Connect

    Bychenkov, V. Yu.; Govras, E. A.; Brantov, A. V.; Popov, K. I.

    2012-07-11

    Improving of intensity contrast ratio of intense short laser pulses is making it possible to use submicron-sized targets, both spherical and plane, in the interest of proton acceleration for different applications. The way of improving of the ion beam quality is utilization of targets with two ion species - heavy ions (majority) and light ions, e.g. protons, (minority). Two different approaches, analytical theory and particle-in-cell simulations (PIC) are presented for studying the characteristics of laser-triggered ions due to the Coulomb-like mechanism of particle acceleration from submicron-sized targets. The comparative analysis of explosions of heterogeneous (layered) and homogeneously mixed targets for production of best quality ion bunches has been performed. We also found the regime of anisotropic proton acceleration from spherical targets with light and heavy ions relevant to the experiments with submicron-diameter droplets from water spray target irradiated by an ultrashort intense laser pulse.

  12. Effects of Target Size and Test Distance on Stereoacuity

    PubMed Central

    Handa, Tomoya; Ishikawa, Hitoshi

    2016-01-01

    Target size and test distance effects on stereoacuity were investigated in 24 subjects using a three-dimensional monitor. Examination 1: Target Size Effects. The test distance was 2.5 m for 0.1°, 0.2°, 0.5°, and 0.9° target sizes; crossed parallax was presented in 22-second units. Average stereoacuity values for 0.1°, 0.2°, 0.5°, and 0.9° target sizes were 59.58 ± 14.86, 47.66 ± 13.71, 41.25 ± 15.95, and 39.41 ± 15.52 seconds, respectively. Stereoacuity was significantly worse with a 0.1° target than with 0.2°, 0.5°, and 0.9° target sizes (P = 0.03, P < 0.0001, and P < 0.0001, resp.). Examination 2: Test Distance Effects. Test distances of 2.5, 5.0, and 7.5 m were investigated for a 0.5° target size; crossed parallax was presented in 22-second units. Average stereoacuity values at 2.5 m, 5.0 m, and 7.5 m test distances were 44.91 ± 16.16, 34.83 ± 10.84, and 24.75 ± 7.27 seconds, respectively. Stereoacuity at a 7.5 m distance was significantly better than at distances of 2.5 m and 5.0 m (P < 0.0001 and P = 0.02, resp.). Stereoacuity at a 5.0 m distance was significantly better than at 2.5 m (P = 0.04). Stereoacuity should be estimated by both parallax and other elements, including test distance and target size.

  13. MOLECULAR TARGETED THERAPIES FOR PANCREATIC CANCER

    PubMed Central

    Borja-Cacho, Daniel; Jensen, Eric Hans; Saluja, Ashok Kumar; Buchsbaum, Donald J; Vickers, Selwyn Maurice

    2008-01-01

    Background Pancreatic cancer cells express different mutations that increase the aggressiveness and confer resistance to conventional chemo- and radiotherapy. Molecules that selectively bind and inhibit these mutations are effective in other solid tumors and are now emerging as a complementary therapy in pancreatic cancer. The objective of this review is to describe the effect of drugs that inhibit specific mutations present in pancreatic cancer with special emphasis in clinical trials. Data sources We reviewed the English-language literature (Medline) addressing the role of drugs that target mutations present in pancreatic cancer. Both preclinical and clinical studies were included. Conclusions The preclinical evidence supports the combination of conventional approved therapies plus drugs that block EGFR, VEGF or induce apoptosis. However, most of the current clinical evidence is limited to small phase I trials evaluating the toxicity and safety of these regimens. The results of additional randomized trials that are still undergoing will clarify the role of these drugs in pancreatic cancer. Mini-abstract The role of molecular targeting in the treatment of pancreatic cancer is expanding. In this review, we summarize the most promising therapeutic targets as well as the current status of ongoing clinical trials. PMID:18718222

  14. Potential molecular targets for Ewing's sarcoma therapy.

    PubMed

    Jully, Babu; Rajkumar, Thangarajan

    2012-10-01

    Ewing's sarcoma (ES) is a highly malignant tumor of children and young adults. Modern therapy for Ewing's sarcoma combines high-dose chemotherapy for systemic control of disease, with advanced surgical and/or radiation therapeutic approaches for local control. Despite optimal management, the cure rate for localized disease is only approximately 70%, whereas the cure rate for metastatic disease at presentation is less than 30%. Patients who experience long-term disease-free survival are at risk for significant side-effects of therapy, including infertility, limb dysfunction and an increased risk for second malignancies. The identification of new targets for innovative therapeutic approaches is, therefore, strongly needed for its treatment. Many new pharmaceutical agents have been tested in early phases of clinical trials in ES patients who have recurrent disease. While some agents led to partial response or stable disease, the percentages of drugs eliciting responses or causing an overall effect have been minimal. Furthermore, of the new pharmaceuticals being introduced to clinical practice, the most effective agents also have dose-limiting toxicities. Novel approaches are needed to minimize non-specific toxicity, both for patients with recurrence and at diagnosis. This report presents an overview of the potential molecular targets in ES and highlights the possibility that they may serve as therapeutic targets for the disease. Although additional investigations are required before most of these approaches can be assessed in the clinic, they provide a great deal of hope for patients with Ewing's sarcoma. PMID:23580819

  15. Estimation of target size using two passive infrared sensors

    NASA Astrophysics Data System (ADS)

    Damarla, Thyagaraju; Sabatier, James M.

    2013-06-01

    Passive infrared (PIR) sensors are widely used as a part of unattended ground sensor suite for situational awareness. Currently, the PIR sensor is mainly used as a wakeup sensor for the imaging sensor in order to conserve power. Since the PIR sensor mainly responds to the thermal radiation from the target, animals in the vicinity of the sensor can cause many false alarms. The number of false alarms can be cut drastically, if the target's size can be estimated and a decision is made based on target size. For example, if the target is 5 ft 9 in tall and 1.5 ft wide, it is most likely a human being as opposed to an animal. In this paper, we present a technique to estimate target size using two PIR sensors with Fresnel lens arrays. One of the PIR sensors is mounted such that its Fresnel zones are horizontal to the ground, and the second PIR sensor is mounted such that its Fresnel zones are at a slant angle to the horizontal plane. The former is used to estimate the width/length, while the latter is used to estimate the height of the target. The relative signal strength between the two sensors is used to estimate the distance of the target from the sensor. The time it takes to cross the Fresnel zones is used to estimate the speed of the target. The algorithm is tested using the data collected in the woods, where several animals are observed roaming.

  16. 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. PMID:21087645

  17. 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

  18. 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.

  19. 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

  20. Treatment planning for molecular targeted radionuclide therapy.

    PubMed

    Siantar, Christine Hartmann; Vetter, Kai; DeNardo, Gerald L; DeNardo, Sally J

    2002-06-01

    Molecular targeted radionuclide therapy promises to expand the usefulness of radiation to successfully treat widespread cancer. The unique properties of radioactive tags make it possible to plan treatments by predicting the radiation absorbed dose to both tumors and normal organs, using a pre-treatment test dose of radiopharmaceutical. This requires a combination of quantitative, high-resolution, radiation-detection hardware and computerized dose-estimation software, and would ideally include biological dose-response data in order to translate radiation absorbed dose into biological effects. Data derived from conventional (external beam) radiation therapy suggests that accurate assessment of the radiation absorbed dose in dose-limiting normal organs could substantially improve the observed clinical response for current agents used in a myeloablative regimen, enabling higher levels of tumor control at lower tumor-to-normal tissue therapeutic indices. Treatment planning based on current radiation detection and simulations technology is sufficient to impact on clinical response. The incorporation of new imaging methods, combined with patient-specific radiation transport simulations, promises to provide unprecedented levels of resolution and quantitative accuracy, which are likely to increase the impact of treatment planning in targeted radionuclide therapy. PMID:12136519

  1. Molecular genetic determinants of human brain size.

    PubMed

    Tang, Bor Luen

    2006-07-01

    Cognitive skills such as tool use, syntactical languages, and self-awareness differentiate humans from other primates. The underlying basis for this cognitive difference has been widely associated with a high encephalization quotient and an anatomically distinct, exceptionally large cerebral cortex. Investigations on congenital microcephaly had revealed several genes that affect mammalian brain size when mutated. At least four of these, microcephalin (MCPH1), abnormal spindle-like microcephaly-associated (ASPM), cyclin-dependent kinase 5 regulatory associated protein 2 (CDK5RAP2), and centromere-associated protein J (CENPJ) are known to have undergone significant positive selection in the great apes and human lineages during primate evolution. MCPH1 and ASPM both have very young single nucleotide polymorphism haplotypes associated with modern humans, and these genes are presumably still evolving in Homo sapiens. Microcephalin has a role in DNA damage response and regulation of cell cycle checkpoints. The other known microcephaly-associated genes encode microtubule-associated centrosomal proteins that might regulate neural progenitor cell division and cell number. Recent reports have also unveiled a previously unknown function of ephrins and Eph in the regulation of neural progenitor cell death with a consequential effect on brain size. Understanding the mechanism for developmental control of brain organogenesis by these genes, and others such as FOXP2, shall provide fresh perspectives on the evolution of human intelligence. PMID:16716254

  2. [Mechanism and clinical progress of molecular targeted cancer therapy].

    PubMed

    Hu, Hong-xiang; Wang, Xue-qing; Zhang, Hua; Zhang, Qiang

    2015-10-01

    Molecular target-based cancer therapy is playing a more and more important role in cancer therapy because of its high specificity, good tolerance and so on. There are different kinds of molecular targeted drugs such as monoclonal antibodies and small molecular kinase inhibitors, and more than 50 drugs have been approved since 1997. When the first monoclonal antibody, rituximab, was on the market. The development of molecular target-based cancer therapeutics has become the main approach. Based on this, we summarized the drugs approved by FDA and introduced their mechanism of actions and clinical applications. In order to incorporate most molecular targeted drugs and describe clearly various characteristics, we divided them into four categories: drugs related to EGFR, drugs related to antiangiogenesis, drugs related to specific antigen and other targeted drugs. The purpose of this review is to provide a current status of this field and discover the main problems in the molecular targeted therapy. PMID:26837167

  3. 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.

  4. 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. PMID:26241920

  5. Molecular mechanism of size control in development and human diseases

    PubMed Central

    Yang, Xiaolong; Xu, Tian

    2011-01-01

    How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy. PMID:21483452

  6. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

    PubMed Central

    Palmieri, Giuseppe; Ombra, MariaNeve; Colombino, Maria; Casula, Milena; Sini, MariaCristina; Manca, Antonella; Paliogiannis, Panagiotis; Ascierto, Paolo Antonio; Cossu, Antonio

    2015-01-01

    Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS–RAF–MEK–ERK and PI3K–AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches. PMID:26322273

  7. Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation

    PubMed Central

    Mashima, Tetsuo; Ushijima, Masaru; Matsuura, Masaaki; Tsukahara, Satomi; Kunimasa, Kazuhiro; Furuno, Aki; Saito, Sakae; Kitamura, Masami; Soma-Nagae, Taeko; Seimiya, Hiroyuki; Dan, Shingo; Yamori, Takao; Tomida, Akihiro

    2015-01-01

    Targeted therapy is a rational and promising strategy for the treatment of advanced cancer. For the development of clinical agents targeting oncogenic signaling pathways, it is important to define the specificity of compounds to the target molecular pathway. Genome-wide transcriptomic analysis is an unbiased approach to evaluate the compound mode of action, but it is still unknown whether the analysis could be widely applicable to classify molecularly targeted anticancer agents. We comprehensively obtained and analyzed 129 transcriptomic datasets of cancer cells treated with 83 anticancer drugs or related agents, covering most clinically used, molecularly targeted drugs alongside promising inhibitors of molecular cancer targets. Hierarchical clustering and principal component analysis revealed that compounds targeting similar target molecules or pathways were clustered together. These results confirmed that the gene signatures of these drugs reflected their modes of action. Of note, inhibitors of oncogenic kinase pathways formed a large unique cluster, showing that these agents affect a shared molecular pathway distinct from classical antitumor agents and other classes of agents. The gene signature analysis further classified kinome-targeting agents depending on their target signaling pathways, and we identified target pathway-selective signature gene sets. The gene expression analysis was also valuable in uncovering unexpected target pathways of some anticancer agents. These results indicate that comprehensive transcriptomic analysis with our database (http://scads.jfcr.or.jp/db/cs/) is a powerful strategy to validate and re-evaluate the target pathways of anticancer compounds. PMID:25911996

  8. 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)

  9. Influence of lateral target size on hot electron production and electromagnetic pulse emission from laser-irradiated metallic targets

    SciTech Connect

    Chen Ziyu; Li Jianfeng; Yu Yong; Li Xiaoya; Peng Qixian; Zhu Wenjun; Wang Jiaxiang

    2012-11-15

    The influences of lateral target size on hot electron production and electromagnetic pulse emission from laser interaction with metallic targets have been investigated. Particle-in-cell simulations at high laser intensities show that the yield of hot electrons tends to increase with lateral target size, because the larger surface area reduces the electrostatic field on the target, owing to its expansion along the target surface. At lower laser intensities and longer time scales, experimental data characterizing electromagnetic pulse emission as a function of lateral target size also show target-size effects. Charge separation and a larger target tending to have a lower target potential have both been observed. The increase in radiation strength and downshift in radiation frequency with increasing lateral target size can be interpreted using a simple model of the electrical capacity of the target.

  10. Molecular diagnosis for personalized target therapy in gastric cancer.

    PubMed

    Cho, Jae Yong

    2013-09-01

    Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy. PMID:24156032

  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. PMID:27121580

  12. High Pressure Size Exclusion Chromatography (HPSEC) of humic substances: molecular sizes, analytical parameters, and column performance

    PubMed

    Conte; Piccolo

    1999-02-01

    High Pressure Size Exclusion chromatography (HPSEC) is increasingly used to evaluate molecular sizes of humic substances from different sources. Asymmetry factors (As), number of theoretical plates (N), coefficient of distribution (k(d)), and column resolution (Rs) were determined for two different HPSEC columns (TSK G3000SW and Biosep S2000) and polysaccharides of known molecular weights were used as standards. Calibration curves were equivalent for both columns whereas analytical parameters revealed that the TSK column was only slightly more efficient in separating polysaccharide standards. Mw and Mn values for humic substances differed according to the molecular weight range of each column but relative standard deviation never exceeded 5% for both columns. Variations between columns were attributed to intrinsic humic properties such as the stability of conformational structures. These results suggested that humic substances in solutions are loosely-bound association of small molecules that may be consistently dispersed by diffusion through size-exclusion pores. HPSEC is confirmed to represent a highly precise method to evaluate the relative molecular-size distribution of dissolved humic substances. PMID:10901671

  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. 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. PMID:26514603

  15. Targeted molecular therapies in thyroid carcinoma.

    PubMed

    Romagnoli, Serena; Moretti, Sonia; Voce, Pasquale; Puxeddu, Efisio

    2009-12-01

    Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results. PMID:20126863

  16. 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.

  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 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

  20. 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

  1. 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.

  2. Biocompatible Nanocomplexes for Molecular Targeted MRI Contrast Agent

    NASA Astrophysics Data System (ADS)

    Chen, Zhijin; Yu, Dexin; Wang, Shaojie; Zhang, Na; Ma, Chunhong; Lu, Zaijun

    2009-07-01

    Accurate diagnosis in early stage is vital for the treatment of Hepatocellular carcinoma. The aim of this study was to investigate the potential of poly lactic acid-polyethylene glycol/gadolinium-diethylenetriamine-pentaacetic acid (PLA-PEG/Gd-DTPA) nanocomplexes using as biocompatible molecular magnetic resonance imaging (MRI) contrast agent. The PLA-PEG/Gd-DTPA nanocomplexes were obtained using self-assembly nanotechnology by incubation of PLA-PEG nanoparticles and the commercial contrast agent, Gd-DTPA. The physicochemical properties of nanocomplexes were measured by atomic force microscopy and photon correlation spectroscopy. The T1-weighted MR images of the nanocomplexes were obtained in a 3.0 T clinical MR imager. The stability study was carried out in human plasma and the distribution in vivo was investigated in rats. The mean size of the PLA-PEG/Gd-DTPA nanocomplexes was 187.9 ± 2.30 nm, and the polydispersity index was 0.108, and the zeta potential was -12.36 ± 3.58 mV. The results of MRI test confirmed that the PLA-PEG/Gd-DTPA nanocomplexes possessed the ability of MRI, and the direct correlation between the MRI imaging intensities and the nano-complex concentrations was observed ( r = 0.987). The signal intensity was still stable within 2 h after incubation of the nanocomplexes in human plasma. The nanocomplexes gave much better image contrast effects and longer stagnation time than that of commercial contrast agent in rat liver. A dose of 0.04 mmol of gadolinium per kilogram of body weight was sufficient to increase the MRI imaging intensities in rat livers by five-fold compared with the commercial Gd-DTPA. PLA-PEG/Gd-DTPA nanocomplexes could be prepared easily with small particle sizes. The nanocomplexes had high plasma stability, better image contrast effect, and liver targeting property. These results indicated that the PLA-PEG/Gd-DTPA nanocomplexes might be potential as molecular targeted imaging contrast agent.

  3. Ultrashort laser ablation of bulk copper targets: Dynamics and size distribution of the generated nanoparticles

    SciTech Connect

    Tsakiris, N.; Gill-Comeau, M.; Lewis, L. J.; Anoop, K. K.; Ausanio, G.; Bruzzese, R.; Amoruso, S.

    2014-06-28

    We address the role of laser pulse fluence on expansion dynamics and size distribution of the nanoparticles produced by irradiating a metallic target with an ultrashort laser pulse in a vacuum, an issue for which contrasting indications are present in the literature. To this end, we have carried out a combined theoretical and experimental analysis of laser ablation of a bulk copper target with ≈50 fs, 800 nm pulses, in an interval of laser fluencies going from few to several times the ablation threshold. On one side, molecular dynamics simulations, with two-temperature model, describe the decomposition of the material through the analysis of the evolution of thermodynamic trajectories in the material phase diagram, and allow estimating the size distribution of the generated nano-aggregates. On the other side, atomic force microscopy of less than one layer nanoparticles deposits on witness plates, and fast imaging of the nanoparticles broadband optical emission provide the corresponding experimental characterization. Both experimental and numerical findings agree on a size distribution characterized by a significant fraction (≈90%) of small nanoparticles, and a residual part (≈10%) spanning over a rather large size interval, evidencing a weak dependence of the nanoparticles sizes on the laser pulse fluence. Numerical and experimental findings show a good degree of consistency, thus suggesting that modeling can realistically support the search for experimental methods leading to an improved control over the generation of nanoparticles by ultrashort laser ablation.

  4. 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

  5. Molecular targets of aspirin and cancer prevention.

    PubMed

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

    2014-07-01

    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

  6. 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

  7. MOLECULAR TARGETS AND MECHANISMS FOR ETHANOL ACTION IN GLYCINE RECEPTORS

    PubMed Central

    Perkins, Daya I.; Trudell, James R.; Crawford, Daniel K.; Alkana, Ronald L.; Davies, Daryl L.

    2010-01-01

    Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed. PMID:20399807

  8. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

    PubMed Central

    Kudo, Masatoshi

    2012-01-01

    Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth, invasion, and metastasis, and enabled the development of molecular-targeted agents. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. In addition, the combination of sorafenib with standard treatment, such as resection, ablation, transarterial embolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways. Finally, the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed. PMID:23155330

  9. Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

    PubMed Central

    Bertino, Gaetano; Demma, Shirin; Ardiri, Annalisa; Proiti, Maria; Gruttadauria, Salvatore; Toro, Adriana; Malaguarnera, Giulia; Bertino, Nicoletta; Malaguarnera, Michele; Malaguarnera, Mariano; Di Carlo, Isidoro

    2014-01-01

    Background. Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and Methods. A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” and “immunotherapy.” Discussion and Conclusion. Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways. PMID:25089265

  10. Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

    PubMed Central

    Marchetti, Philippe; Guerreschi, Pierre; Mortier, Laurent; Kluza, Jerome

    2015-01-01

    Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic “drivers” inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy. PMID:26713093

  11. [Progress in molecularly targeted therapies for acute myeloid leukemia].

    PubMed

    Tomita, Akihiro

    2015-02-01

    Genetic abnormalities including specific point mutations have recently been confirmed by applying comprehensive genome sequencing analyses. Molecular targeting therapies, which focus on the mutated proteins and over-expressed proteins in acute myeloid leukemia (AML) cells, are now being developed in clinical studies and/or based on in vitro analyses. This manuscript summarizes the genetic abnormalities in AML cells and some of the current molecular targeting therapies including FLT3 inhibitors (e.g. AC220; Quizartinib), Polo like kinase 1 (PLK1) inhibitors (e.g. BI-6727; Volasertib), IDH2 inhibitors (e.g. AG-221), and XPO1 inhibitors (e.g. KPT-330; Selinexor). PMID:25765792

  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

    2016-01-01

    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

  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 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

  15. 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

  16. Molecular Targets for the Treatment of Juvenile Myelomonocytic Leukemia

    PubMed Central

    Liu, Xiaoling; Sabnis, Himalee; Bunting, Kevin D.; Qu, Cheng-Kui

    2012-01-01

    Significant advances in our understanding of the genetic defects and the pathogenesis of juvenile myelomonocytic leukemia (JMML) have been achieved in the last several years. The information gathered tremendously helps us in designing molecular targeted therapies for this otherwise fatal disease. Various approaches are being investigated to target defective pathways/molecules in this disease. However, effective therapy is still lacking. Development of specific target-based drugs for JMML remains a big challenge and represents a promising direction in this field. PMID:22162691

  17. 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

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

    PubMed Central

    Chhabra, Gagan; Eggert, Ashley; Puri, Neelu

    2016-01-01

    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.

  19. Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

    PubMed Central

    Thaker, Nikhil G; Pollack, Ian F

    2010-01-01

    Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

  20. MR Molecular Imaging of Tumor Vasculature and Vascular Targets

    PubMed Central

    Pathak, Arvind P.; Penet, Marie-France; Bhujwalla, Zaver M.

    2016-01-01

    Tumor angiogenesis and the ability of cancer cells to induce neovasculature continue to be a fascinating area of research. As the delivery network that provides substrates and nutrients, as well as chemotherapeutic agents to cancer cells, but allows cancer cells to disseminate, the tumor vasculature is richly primed with targets and mechanisms that can be exploited for cancer cure or control. The spatial and temporal heterogeneity of tumor vasculature, and the heterogeneity of response to targeting, make noninvasive imaging essential for understanding the mechanisms of tumor angiogenesis, tracking vascular targeting, and detecting the efficacy of antiangiogenic therapies. With its noninvasive characteristics, exquisite spatial resolution and range of applications, magnetic resonance imaging (MRI) techniques have provided a wealth of functional and molecular information on tumor vasculature in applications spanning from “bench to bedside”. The integration of molecular biology and chemistry to design novel imaging probes ensures the continued evolution of the molecular capabilities of MRI. In this review, we have focused on developments in the characterization of tumor vasculature with functional and molecular MRI. PMID:20807600

  1. The Proteasome Is a Molecular Target of Environmental Toxic Organotins

    PubMed Central

    Shi, Guoqing; Chen, Di; Zhai, Guangshu; Chen, Marina S.; Cui, Qiuzhi Cindy; Zhou, Qunfang; He, Bin; Dou, Q. Ping; Jiang, Guibin

    2009-01-01

    Background Because of the vital importance of the proteasome pathway, chemicals affecting proteasome activity could disrupt essential cellular processes. Although the toxicity of organotins to both invertebrates and vertebrates is well known, the essential cellular target of organotins has not been well identified. We hypothesize that the proteasome is a molecular target of environmental toxic organotins. Objectives Our goal was to test the above hypothesis by investigating whether organotins could inhibit the activity of purified and cellular proteasomes and, if so, the involved molecular mechanisms and downstream events. Results We found that some toxic organotins [e.g., triphenyltin (TPT)] can potently and preferentially inhibit the chymotrypsin-like activity of purified 20S proteasomes and human breast cancer cellular 26S proteasomes. Direct binding of tin atoms to cellular proteasomes is responsible for the observed irreversible inhibition. Inhibition of cellular proteasomes by TPT in several human cell lines results in the accumulation of ubiquitinated proteins and natural proteasome target proteins, accompanied by induction of cell death. Conclusions The proteasome is one of the molecular targets of environmental toxic organotins in human cells, and proteasome inhibition by organotins contributes to their cellular toxicity. PMID:19337512

  2. 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.

  3. 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

  4. The emerging molecular machinery and therapeutic targets of metastasis

    PubMed Central

    Sun, Yutong; Ma, Li

    2015-01-01

    Metastasis is a 100-year-old research topic. Technological advancements during the past few decades have led to significant progress in our understanding of metastatic disease. However, metastasis remains the leading cause of cancer-related mortalities. The lack of appropriate clinical trials for metastasis preventive drugs and incomplete understanding of the molecular machinery are major obstacles in metastasis prevention and treatment. A number of processes, factors, and signaling pathways are involved in regulating metastasis. Here, we discuss recent progress in metastasis research, including epithelial-mesenchymal plasticity, cancer stem cells, emerging molecular determinants and therapeutic targets, and the link between metastasis and therapy resistance. PMID:25939811

  5. Treatment of advanced thyroid cancer: role of molecularly targeted therapies.

    PubMed

    Covell, Lorinda L; Ganti, Apar Kishor

    2015-09-01

    Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease. PMID:26335853

  6. 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

  7. 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

  8. 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.

  9. 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

  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 imaging using a targeted magnetic resonance hyperpolarized biosensor.

    PubMed

    Schröder, Leif; Lowery, Thomas J; Hilty, Christian; Wemmer, David E; Pines, Alexander

    2006-10-20

    A magnetic resonance approach is presented that enables high-sensitivity, high-contrast molecular imaging by exploiting xenon biosensors. These sensors link xenon atoms to specific biomolecular targets, coupling the high sensitivity of hyperpolarized nuclei with the specificity of biochemical interactions. We demonstrated spatial resolution of a specific target protein in vitro at micromolar concentration, with a readout scheme that reduces the required acquisition time by >3300-fold relative to direct detection. This technique uses the signal of free hyperpolarized xenon to dramatically amplify the sensor signal via chemical exchange saturation transfer (CEST). Because it is approximately 10,000 times more sensitive than previous CEST methods and other molecular magnetic resonance imaging techniques, it marks a critical step toward the application of xenon biosensors as selective contrast agents in biomedical applications. PMID:17053143

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

    PubMed

    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

  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. [Development of molecular targeted therapies in lung cancers].

    PubMed

    Suda, Kenichi; Mitsudomi, Tetsuya

    2014-05-01

    Human cancers usually possess cumulative genetic aberrations. However, recent studies have revealed that the proliferation and survival of specific subsets of lung cancer depend on a few somatic mutation(s), so-called driver mutations. Representative driver mutations include the EGFR mutation and ALK translocation identified in about 40% and 3% of lung adenocarcinomas in Japan, respectively. These tumors are extremely sensitive to the respective tyrosine kinase inhibitors. This sensitivity has encouraged researchers and clinicians to explore novel driver mutations in lung cancers as future molecular targets. Driver mutations reported so far include the HER2 mutation, BRAF mutation, ROS1 translocation, RET translocation, and NTRK translocation in lung adenocarcinomas, and FGFR1 amplification, DDR2 mutation, and FGFR3 translocation in lung squamous cell carcinomas. However, despite initial dramatic responses, the acquisition of resistance to molecular targeted drugs is almost inevitable. Overcoming resistance to molecular targeted drugs, the key drugs at this time, is an urgent issue to improve the outcomes of lung cancer patients. PMID:24946519

  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. PMID:19130054

  16. 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

  17. 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. PMID:25453958

  18. Molecular mechanisms for vascular complications of targeted cancer therapies.

    PubMed

    Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

    2016-10-01

    Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. PMID:27612952

  19. Renal Cell Carcinoma: Molecular Biology and Targeted Therapy

    PubMed Central

    Su, Daniel; Stamatakis, Lambros; Singer, Eric A.; Srinivasan, Ramaprasad

    2014-01-01

    Purpose of review Renal cell carcinoma (RCC) continues to be the subject of vigorous clinical and translational investigation. Advances in systemic targeted therapies, new molecular pathways, and immunotherapy approaches will be discussed. Recent findings Agents targeting the vascular endothelial growth factor (VEGF) and/or the mammalian target of rapamycin (mTOR) pathways continue to be the mainstay for treating metastatic RCC (mRCC). Although enhanced target specificity has improved the toxicity profile associated with newer VEGF-pathway antagonists, durable complete responses remain the exception. Identification of novel pathways/agents, as well as the optimal sequencing and combination of existing targeted agents, remain areas of active study. In addition, emerging data from early clinical trials has reinvigorated interest in immunomodulatory agents. Summary The therapeutic armamentarium available to genitourinary oncologists continues to grow but much work remains to be done to fully realize the potential of pathway-specific targeted strategies and immune-based approaches for mRCC. PMID:24675233

  20. Novel molecular targets for prevention of obesity and osteoporosis.

    PubMed

    Rayalam, Srujana; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A

    2011-12-01

    Evidence from both epidemiological studies and basic research suggests that obesity and osteoporosis are interrelated. Though there is an increase in the prevalence of these disorders, a limited number of treatments are available, one of the reasons being the complexity of the pathways involved and difficulty in identifying a single molecular target. Due to adverse effects of pharmaceuticals, intake of herbal drugs by patients without a physician's recommendation is increasing globally. Lack of success with targeted monotherapy has encouraged scientists to determine whether combinations of phytochemicals that interfere with numerous cell-signaling pathways can be a more effective approach to treat complex diseases. For example, evidence is emerging that specific combinations of phytochemicals are far more effective than single compounds in decreasing adipogenesis and promoting bone formation. Since multiple pathways are dysfunctional in obesity and osteoporosis, an ideal approach for preventing and treating these diseases may be to use a combination of phytochemicals to address several targets simultaneously. PMID:21429725

  1. Size dependence of cavity volume: a molecular dynamics study.

    PubMed

    Patel, Nisha; Dubins, David N; Pomès, Régis; Chalikian, Tigran V

    2012-02-01

    Partial molar volume, V°, has been used as a tool to sample solute hydration for decades. The efficacy of volumetric investigations of hydration depends on our ability to reliably discriminate between the cavity, V(C), and interaction, V(I), contributions to the partial molar volume. The cavity volume, V(C), consists of the intrinsic volume, V(M), of a solute molecule and the thermal volume, V(T), with the latter representing the volume of the effective void created around the solute. In this work, we use molecular dynamics simulations in conjunction with the Kirkwood-Buff theory to compute the partial molar volumes for organic solutes of varying sizes in water. We perform our computations using the Lennard-Jones and Coulombic pair potentials as well as truncated potentials which contain only the Lennard-Jones but not the Coulombic contribution. The partial molar volume computed with the Lennard-Jones potentials in the absence of the Coulombic term nearly coincides with the cavity volume, V(C). We determine the thermal volume, V(T), for each compound by subtracting its van der Waals volume, V(W), from V(C). Finally, we apply the spherical approximation of solute geometry to evaluate the thickness of the thermal volume, δ. Our results reveal an increase in the thickness of thermal volume, δ, with an increase in the size of the solute. This finding may be related to dewetting of large nonpolar solutes and the concomitant increase in the compressibility of water of hydration. PMID:22133917

  2. Molecular targets in cerebral ischemia for developing novel therapeutics.

    PubMed

    Mehta, Suresh L; Manhas, Namratta; Raghubir, Ram

    2007-04-01

    Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of

  3. Gene mutations and molecularly targeted therapies in acute myeloid leukemia

    PubMed Central

    Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

    2013-01-01

    Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

  4. 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

  5. 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

  6. 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. PMID:26807608

  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. Pancreatic cancer: molecular pathogenesis and new therapeutic targets

    PubMed Central

    Wong, Han H.; Lemoine, Nicholas R.

    2010-01-01

    Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically, despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. Over the past decade, a large number of studies that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis have been published. This research is of particular importance, as recent data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth-factor receptor tyrosine kinase inhibitor, has demonstrated modest survival benefit in combination with gemcitabine in a phase III clinical trial. Whilst the failures of targeted therapies in the clinical setting are discouraging, lessons have been learnt and new therapeutic targets that hold promise for the future management of the disease are continuously emerging. This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials. PMID:19506583

  9. XUV spectroscopy of laser plasma from molecular coated metal targets

    NASA Astrophysics Data System (ADS)

    Papanyan, Valeri O.; Nersisyan, Gagik T.; Tittel, Frank K.

    1999-12-01

    Metal targets covered by micrometer layers of metal- phthalocyanines or fullerenes are studied here. An increase in XUV yield due to the optimized absorption of the laser field is reported. Effects of high-temperature plasma rapid expansion (velocity about 106 cm/s) were observed. Moderate power nanosecond and picosecond neodymium lasers are used to produce an incident intensity of 1011 to 1013 W/cm2 on the targets. The plasma electron density was measured by fitting observed spectral profiles to the theoretical profiles. Collisional, Doppler, and Stark broadening mechanisms were considered in the calculations. Our measurement technique permits us to determine the electron density and temperature dependence on distances from the target surface from 1 mm (where Ne approximately equals 1018 cm-3 and Te approximately equals 14 eV are measured for aluminum plasma) up to approximately 5 mm (where Ne molecular coated targets is greater by a factor of approximately 1.5 than measured from bulk solid metal targets.

  10. XUV spectroscopy of laser plasma from molecular coated metal targets

    NASA Astrophysics Data System (ADS)

    Papanyan, Valeri O.; Nersisyan, Gagik T.; Tittel, Frank K.

    1999-10-01

    Metal targets covered by micrometer layers of metal- phthalocyanines are studied here. An increase in EUV yield due to optimized absorption of the laser field is reported. Effects of high-temperature plasma rapid expansion (velocity about 106 cm/s) were observed. Moderate power nanosecond and picosecond neodymium lasers are used to product an incident intensity of 1011 to 1013 W/cm2 on the targets. The plasma electron density was measured by fitting observed spectral profiles to theoretical profiles. Collisional, Doppler, and Stark broadening mechanisms were considered in the calculations. Our measurement technique makes it possible to determine the electron density and temperature dependence on distances from the target surface from 1 mm (where Ne equals 2.0 (+/- 0.5)1018 cm-3 and Te equals 14 eV are measured for aluminum plasma) up to approximately 5 mm (where Ne molecular coated targets is greater by a factor of approximately 1.5 than measured from bulk solid metal targets.

  11. Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapy.

    PubMed

    Braconi, C; Bracci, R; Cellerino, R

    2008-08-01

    Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75-80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5-10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation. PMID:18690842

  12. 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. PMID:25699098

  13. Small Sized EGFR1 and HER2 Specific Bifunctional Antibody for Targeted Cancer Therapy

    PubMed Central

    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. PMID:25699098

  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. 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

  16. 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.

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

    PubMed

    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

  18. Contrast, size, and orientation-invariant target detection in infrared imagery

    NASA Astrophysics Data System (ADS)

    Zhou, Yi-Tong; Crawshaw, Richard D.

    1991-08-01

    Automatic target detection in IR imagery is a very difficult task due to variations in target brightness, shape, size, and orientation. In this paper, the authors present a contrast, size, and orientation invariant algorithm based on Gabor functions for detecting targets from a single IR image frame. The algorithms consists of three steps. First, it locates potential targets by using low-resolution Gabor functions which resist noise and background clutter effects, then, it removes false targets and eliminates redundant target points based on a similarity measure. These two steps mimic human vision processing but are different from Zeevi's Foveating Vision System. Finally, it uses both low- and high-resolution Gabor functions to verify target existence. This algorithm has been successfully tested on several IR images that contain multiple examples of military vehicles with different size and brightness in various background scenes and orientations.

  19. Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.

    PubMed

    Moeini, Agrin; Sia, Daniela; Bardeesy, Nabeel; Mazzaferro, Vincenzo; Llovet, Josep M

    2016-01-15

    Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA- and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatin-remodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarker-driven trials are currently underway. PMID:26405193

  20. 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

  1. Evolving molecular targets in the treatment of nonmalignant gastrointestinal diseases.

    PubMed

    Katzka, D A; Loftus, E V; Camilleri, M

    2012-09-01

    Novel treatments for gastrointestinal (GI) diseases are based on molecular targets. Novel pharmacologic and biological agents with greater selectivity and specificity are being developed for a variety of epithelial diseases, including eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), celiac disease, short bowel syndrome (SBS), and inflammatory bowel diseases (IBDs; Crohn's disease and ulcerative colitis). Motility and secretory agents are being developed for gastroparesis, irritable bowel syndrome (IBS), functional constipation, and diarrhea. Here we focus on data from clinical trials involving validated pharmacodynamic or patient response outcomes. PMID:22828717

  2. Molecular targets in melanoma: time for `ethnic personalization'

    PubMed Central

    Morita, Shane Y; Markovic, Svetomir N

    2016-01-01

    Worldwide, the incidence of melanoma continues to rise. Although not the most common cutaneous malignancy, it is the most lethal. Until recently, while other oncologic patients benefited from the nuances of targeted therapy, those afflicted with melanoma lacked that option. In 2011, the US FDA approved an oral agent that targets the BRAF oncogene. As this information is promising, it is essential that other populations (in addition to Caucasians) are examined, in order to further comprehend the biology of melanoma. Recent studies profiling various ethnicities, including Asians, have provided novel data with respect to the molecular characterization (c-KIT, BRAF, NRAS) of melanoma. It is hopeful that the management of melanoma will be universally applicable to all ethnic groups. PMID:22594895

  3. Immunotoxins, ligand-toxin conjugates and molecular targeting.

    PubMed

    Soria, M

    1989-01-01

    Biotechnology provides tools for therapeutic exploitation following advances in the elucidation of protein-to-cell and cell-to-cell interactions. Molecular targeting of bacterial and plant toxins to the desired district of action can be achieved through effector molecules like monoclonal antibodies or protein ligands. Biochemical conjugation of these effectors to SO-6, a single-chain Ribosome Inactivating Protein from Saponaria officinalis, yielded powerful cytotoxic agents that are attractive candidates for therapeutic evaluation. Cloning of the gene for this plant toxin has been achieved. Technologies for expression of protein ligands, such as apolipoproteins or several growth factors, are available in recombinant microorganisms, providing adequate partners for the assembly of targeted chimaeras. Domain engineering of structural and functional regions in effector proteins is now possible and will be carried out with the available technologies to improve existing therapy. PMID:2698471

  4. 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....219-21 Small Business Size Representation for Targeted Industry Categories Under the Small Business... Size Representation for Targeted Industry Categories Under the Small Business...

  5. 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

  6. Novel molecular targets in cancer chemotherapy waiting for discovery.

    PubMed

    Kunick, Conrad

    2004-09-01

    Despite a number of advances in the past decades the medicinal cancer therapy is hampered by problems of severe unwanted side effects and the development of resistances. Many established anti-cancer drugs are directed toward targets that are not specific for cancer but are essential biochemical molecules in living cells. Because cancer cells do not only carry one but multiple genetic alterations which are more characteristic for the individual patient than for the tumor entity, an individualized medicinal approach could improve the success of a tumor therapy. A prerequisite for personalized tumor therapies is an upgrade of the array of anticancer drugs directed to different molecular targets. Therefore, a systematic search for anticancer drug targets should constitute a research priority. The database of fingerprints of new chemical entities generated in the National Cancer Institute's Anticancer Drug Screening is a rich source of novel targets which might be uncovered by the interdisciplinary application of methods from bioinformatics, biochemistry, chemistry, tumor biology and related sciences. PMID:15379696

  7. Magnetized Target Fusion With Centimeter-Size Liner

    SciTech Connect

    Ryutov, D

    2005-07-21

    The author concentrates on the version of magnetized target fusion (MTF) that involves 3D implosions of a wall-confined plasma with the density in the compressed state {approx} 10{sup 21}-10{sup 22} cm{sup -3}. Possible plasma configurations suitable for this approach are identified. The main physics issues are outlined (equilibrium, stability, transport, plasma-liner interaction, etc). Specific parameters of the experiment reaching the plasma Q{approx}1 are presented (Q is the ratio of the fusion yield to the energy delivered to the plasma). It is emphasized that there exists a synergy between the physics and technology of MTF and dense Z-pinches (DZP). Specific areas include the particle and heat transport in a high-beta plasma, plasma-liner interaction, liner stability, stand-off problem for the power source, reaching a rep-rate regime in the energy-producing reactor, etc. Possible use of existing pulsed-power facilities for addressing these issues is discussed.

  8. [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. PMID:25656022

  9. 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. PMID:25753513

  10. 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

  11. A targeted molecular probe for colorectal cancer imaging

    NASA Astrophysics Data System (ADS)

    Attramadal, T.; Bjerke, R.; Indrevoll, B.; Moestue, S.; Rogstad, A.; Bendiksen, R.; Healey, A.; Johannesen, E.

    2008-02-01

    Colorectal cancer is a major cause of cancer death. Morbidity, mortality and healthcare costs can be reduced if the disease can be detected at an early stage. Screening is a viable approach as there is a clear link to risk factors such as age. We have developed a fluorescent contrast agent for use during colonoscopy. The agent is administered intravenously and is targeted to an early stage molecular marker for colorectal cancer. The agent consists of a targeting section comprising a peptide, and a fluorescent reporter molecule. Clinical imaging of the agent is to be performed with a far red fluorescence imaging channel (635 nm excitation/660-700 nm emission) as an adjunct to white light colonoscopy. Preclinical proof of mechanism results are presented. The compound has a K d of ~3nM. Two human xenograft tumour models were used. Tumour cells were implanted and grown subcutaneously in nude mice. Imaging using a fluorescence reflectance imaging system and quantitative biodistribution studies were performed. Substances tested include the targeted agent, and a scrambled sequence of the peptide (no binding) used as a negative control. Competition studies were also performed by co-administration of 180 times excess unlabelled peptide. Positive imaging contrast was shown in the tumours, with a clear relationship to expression levels (confirmed with quantitative biodistribution data). There was a significant difference between the positive and negative control substances, and a significant reduction in contrast in the competition experiment.

  12. Molecular targets in osteoarthritis: metalloproteinases and their inhibitors.

    PubMed

    Burrage, P S; Brinckerhoff, C E

    2007-02-01

    The debilitating destruction of joint tissues seen in osteoarthritis (OA) is due, in large part, to the degradative activity of metalloproteinase (MP) enzymes that target extracellular matrix (ECM) components within articular cartilage. Although successful in suppressing the pain and inflammation associated with this disease, conventional OA therapeutics do not inhibit the underlying tissue catabolism, allowing the disease to progress into irreversible ECM loss and chronic disability. Therapeutic inhibition of metalloproteinase activity is not a new concept, however, its transfer into clinical use has been frustrating. Disappointing results from clinical trials with small molecule inhibitors of metalloproteinases have highlighted the critical importance of inhibitor specificity, and the need to identify the individual metalloproteinases responsible for joint destruction. We discuss strategies of inhibition using small molecule inhibitors and tissue inhibitors of metalloproteinases (TIMPs) engineered to increase inhibitory specificity, and present new data using of new reagents such as ribozymes and inhibitory RNAs that repress expression of specific enzymes. Recent data has implicated the disease stage-dependent involvement of matrix metalloproteinase-1, -2, -3, -9, -13, ADAM-17/TACE (tumor-necrosis factor-alpha converting enzyme), and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin 1 motifs) as major in vivo mediators of the ECM degradation seen in OA, and as such, they represent promising therapeutic targets. We conclude that the concept of molecular polypharmacy, in which the relevant enzymes are selectively targeted with multiple directed therapies, may offer a new therapeutic strategy that prevents joint destruction and minimizes toxicities. PMID:17305507

  13. 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

  14. Progress of molecular targeted therapies for prostate cancers

    PubMed Central

    Fu, Weihua; Madan, Elena; Yee, Marla; Zhang, Hongtao

    2011-01-01

    Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients. PMID:22146293

  15. Angle dependent focal spot size of a conical X-ray target.

    PubMed

    Raza, Hamid Saeed; Kim, Hyun Jin; Kim, Hyun Nam; Cho, Sung Oh

    2015-02-01

    Misaligned phantoms may severely affect the focal spot calculations. A method is proposed to determine the geometry of the X-ray target and the position of the image radiograph around the X-ray target to get a relatively smaller focal spot size. Results reveal that the focal spot size is not always isotropic around the target but it decreases as the point of observation shifts radially away from the center line of the conical X-ray target. This research will help in producing high quality X-ray images in multi-directions by properly aligning the phantoms and the radiograph tallies. PMID:25474766

  16. Dominant luminescence is not due to quantum confinement in molecular-sized silicon carbide nanocrystals.

    PubMed

    Beke, David; Szekrényes, Zsolt; Czigány, Zsolt; Kamarás, Katalin; Gali, Ádám

    2015-07-01

    Molecular-sized colloid silicon carbide (SiC) nanoparticles are very promising candidates to realize bioinert non-perturbative fluorescent nanoparticles for in vivo bioimaging. Furthermore, SiC nanoparticles with engineered vacancy-related emission centres may realize magneto-optical probes operating at nanoscale resolution. Understanding the nature of molecular-sized SiC nanoparticle emission is essential for further applications. Here we report an efficient and simple method to produce a relatively narrow size distribution of water soluble molecular-sized SiC nanoparticles. The tight control of their size distribution makes it possible to demonstrate a switching mechanism in the luminescence correlated with particle size. We show that molecular-sized SiC nanoparticles of 1-3 nm show a relatively strong and broad surface related luminescence whilst the larger ones exhibit a relatively weak band edge and structural defect luminescence with no evidence of quantum confinement effect. PMID:26055555

  17. 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.

  18. 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.

  19. Molecular Approach to Targeted Therapy for Multiple Sclerosis.

    PubMed

    Sherbet, Gajanan V

    2016-01-01

    The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems. PMID:26560895

  20. 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

  1. Identification of Molecular Targets for Predicting Colon Adenocarcinoma.

    PubMed

    Wang, Yansheng; Zhang, Jun; Li, Li; Xu, Xin; Zhang, Yong; Teng, Zhaowei; Wu, Feihu

    2016-01-01

    BACKGROUND Colon adenocarcinoma mostly happens at the junction of the rectum and is a common gastrointestinal malignancy. Accumulated evidence has indicated that colon adenocarcinoma develops by genetic alterations and is a complicated disease. The aim of this study was to screen differentially expressed miRNAs (DEMs) and genes with diagnostic and prognostic potentials in colon adenocarcinoma. MATERIAL AND METHODS In this study we screened DEMs and their target genes (DEGs) between 100 colon adenocarcinoma and normal samples in The Cancer Genome Atlas (TCGA) database by using the DEseq toolkit in Bioconductor. Then Go enrichment and KEGG pathway analysis were performed on the selected differential genes by use of the DAVID online tool. A regulation network of miRNA-gene was constructed and analyzed by Cytoscape. Finally, we performed ROC analysis of 8 miRNAs and ROC curves were drawn. RESULTS A total of 159 DEMs and 1921 DEGs were screened, and 1881 pairs of miRNA-target genes with significant negative correlations were also obtained. A regulatory network of miRNA-gene, including 60 cancer-related genes and 47 miRNAs, was successfully constructed. In addition, 5 clusters with several miRNAs regulating a set of target genes simultaneously were identified through cluster analysis. There were 8 miRNAs involved in these 5 clusters, and these miRNAs could serve as molecular biomarkers to distinguish colon adenocarcinoma and normal samples indicated by ROC analysis. CONCLUSIONS The identified 8 miRNAs were closely associated with colon adenocarcinoma, which may have great clinical value as diagnostic and prognostic biomarkers and provide new ideas for targeted therapy. PMID:26868022

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

    SciTech Connect

    Kondo, Natsuko; Department of Neurosurgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 ; 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.

  3. Resonant Laser Incisions: Molecular Targets Using the Free Electron Laser

    NASA Astrophysics Data System (ADS)

    Reinisch, Lou; Bryant, Grady; Ossoff, Robert H.

    1996-03-01

    Laser ablation of tissue for medical incisions is normally concerned with the energy absorption and the subsequent vaporization of intracellular water. Using Fourier transform infrared spectroscopy, we have identified specific non-water resonances within tissues. Then, using the Vanderbilt Free Electron Laser (wavelength tunable from 2 to 10 microns) and our Computer Assisted Surgical Techniques program (to standardize the laser delivery), we have targeted specific molecular resonances for laser incisions and tissue removal. Using both acute and chronic studies, we can map out the resonant action spectrum to improve surgical outcomes. We have modeled these ablation mechanisms and working to establish the link between these ablation mechanisms and wound healing. This work has been supported, in part, by a grant from the Department of Defense, Medical Free Electron Laser Program, ONR Grant #N000149411023.

  4. Human Fortilin Is A Molecular Target of Dihydroartemisinin

    PubMed Central

    Fujita, Takayuki; Felix, Kumar; Pinkaew, Decha; Liu, Zhihe; Fujise, Ken

    2009-01-01

    Dehydroartemisinin (DHA) is an effective anti-malaria agent. Fortilin is an anti-apoptotic molecule overexpressed in many human cancers. Here, we show that DHA binds human fortilin, increases the ubiquitination of fortilin, shortens fortilin’s half-life in a proteasome-dependent fashion, and reduces cellular levels of fortilin in varieties of cells. DHA induced DNA fragementation in U2OS cells in a fortilin-dependent manner. The fortilin-knocked-down cells were less susceptible—and fortilin-overexpressing cells more susceptible—to DHA than were wild type cells, suggesting that apoptotic effects of DHA are—at least partly—conferred through fortilin. Together, these data suggest that fortilin is a molecular target of DHA. DHA and its derivative may prove to be viable anti-cancer agents in fortilin-overexpressing cancers. (115 words) PMID:18325342

  5. 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

  6. Molecular mechanisms and proposed targets for selected anticancer gold compounds.

    PubMed

    Casini, Angela; Messori, Luigi

    2011-01-01

    Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probable biomolecular targets for a few representative gold compounds on which extensive biochemical and cellular data have been gathered. In particular, we will focus on auranofin and analogues, on gold(III) porphyrins and gold(III) dithiocarbamates. For these three families markedly distinct molecular mechanisms were recently invoked: a direct mitochondrial mechanism involving thioredoxin reductase inhibition in the case of the gold(I) complexes, the influence on some apoptotic proteins--i.e. MAPKs and Bcl-2--for gold(III) porphyrins, and the proteasome inhibition for gold(III) dithiocarbamates. In a few cases the distinct mechanisms may overlap. The general perspectives for the development of new gold compounds as effective anticancer agents with innovative modes of action are critically discussed. PMID:22039866

  7. 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. PMID:26925962

  8. 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

  9. 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

  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. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology

    PubMed Central

    Cyphert, Jaime M.; Trempus, Carol S.; Garantziotis, Stavros

    2015-01-01

    Hyaluronan signaling properties are unique among other biologically active molecules, that they are apparently not influenced by postsynthetic molecular modification, but by hyaluronan fragment size. This review summarizes the current knowledge about the generation of hyaluronan fragments of different size and size-dependent differences in hyaluronan signaling as well as their downstream biological effects. PMID:26448754

  12. Functional and physical molecular size of the chicken hepatic lectin determined by radiation inactivation and sedimentation equilibrium analysis

    SciTech Connect

    Steer, C.J.; Osborne, J.C. Jr.; Kempner, E.S. )

    1990-03-05

    Radiation inactivation and sedimentation equilibrium analysis were used to determine the functional and physical size of the chicken hepatic membrane receptor that binds N-acetylglucosamine-terminated glycoproteins. Purified plasma membranes from chicken liver were irradiated with high energy electrons and assayed for 125I-agalactoorosomucoid binding. Increasing the dose of ionizing radiation resulted in a monoexponential decay in binding activity due to a progressive loss of binding sites. The molecular mass of the chicken lectin, determined in situ by target analysis, was 69,000 +/- 9,000 Da. When the same irradiated membranes were solubilized in Brij 58 and assayed, the binding protein exhibited a target size of 62,000 +/- 4,000 Da; in Triton X-100, the functional size of the receptor was 85,000 +/- 10,000 Da. Sedimentation equilibrium measurements of the purified binding protein yielded a lower limit molecular weight of 79,000 +/- 7,000. However, the solubilized lectin was detected as a heterogeneous population of oligomers with molecular weights as high as 450,000. Addition of calcium or calcium plus N-acetylglucosamine decreased the higher molecular weight species, but the lower limit molecular weights remained invariant. Similar results were determined when the chicken lectin was solubilized in Brij 58, C12E9, or 3-((3-cholamidopropyl)dimethylammonio)-1-propane-sulfonic acid (CHAPS). Results from the present study suggest that in the plasma membrane, the functional species of the chicken hepatic lectin exists as a trimer. However, in detergent solution, the purified receptor forms a heterogeneous population of irreversible oligomers that exhibit binding activity proportional to size.

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

    PubMed Central

    Chen, Di; Milacic, Vesna; Chen, Marina Si; Wan, Sheng Biao; Lam, Wai Har; Huo, Congde; Landis-Piwowar, Kristin R.; Cui, Qiuzhi Cindy; Wali, Anil; Chan, Tak Hang; Dou, Q. Ping

    2013-01-01

    Summary 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. PMID:18228206

  14. 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].

  15. The molecular size and shape of liver glycogen.

    PubMed

    Geddes, R; Harvey, J D; Wills, P R

    1977-05-01

    The molecular-weight distribution of liver glycogen has been established from the analysis of sedimentation rates of fractions separated on sucrose density gradients and from the direct measurement of the diffusion coefficients of these fractions by laser-intensity-fluctuation spectroscopy. Hydrodynamic studies indicated that all fractions of glycogen of mol.wt.exceeding 25x10(6) had about 1.1 g of water per g of polysaccharide associated with them. The hydration and hydrodynamic behaviour of all fractions of mol.wt. exceeding 25x10(6) was similar, whereas smaller fractions behaved anomalously, indicating a substantially different overall structure. PMID:869923

  16. The molecular size and shape of liver glycogen.

    PubMed Central

    Geddes, R; Harvey, J D; Wills, P R

    1977-01-01

    The molecular-weight distribution of liver glycogen has been established from the analysis of sedimentation rates of fractions separated on sucrose density gradients and from the direct measurement of the diffusion coefficients of these fractions by laser-intensity-fluctuation spectroscopy. Hydrodynamic studies indicated that all fractions of glycogen of mol.wt.exceeding 25x10(6) had about 1.1 g of water per g of polysaccharide associated with them. The hydration and hydrodynamic behaviour of all fractions of mol.wt. exceeding 25x10(6) was similar, whereas smaller fractions behaved anomalously, indicating a substantially different overall structure. PMID:869923

  17. 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

  18. 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

  19. 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. PMID:25033959

  20. 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

  1. Molecular targeting of intracellular compartments specifically in cancer cells.

    PubMed

    Pandya, Hetal; Gibo, Denise M; Debinski, Waldemar

    2010-05-01

    We have implemented a strategy in which a genetically engineered, single-chain protein specifically recognizes cancer cells and is trafficked to a targeted subcellular compartment, such as the nucleus. The recombinant protein termed IL-13.E13K-D2-NLS has a triple functional property: (1) it binds a cancer-associated receptor, interleukin 13 receptor alpha 2 (IL-13Rα2), using modified IL-13 ligand, IL-13.E13K; (2) it exports its C-terminal portion out of the endosomal compartment using Pseudomonas aeruginosa exotoxin A (PE) translocation domain (D2); and (3) it travels to and accumulates in the nucleus guided by the nuclear localization signal (NLS). Here, we have demonstrated that this protein is transported into the brain tumor cells' nucleus, using 3 different methods of protein conjugation to dyes for the purpose of direct visualization of the protein's intracellular trafficking. IL-13.E13K-D2-NLS, and not the controls such as IL-13.E13K-D2, IL-13.E13K-NLS, or IL-13.E13K, accumulated in nuclei very efficiently, which increased with the time the cells were exposed to the protein. Also, IL-13.E13K-D2-NLS did not exhibit nuclear transport in cells with low expression levels of IL-13Rα2. Thus, it is possible to recognize cancer cells through their specific receptors and deliver a conjugated protein that travels specifically to the nucleus. Hence, our molecular targeting strategy succeeded in generating a single-chain proteinaceous agent capable of delivering drugs/labels needed to be localized to the cells' nuclei or potentially any other subcellular compartment, for their optimal efficacy or ability to exert their specific action. PMID:20740056

  2. Molecular Targeting of Intracellular Compartments Specifically in Cancer Cells

    PubMed Central

    Pandya, Hetal; Gibo, Denise M.; Debinski, Waldemar

    2010-01-01

    We have implemented a strategy in which a genetically engineered, single-chain protein specifically recognizes cancer cells and is trafficked to a targeted subcellular compartment, such as the nucleus. The recombinant protein termed IL-13.E13K-D2-NLS has a triple functional property: (1) it binds a cancer-associated receptor, interleukin 13 receptor alpha 2 (IL-13Rα2), using modified IL-13 ligand, IL-13.E13K; (2) it exports its C-terminal portion out of the endosomal compartment using Pseudomonas aeruginosa exotoxin A (PE) translocation domain (D2); and (3) it travels to and accumulates in the nucleus guided by the nuclear localization signal (NLS). Here, we have demonstrated that this protein is transported into the brain tumor cells’ nucleus, using 3 different methods of protein conjugation to dyes for the purpose of direct visualization of the protein’s intracellular trafficking. IL-13.E13K-D2-NLS, and not the controls such as IL-13.E13K-D2, IL-13.E13K-NLS, or IL-13.E13K, accumulated in nuclei very efficiently, which increased with the time the cells were exposed to the protein. Also, IL-13.E13K-D2-NLS did not exhibit nuclear transport in cells with low expression levels of IL-13Rα2. Thus, it is possible to recognize cancer cells through their specific receptors and deliver a conjugated protein that travels specifically to the nucleus. Hence, our molecular targeting strategy succeeded in generating a single-chain proteinaceous agent capable of delivering drugs/labels needed to be localized to the cells’ nuclei or potentially any other subcellular compartment, for their optimal efficacy or ability to exert their specific action. PMID:20740056

  3. 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

  4. Fluorescence characteristics of size-fractionated dissolved organic matter: implications for a molecular assembly based structure?

    PubMed

    Romera-Castillo, Cristina; Chen, Meilian; Yamashita, Youhei; Jaffé, Rudolf

    2014-05-15

    Surface freshwater samples from Everglades National Park, Florida, were used to investigate the size distributions of natural dissolved organic matter (DOM) and associated fluorescence characteristics along the molecular weight continuum. Samples were fractionated using size exclusion chromatography (SEC) and characterized by spectroscopic means, in particular Excitation-Emission Matrix fluorescence modeled with parallel factor analysis (EEM-PARAFAC). Most of the eight components obtained from PARAFAC modeling were broadly distributed across the DOM molecular weight range, and the optical properties of the eight size fractions for all samples studied were quite consistent among each other. Humic-like components presented a similar distribution in all the samples, with enrichment in the middle molecular weight range. Some variability in the relative distribution of the different humic-like components was observed among the different size fractions and among samples. The protein like fluorescence, although also generally present in all fractions, was more variable but generally enriched in the highest and lowest molecular weight fractions. These observations are in agreement with the hypothesis of a supramolecular structure for DOM, and suggest that DOM fluorescence characteristics may be controlled by molecular assemblies with similar optical properties, distributed along the molecular weight continuum. This study highlights the importance of studying the molecular structure of DOM on a molecular size distribution perspective, which may have important implications in understanding the environmental dynamics such materials. PMID:24602859

  5. [Molecular target drugs for AML--current state and prospects for the future].

    PubMed

    Kohgo, Yutaka; Inamura, Junki; Shindo, Motohiro

    2014-06-01

    Acute myeloblastic leukemia (AML) is a disease which may be completely cured by intensive chemotherapy or stem cell transplantation. However, the prognoses are poor in elderly, refractory or recurrence cases. Molecular targeted drugs have been expected to improve the prognoses of patients with various cancers, but there are few kinds of molecular target drugs for AML. On the other hand, excellent drug exists such as tretinoin for acute promyelocytic leukemia. Molecular mechanisms have been elucidated in AML cells, and the molecules which can be the good target of the treatment have been identified. Novel molecular target drugs are also expected. PMID:25016805

  6. Adrenaline and noradrenaline: protectors against oxidative stress or molecular targets?

    PubMed

    Álvarez-Diduk, Ruslán; Galano, Annia

    2015-02-26

    Density functional theory was used to investigate the potential role of neurotransmitters adrenaline and noradrenaline regarding oxidative stress. It is predicted that they can be efficient as free radical scavengers both in lipid and aqueous media, with the main reaction mechanism being the hydrogen transfer and the sequential proton loss electron transfer, respectively. Despite the polarity of the environment, adrenaline and noradrenaline react with (•)OOH faster than Trolox, which suggests that they are better peroxyl radical scavengers than the reference compound. Both catecholamines are also proposed to be capable of efficiently inhibiting the oxidative stress induced by copper(II)-ascorbate mixtures, and the (•)OH production via Haber-Weiss reaction, albeit the effects on the later are only partial. They exert such beneficial effects by sequestering Cu(II) ions. In summary, these catecholamines can be capable of reducing oxidative stress, by scavenging free radicals and by sequestering metal ions. However, at the same time they might lose their functions in the process due to the associated structural modifications. Consequently, adrenaline and noradrenaline can be considered as both protectors and molecular targets of oxidative stress. Fortunately, under the proper conditions, both catecholamines can be regenerated to their original form so their functions are restored. PMID:25646569

  7. Molecular Targets of Dietary Polyphenols with Anti-inflammatory Properties

    PubMed Central

    Yoon, Joo-Heon

    2005-01-01

    There is persuasive epidemiological and experimental evidence that dietary polyphenols have anti-inflammatory activity. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have long been used to combat inflammation. Recently, cyclooxygenase (COX) inhibitors have been developed and recommended for treatment of rheumatoid arthritis (RA) and osteoarthritis (OA). However, two COX inhibitors have been withdrawn from the market due to unexpected side effects. Because conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of many inflammatory diseases, there is an urgent need to find safer compounds and to develop mechanism-based approaches for the management of these diseases. Polyphenols are found in many dietary plant products, including fruits, vegetables, beverages, herbs, and spices. Several of these compounds have been found to inhibit the inflammation process as well as tumorigenesis in experimental animals; they can also exhibit potent biological properties. In addition, epidemiological studies have indicated that populations who consume foods rich in specific polyphenols have lower incidences of inflammatory disease. This paper provides an overview of the research approaches that can be used to unravel the biology and health effects of polyphenols. Polyphenols have diverse biological effects, however, this review will focus on some of the pivotal molecular targets that directly affect the inflammation process. PMID:16259055

  8. 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.

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

    PubMed

    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

  10. 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

  11. 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.

  12. Molecular diversity of riverine alkaline-extractable sediment organic matter and its linkages with spectral indicators and molecular size distributions.

    PubMed

    He, Wei; Chen, Meilian; Park, Jae-Eun; Hur, Jin

    2016-09-01

    Few studies have been conducted to examine the spatial heterogeneity of riverine sediment organic matter (SOM) at the molecular level. The present study explored the chemical and molecular heterogeneity of alkaline-extractable SOM from riverine sediments via multiple analytical tools including molecular composition, absorption and fluorescence spectra, and molecular size distributions. The riverine SOM revealed complex and diverse characteristics, exhibiting a great number of non-redundant formulas and high spatial variations. The molecular diversity was more pronounced for the sediments affected by a higher degree of anthropogenic activities. Unlike the cases of aquatic dissolved organic matter, highly-unsaturated structures with oxygen (HUSO) of SOM were more associated with the spectral and size features of humic-like (or terrestrial) substances than aromatic molecules were, cautioning the interpretation of the SOM molecules responsible for apparent indicators. Noting that a higher detection rate (DR) produces fewer common molecules, the common molecules of 23 different SOMs were determined at a reasonable DR value of 0.35, which accounted for a small portion (5.8%) of all detected molecules. They were mainly CHO compounds (>98%), which positively correlated with spectral indicators of biological production. Despite the low abundance, however, the ratios of aromatic to aliphatic substances could be indexed to classify the common molecules into several geochemical molecular groups with different degrees of the associations with the apparent spectral and size indicators. PMID:27192357

  13. 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.

  14. 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. PMID:16530755

  15. Molecular and Cell Signaling Targets for PTSD Pathophysiology and Pharmacotherapy

    PubMed Central

    Hauger, Richard L.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.; Lohr, James B.; Braun, Sandra; Oakley, Robert H.

    2012-01-01

    The reasons for differences in vulnerability or resilience to the development of posttraumatic stress disorder (PTSD) are unclear. Here we review key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. Sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax have been implicated in PTSD pathophysiology. Furthermore, Akt, NFκB, MKP-1, and p11, which are G protein-coupled receptor (GPCR) pathway molecules, can promote or prevent sustained high anxiety and depressive-like behavior following severe stress. Agonist-induced activation of the corticotropin-releasing factor CRF1 receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF1 receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF1 receptor single nucleotide polymorphisms (SNPs) can confer susceptibility or resilience to childhood trauma while a SNP for the PAC1 receptor, another class B1 GPCR, has been linked genetically to PTSD. GRK3 phosphorylation of the CRF1 receptor protein and subsequent binding of βarrestin2 rapidly terminate Gs-coupled CRF1 receptor signaling by homologous desensitization. A deficient GRK-βarrestin2 mechanism would result in excessive CRF1 receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF1 receptor antagonists are effective prophylactic agents when administered immediately after trauma. βarrestin2-biased agonists for CRF receptors and possibly other GPCRs implicated in PTSD, however, may prove to be novel pharmacotherapy with greater selectivity and therapeutic efficacy. PMID:22122881

  16. 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…

  17. Controllable Self-Assembly of RNA Tetrahedrons with Precise Shape and Size for Cancer Targeting.

    PubMed

    Li, Hui; Zhang, Kaiming; Pi, Fengmei; Guo, Sijin; Shlyakhtenko, Luda; Chiu, Wah; Shu, Dan; Guo, Peixuan

    2016-09-01

    RNA tetrahedral nanoparticles with two different sizes are successfully assembled by a one-pot bottom-up approach with high efficiency and thermal stability. The reported design principles can be extended to construct higher-order polyhedral RNA architectures for various applications such as targeted cancer imaging and therapy. PMID:27322097

  18. 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.

  19. 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…

  20. 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

  1. 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

  2. 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

  3. Uniform-sized molecularly imprinted polymer for (S)-naproxen selectively modified with hydrophilic external layer.

    PubMed

    Haginaka, J; Takehira, H; Hosoya, K; Tanaka, N

    1999-07-23

    A uniform-sized molecularly imprinted polymer (MIP) for (S)-naproxen selectively modified with hydrophilic external layer has been prepared. First, the molecularly imprinted polymer for (S)-naproxen was prepared using 4-vinylpyridine and ethylene glycol dimethacrylate (EDMA) as a functional monomer and cross-linker, respectively, by a multi-step swelling and thermal polymerization method. Next, a 1:1 mixture of glycerol monomethacrylate (GMMA) and glycerol dimethacrylate (GDMA) was used for hydrophilic surface modification, and it was added directly to the molecularly imprinted polymer for (S)-naproxen 4 h after the start of molecular imprinting. The retention factors of all solutes tested were decreased with the surface modified molecularly imprinted polymer, compared with the unmodified molecularly imprinted polymer. However, chiral recognition of racemic naproxen was attained with the surface modified molecularly imprinted polymer as well as the unmodified molecularly imprinted polymer. Further, bovine serum albumin was completely recovered from the surface modified molecularly imprinted polymer. These results revealed that the chiral recognition sites of (S)-naproxen remained unchanged with hydrophilic surface modification, and that the molecularly imprinted polymer for (S)-naproxen was selectively modified with hydrophilic external layer. Preliminary results reveal that the surface modified molecularly imprinted polymer could be applicable to direct serum injection assays of (S)-naproxen. PMID:10457431

  4. Effect of sputtering target's grain size on the sputtering yield, particle size and coercivity (Hc) of Ni and Ni20Al thin films

    NASA Astrophysics Data System (ADS)

    Reza, M.; Sajuri, Z.; Yunas, J.; Syarif, J.

    2016-02-01

    Researches on magnetic thin films concentrated mainly on optimizing the sputtering parameters to obtain the desired thin film's properties. However, the effect of the sputtering target's properties towards the thin film's properties is not well established. This study is focused on analysing the effect of sputtering target's grain size towards the sputtering yield, particle size and the magnetic coercivity (Hc) of thin film. Two sets of sputtering targets; pure Ni (magnetic) and Ni20Al (at.%) (non-magnetic) were prepared. Each target has 2 sets of samples with different grain sizes; (a) 30 to 50μm and (b) 80 to 100μm. Thin films from each target were sputtered onto glass substrates under fixed sputtering parameters. The initial results suggested that the sputtering target's grain size has significant effect on the thin film's sputtering yield, particle size and Hc. Sputtering target with smaller grain size has 12% (pure Ni) to 60% (Ni20Al) higher sputtering yield, which produces thin films with smaller particle size and larger Hc value. These initial findings provides a basis for further magnetic thin film research, particularly for the seed layer in hard disk drive (HDD) media, where seed layer with smaller particle size is essential in reducing signal-to-noise ratio (SNR).

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

    PubMed

    Perilla, Juan R; Hadden, Jodi A; Goh, Boon Chong; Mayne, Christopher G; Schulten, Klaus

    2016-05-19

    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

  6. 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

  7. Advanced CPMAS-13C NMR techniques for molecular characterization of size-separated fractions from a soil humic acid.

    PubMed

    Conte, Pellegrino; Spaccini, Riccardo; Piccolo, Alessandro

    2006-09-01

    A humic acid extracted from a volcanic soil was subjected to preparative high-performance size-exclusion chromatography (HPSEC) to reduce its molecular complexity and eleven different size fractions were obtained. Cross-polarization magic-angle spinning 13C NMR (CPMAS 13C NMR) analysis performed with variable contact-time (VCT) pulse sequences showed that the largest molecular-size fractions contained aromatic, alkyl, and carbohydrate-like components. The carbohydrate-like content and the alkyl chain length seemed to decrease with decreasing molecular size. Progressive reduction of aromatic carbon atoms was also observed with decreasing molecular size of the separated fractions. Mathematical treatment of the results from VCT experiments enabled cross polarization (T (CH)) and proton spin-lattice relaxation (T(1rho)(H)) times to be related to structural differences among the size fractions. The conformational distribution indicated that the eleven size fractions could be allocated to two main groups. The first group, with larger nominal molecular sizes, was characterized by molecular domains with slower local molecular motion. The second group of size fractions, with smaller nominal molecular sizes, was characterized by a larger number of molecular domains with faster local molecular motion. The T (CH) and (T(1rho)(H)) values suggested that either condensed or strongly associated aromatic systems were predominant in the size fractions with the largest apparent molecular dimensions. PMID:16896626

  8. 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. PMID:26794765

  9. 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

  10. Sub-2 nm size and density tunable platinum nanoparticles using room temperature tilted-target sputtering.

    PubMed

    Ramalingam, Balavinayagam; Mukherjee, Somik; Mathai, Cherian J; Gangopadhyay, Keshab; Gangopadhyay, Shubhra

    2013-05-24

    This paper describes a tilted-target RF magnetron sputter deposition system to grow nanoparticles in a controlled way. With detailed characterization of ultra-high density (up to 1.1 × 10¹³ cm⁻²) and ultra-small size Pt nanoparticles (0.5-2 nm), it explains their growth and crystalline properties on amorphous Al₂O₃ thin films. It is shown that Pt nanoparticle size and number density can be precisely engineered by varying selected experimental parameters such as target angle, sputtering power and time of deposition to control the energy of the metal atoms in the deposition flux. Based on rate equation modelling of nanoparticle growth, three distinct growth regimes, namely nucleation dependent, coalescence dependent and agglomeration dependent regimes, were observed. The correlation between different nanoparticle growth regimes and the consequent crystal structure transformation, non-crystalline clusters → single crystalline nanoparticles → polycrystalline islands, is also discussed. PMID:23609435

  11. Effects of target size on the comparison of photon and charged particle dose distributions

    SciTech Connect

    Phillips, M.H.; Frankel, K.A.; Tjoa, T.; Lyman, J.T.; Fabrikant, J.I.; Levy, R.P.

    1989-12-01

    The work presented here is part of an ongoing project to quantify and evaluate the differences in the use of different radiation types and irradiation geometries in radiosurgery. We are examining dose distributions for photons using the Gamma Knife'' and the linear accelerator arc methods, as well as different species of charged particles from protons to neon ions. A number of different factors need to be studied to accurately compare the different modalities such as target size, shape and location, the irradiation geometry, and biological response. This presentation focuses on target size, which has a large effect on the dose distributions in normal tissue surrounding the lesion. This work concentrates on dose distributions found in radiosurgery, as opposed to those usually found in radiotherapy. 5 refs., 2 figs.

  12. 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.

  13. Size-dependent elastic properties of crystalline polymers via a molecular mechanics model

    NASA Astrophysics Data System (ADS)

    Zhao, Junhua; Guo, Wanlin; Zhang, Zhiliang; Rabczuk, Timon

    2011-12-01

    An analytical molecular mechanics model is developed to obtain the size-dependent elastic properties of crystalline polyethylene. An effective "stick-spiral" model is adopted in the polymer chain. Explicit equations are derived from the Lennard-Jones potential function for the van der Waals force between any two polymer chains. By using the derived formulas, the nine size-dependent elastic constants are investigated systematically. The present analytical results are in reasonable agreement with those from present united-atom molecular dynamics simulations. The established analytical model provides an efficient route for mechanical characterization of crystalline polymers and related materials toward nanoelectromechanical applications.

  14. New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions.

    PubMed

    Chuma, Makoto; Terashita, Katsumi; Sakamoto, Naoya

    2015-10-01

    Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-mesenchymal-epithelial transition factor-1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents. PMID:25472913

  15. Electron Beam-Target Interaction and Spot Size Stabilization in Flash X-Ray Radiography*

    NASA Astrophysics Data System (ADS)

    Kwan, Thomas J. T.

    1999-11-01

    The Dual Axis Radiographic Hydro-Test (DARHT) facility is one of the most important capabilities in science based stockpile stewardship program of the US Department of Energy. DARHT uses an intense relativistic electron beam (20 MeV, 2-4 kA) to provide the necessary dose and a very small radiation spot size ( 1 mm) to achieve the desired optical resolution. Linear induction accelerator technology and electron beam diode technology can produce beams with the desirable characteristics. However, the high current densities at the converter target will cause strong nonlinear effects, which can adversely influence the radiographic performance. Over a time scale of tens of nanoseconds, intense space charge fields of the electron beam will extract positively charged ions from the vaporized target. These ions will partially neutralize the electron beam, reducing its Coulomb self-repulsive force. Initially the beam will pinch near the target, giving a favorable reduction in spot size but possibly degrading the beam quality. The ion column will then propagate upstream, moving the location of the pinch away from the target. The beam will pinch on axis and expand, producing a progressive increase in spot size as the pinch migrates upstream. This phenomenon can severely degrade resolution. In multiple-pulse applications where longer time scale phenomena become important, the expanding plasma plume of the vaporized target material can cause disruption of subsequent electron beam pulses. In this study, we investigate the physics of beam transport and explore methods for mitigating the undesirable effects. Theoretical models have been developed and validated against available experimental data from the Los Alamos Integrated Test Stand (ITS). It is shown that ion propagation can be suppressed by applying a negative bias potential to the target. The ions then become trapped in the target vicinity and actually reduce the spot size rather than increasing it due to the additional ion

  16. Time-dependent Gas-liquid Interaction in Molecular-sized Nanopores

    PubMed Central

    Sun, Yueting; Li, Penghui; Qiao, Yu; Li, Yibing

    2014-01-01

    Different from a bulk phase, a gas nanophase can have a significant effect on liquid motion. Herein we report a series of experimental results on molecular behaviors of water in a zeolite β of molecular-sized nanopores. If sufficient time is provided, the confined water molecules can be “locked” inside a nanopore; otherwise, gas nanophase provides a driving force for water “outflow”. This is due to the difficult molecular site exchanges and the relatively slow gas-liquid diffusion in the nanoenvironment. Depending on the loading rate, the zeolite β/water system may exhibit either liquid-spring or energy-absorber characteristics. PMID:25293525

  17. 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.

  18. 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

  19. RET-targeting molecular stratified non-small-cell lung cancers

    PubMed Central

    2013-01-01

    Recent advances in lung cancer genomics have successfully characterized therapeutic targets of lung cancer. RET fusion gene products are among the newest target molecules for lung adenocarcinoma. Preclinical findings and preliminary reports regarding potential tumor control by RET-targeting multi-kinase inhibitors encourage further clinical trials. The infrequent prevalence of RET fusion gene-positive cases may be a major obstacle hindering the development of RET-targeted therapy. Thus, it is necessary to recruit appropriate participants for trials to develop an efficient RET fusion gene detection system to achieve targeted therapy for lung adenocarcinomas stratified by this molecular target. PMID:25806272

  20. 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

  1. Selection of molecular targets for drug development against trypanosomatids.

    PubMed

    Smirlis, Despina; Soares, Milena Botelho Pereira

    2014-01-01

    Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design. PMID:24264240

  2. 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

  3. Laser ablation of a platinum target in water. II. Ablation rate and nanoparticle size distributions

    SciTech Connect

    Nichols, William T.; Sasaki, Takeshi; Koshizaki, Naoto

    2006-12-01

    This is the second in a series of three papers examining nanomaterial formation in laser ablation in liquids (LAL). Here we study the effect of the laser wavelength and fluence on the mass yield and size distribution of nanoparticles prepared by laser ablation of a platinum target immersed in water. For all wavelengths tested, laser fluences in the range of 10-70 J/cm{sup 2} resulted in spheroidal, nonagglomerated platinum nanoparticles with sizes ranging from 1 to 30 nm. Nanoparticle size distributions are found to be composed of two modes that are attributed to thermal vaporization and explosive boiling mechanisms. The peak of the smaller size mode remains nearly constant at 3 nm for all laser conditions, which is suggested to be due to the strong confinement of the vapor plume by the liquid. The larger size mode peaks in the range of 5-15 nm with a population that is strongly dependent on the laser parameters. It is concluded that changes in the mean size reported in many earlier studies on LAL of metal targets are a result of the relative quantity of nanoparticles from each mechanism rather than direct control over the ablation process. Additionally, it was observed that the yield of platinum nanoparticles was significantly larger for 1064 nm wavelength at fluences greater than 10 J/cm{sup 2}. The maximum ablation rate was approximately 4.4 mg/h, with an estimated ablation and collection efficiency of 0.9 {mu}g/J. Dependence of the mass yield on wavelength and fluence is seen to be dependent primarily on the extent of the explosive mechanism.

  4. Targeting molecular resistance in castration-resistant prostate cancer.

    PubMed

    Chandrasekar, Thenappan; Yang, Joy C; Gao, Allen C; Evans, Christopher P

    2015-01-01

    Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes. PMID:26329698

  5. Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies.

    PubMed

    Oda, Katsutoshi; Ikeda, Yuji; Kashiyama, Tomoko; Miyasaka, Aki; Inaba, Kanako; Fukuda, Tomohiko; Asada, Kayo; Sone, Kenbun; Wada-Hiraike, Osamu; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki

    2016-07-01

    Recent developments in genomic analysis have unveiled the key signaling pathways in human cancer. However, only a limited number of molecular-targeted drugs are applicable for clinical use in gynecologic malignancies. TP53 signaling and phosphatidylinositol 3 kinase pathways are frequently mutated in cancer, and have received much attention as molecular targets in human cancers. In this review, we mainly focus on the functions of these pathways, and discuss the molecular-targeted drugs under clinical trials. The molecular-targeted drugs described in this review include dual phosphatidylinositol 3 kinase/mTOR inhibitors (NVP-BEZ235, DS-7423, SAR245409), an mTOR inhibitor (everolimus), an MEK inhibitor (pimasertib), an autophagy inhibitor (chloroquine), a cyclin-dependent kinases 4/6 inhibitor (PD0332991), and a poly (ADP-ribose) polymerase inhibitor (olaparib). PMID:27094348

  6. Progress of Molecular Targeted Therapies for Advanced Renal Cell Carcinoma

    PubMed Central

    Santoni, Matteo; Amantini, Consuelo; Burattini, Luciano; Berardi, Rossana; Santoni, Giorgio; Cascinu, Stefano; Muzzonigro, Giovanni

    2013-01-01

    Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis. VEGF expression in metastatic renal cell carcinoma (mRCC) is mostly regulated by hypoxia, predominantly via the hypoxia-induced factor (HIF)/Von Hippel-Lindau (VHL) pathway. Advances in our knowledge of VEGF role in tumor angiogenesis, growth, and progression have permitted development of new approaches for the treatment of mRCC, including several agents targeting VEGF and VEGF receptors: tyrosine kinase pathway, serine/threonine kinases, α5β1-integrin, deacetylase, CD70, mammalian target of rapamycin (mTOR), AKT, and phosphatidylinositol 3′-kinase (PI3K). Starting from sorafenib and sunitinib, several targeted therapies have been approved for mRCC treatment, with a long list of agents in course of evaluation, such as tivozanib, cediranib, and VEGF-Trap. Here we illustrate the main steps of tumor angiogenesis process, defining the pertinent therapeutic targets and the efficacy and toxicity profiles of these new promising agents. PMID:24093097

  7. Transcription factors: molecular targets for prostate cancer intervention by phytochemicals.

    PubMed

    Kaur, Manjinder; Agarwal, Rajesh

    2007-06-01

    With increasing incidence of cancer at most of the sites, and growing economic burden and associated psychological and emotional trauma, it is becoming clearer that more efforts are needed for cancer cure. Since most of the chemotherapeutic drugs are non-selective because they are also toxic to the normal cells, new and improved strategies are needed that selectively target the killing of cancer cells. Since aberrant activation of numerous signaling pathways is a key element of cancer cell survival and growth, blocking all of them is not that practical, which leads to the step where most of them commonly converge; the transcription factors. Recent research efforts, therefore, are also directed on targeting the activity and activation of transcription factors, which ultimately control the expression of genes that are involved in almost all aspects of cell biology. One class of agents that is becoming increasingly successful, not only in targeting signaling cascades, but also transcription factors is phytochemicals present in diet and those consumed as supplement. The added advantage with these agents is that they are mostly non-toxic when compared to chemotherapeutic agents. This review focuses on the efficacy of various phytochemicals in targeting transcription factors such as AR, Sp1, STATs, E2F, Egr1, c-Myc, HIF-1 alpha, NF-kappaB, AP-1, ETS2, GLI and p53 in the context of prostate cancer intervention. PMID:17979630

  8. Imaging of Isotopically Enhanced Molecular Targeting Agents Final Report

    SciTech Connect

    Quong, J N

    2004-02-19

    The goal of this project is to develop experimental and computational protocols to use SIMS to image the chemical composition of biological samples, focusing on optimizing sample preparation protocols and developing multivariate data analysis methods. Our results on sample preparation, molecular imaging, and multivariate analysis have been presented at several meeting abstracts (UCRL151797ABS, UCRL151797ABSREV1, UCRL151426ABS, UCRL201277, UCRL154757). A refereed paper describing our results for sample preparation and molecular imaging of various endogenous biomolecules as well as the mutagen PhIP has been accepted for publication (UCRL-JC-151797). We are also preparing two additional papers describing our multivariate analysis methods to analyze spectral data. As these papers have not been submitted, their content is included in this final report.

  9. 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. PMID:27058292

  10. 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. PMID:26952466

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

    PubMed

    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 identified 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

  12. 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

  13. Common molecular weight of the androgen receptor monomer in different target tissues

    SciTech Connect

    Johnson, M.P.; Young, C.Y.F.; Rowley, D.R.; Tindall, D.J.

    1987-06-02

    Previously reported molecular weights for the monomeric steroid binding subunit of the androgen receptor protein have ranged from 25,000 to 167,000. The molecular weight appeared to vary among different species and target organs, as well as between different investigators. This study has examined androgen receptors from a diverse group of organs and species to determine whether these tissues share a common monomeric form. Gel filtration revealed peaks of specific (/sup 3/H)dihydrotestosterone binding activity corresponding to Stokes radii of 54, 33, and 20 A in cytosols from several tissues. Phosphocellulose chromatography diminished the appearance of the smaller androgen receptor forms and facilitated the appearance of the larger 54-A form. Mixing experiments suggested that phosphocellulose was stabilizing the 54-A form by binding putative proteases which cleave this larger form. Methods were developed to generate homogeneous preparations of a given androgen receptor size for comparative study. Sucrose density gradient analysis showed sedimentation coefficients of 4.5-5.0, 3.5-4.0, and 2.5-3.0 S, respectively. The corresponding calculated molecular weights were 109,000-121,000, 52,000-59,000, and 22,000-27,000. Scatchard analysis of each of these androgen receptor forms demonstrated very similar affinity for (/sup 3/H)dihydrotestosterone. Extensively purified preparations of androgen receptor from R3327 tumor contained varying amounts of the three receptor forms even though molybdate and phosphocellulose were used to stabilize the androgen receptor protein during purification. It is concluded that androgen receptors from a variety of tissues share a common monomeric subunit and that stabilization is necessary during analytical and purification procedures to prevent cleavage of the monomer by endogenous proteases.

  14. Target Molecular Simulations of RecA Family Protein Filaments

    PubMed Central

    Su, Zhi-Yuan; Lee, Wen-Jay; Su, Wan-Sheng; Wang, Yeng-Tseng

    2012-01-01

    Modeling of the RadA family mechanism is crucial to understanding the DNA SOS repair process. In a 2007 report, the archaeal RadA proteins function as rotary motors (linker region: I71-K88) such as shown in Figure 1. Molecular simulations approaches help to shed further light onto this phenomenon. We find 11 rotary residues (R72, T75-K81, M84, V86 and K87) and five zero rotary residues (I71, K74, E82, R83 and K88) in the simulations. Inclusion of our simulations may help to understand the RadA family mechanism. PMID:22837683

  15. Integrative systems medicine approaches to identify molecular targets in lymphoid malignancies.

    PubMed

    Frazzi, Raffaele; Auffray, Charles; Ferrari, Angela; Filippini, Perla; Rutella, Sergio; Cesario, Alfredo

    2016-01-01

    Although survival rates for lymphoproliferative disorders are steadily increasing both in the US and in Europe, there is need for optimizing front-line therapies and developing more effective salvage strategies. Recent advances in molecular genetics have highlighted the biological diversity of lymphoproliferative disorders. In particular, integrative approaches including whole genome sequencing, whole exome sequencing, and transcriptome or RNA sequencing have been instrumental to the identification of molecular targets for treatment. Herein, we will discuss how genomic, epigenomic and proteomic approaches in lymphoproliferative disorders have supported the discovery of molecular lesions and their therapeutic targeting in the clinic. PMID:27580852

  16. 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

  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. 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. PMID:23651790

  19. 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

  20. 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).

  1. Joint detection and tracking of size-varying infrared targets based on block-wise sparse decomposition

    NASA Astrophysics Data System (ADS)

    Li, Miao; Lin, Zaiping; Long, Yunli; An, Wei; Zhou, Yiyu

    2016-05-01

    The high variability of target size makes small target detection in Infrared Search and Track (IRST) a challenging task. A joint detection and tracking method based on block-wise sparse decomposition is proposed to address this problem. For detection, the infrared image is divided into overlapped blocks, and each block is weighted on the local image complexity and target existence probabilities. Target-background decomposition is solved by block-wise inexact augmented Lagrange multipliers. For tracking, label multi-Bernoulli (LMB) tracker tracks multiple targets taking the result of single-frame detection as input, and provides corresponding target existence probabilities for detection. Unlike fixed-size methods, the proposed method can accommodate size-varying targets, due to no special assumption for the size and shape of small targets. Because of exact decomposition, classical target measurements are extended and additional direction information is provided to improve tracking performance. The experimental results show that the proposed method can effectively suppress background clutters, detect and track size-varying targets in infrared images.

  2. Advances in molecular imaging: targeted optical contrast agents for cancer diagnostics

    PubMed Central

    Hellebust, Anne; Richards-Kortum, Rebecca

    2012-01-01

    Over the last three decades, our understanding of the molecular changes associated with cancer development and progression has advanced greatly. This has led to new cancer therapeutics targeted against specific molecular pathways; such therapies show great promise to reduce mortality, in part by enabling physicians to tailor therapy for patients based on a molecular profile of their tumor. Unfortunately, the tools for definitive cancer diagnosis – light microscopic examination of biopsied tissue stained with nonspecific dyes – remain focused on the analysis of tissue ex vivo. There is an important need for new clinical tools to support the molecular diagnosis of cancer. Optical molecular imaging is emerging as a technique to help meet this need. Targeted, optically active contrast agents can specifically label extra-and intracellular biomarkers of cancer. Optical images can be acquired in real time with high spatial resolution to image-specific molecular targets, while still providing morphologic context. This article reviews recent advances in optical molecular imaging, highlighting the advances in technology required to improve early cancer detection, guide selection of targeted therapy and rapidly evaluate therapeutic efficacy. PMID:22385200

  3. 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.

  4. 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.

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

    PubMed

    Kleman-Leyer, K; Agosin, E; Conner, A H; Kirk, T K

    1992-04-01

    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

  6. 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

  7. Molecular Approaches To Target GPCRs in Cancer Therapy

    PubMed Central

    Innamorati, Giulio; Valenti, Maria Teresa; Giovinazzo, Francesco; Carbonare, Luca Dalle; Parenti, Marco; Bassi, Claudio

    2011-01-01

    Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells' coexistence, cancer has to deceive cell-cell communication in order to grow and spread. GPCRs play a critical role in this process. Despite the fact that GPCRs represent one of the most common drug targets, current medical practice includes only a few anticancer compounds directly acting on their signaling. Many approaches can be envisaged to target GPCRs involved in oncology. Beyond interfering with GPCRs signaling by using agonists or antagonists to prevent cell proliferation, favor apoptosis, induce maturation, prevent migration, etc., the high specificity of the interaction between the receptors and their ligands can be exploited to deliver toxins, antineoplastic drugs or isotopes to transformed cells. In this review we describe the strategies that are in use, or appear promising, to act directly on GPCRs in the fight against neoplastic transformation and tumor progression.

  8. Metastatic cancer stem cells: new molecular targets for cancer therapy.

    PubMed

    Leirós, G J; Balañá, M E

    2011-11-01

    The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge. PMID:21470128

  9. ROS1 Kinase Inhibitors for Molecular-Targeted Therapies.

    PubMed

    Al-Sanea, M M; Abdelazem, A Z; Park, B S; Yoo, K H; Sim, T; Kwon, Y J; Lee, S H

    2016-01-01

    ROS1 is a pivotal transmembrane receptor protein tyrosine kinase which regulates several cellular processes like apoptosis, survival, differentiation, proliferation, cell migration, and transformation. There is increasing evidence supporting that ROS1 plays an important role in different malignancies including glioblastoma, colorectal cancer, gastric adenocarcinoma, inflammatory myofibroblastic tumor, ovarian cancer, angiosarcoma, and non small cell lung cancer; thus, ROS1 has become a potential drug discovery target. ROS1 shares about 49% sequence homology with ALK primary structure; therefore, wide range of ALK kinase inhibitors have shown in vitro inhibitory activity against ROS1 kinase. After Crizotinib approval by FDA for the management of ALK-rearranged lung cancer, ROS1-positive tumors have been focused. Although significant advancements have been achieved in understanding ROS1 function and its signaling pathways plus recent discovery of small molecules modulating ROS1 protein, a vital need of medicinal chemistry efforts is still required to produce selective and potent ROS1 inhibitors as an important therapeutic strategy for different human malignancies. This review focuses on the current knowledge about different scaffolds targeting ROS1 rearrangements, methods to synthesis, and some biological data about the most potent compounds that have delivered various scaffold structures. PMID:26438251

  10. Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis.

    PubMed

    Corcoran, Niall M; Clarkson, Michael J; Stuchbery, Ryan; Hovens, Christopher M

    2016-07-01

    The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair-deficient tumors with drugs that take advantage of the fundamental differences between normal repair-proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132-7. ©2016 AACR. PMID:27169997

  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 targets of natural health products in arthritis.

    PubMed

    Khalifé, Sarah; Zafarullah, Muhammad

    2011-01-01

    Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) consume 'natural health products' (NHPs) whose therapeutic efficacy, toxicity and mechanisms of action are poorly understood. In a previous issue of Arthritis Research and Therapy, Haqqi and colleagues characterized IL-1-activated mitogen-activated protein kinase kinase 3 (MKK3) and p38-mitogen-activated protein kinase (MAPK) isoforms in human OA chondrocytes. The cartilageprotective mechanisms of pomegranate extract involve diminishing MKK3-activated p38α, JNK, NF-κB and Runx2 pathways, which regulate inflammatory proteins and cartilage-destroying proteases. Epigallocatechin- 3-gallate, resveratrol, curcumin and other NHP active ingredients suppress multiple inflammatory and catabolic molecular mediators of arthritis. Non-toxicity, reduced severity and incidence of arthritis in animal models warrant testing NHP active ingredients for preventing human OA and RA. PMID:21345249

  13. 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

  14. Molecular signaling and targets from itch: lessons for cough

    PubMed Central

    2013-01-01

    Itch is described as an unpleasant sensation that elicits the desire to scratch, which results in the removal of the irritant from the skin. The cough reflex also results from irritation, with the purpose of removing said irritant from the airway. Could cough then be similar to itch? Anatomically, both pathways are mediated by small-diameter sensory fibers. These cough and itch sensory fibers release neuropeptides upon activation, which leads to inflammation of the nerves. Both cough and itch also involve mast cells and their mediators, which are released upon degranulation. This common inflammation and interaction with mast cells are involved in the development of chronic conditions of itch and cough. In this review, we examine the anatomy and molecular mechanisms of itch and compare them to known mechanisms for cough. Highlighting the common aspects of itch and cough could lead to new thoughts and perspectives in both fields. PMID:23497684

  15. 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.

  16. 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

  17. 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

  18. Curcumin: a Polyphenol with Molecular Targets for Cancer Control.

    PubMed

    Qadir, Muhammad Imran; Naqvi, Syeda Tahira Qousain; Muhammad, Syed Aun

    2016-01-01

    Curcumin, is a polyphenol from Curcuma longa (turmeric plant), is a polyphenol that belongs to the ginger family which has long been used in Ayurveda medicines to treat various diseases such as asthma, anorexia, coughing, hepatic diseases, diabetes, heart diseases, wound healing and Alzheimer's. Various studies have shown that curcumin has anti-infectious, anti-inflammatory, anti-oxidant, hepatoprotective, thrombosuppressive, cardio protective, anti-arthritic, chemo preventive and anti-carcinogenic activities. It may suppress both initiation and progression stages of cancer. Anticancer activity of curcumin is due to negative regulation of inflammatory cytokines, transcription factors, protein kinases, reactive oxygen species (ROS) and oncogenes. This review focuses on the different targets of curcumin to treat cancer. PMID:27356682

  19. [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. PMID:26059306

  20. Novel molecular targeted therapies for refractory thyroid cancer.

    PubMed

    Perez, Cesar A; Santos, Edgardo S; Arango, Belisario A; Raez, Luis E; Cohen, Ezra E W

    2012-05-01

    The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer. PMID:21544895

  1. A Molecularly Targeted Theranostic Probe for Ovarian Cancer

    PubMed Central

    Chen, Wenxue; Bardhan, Rizia; Bartels, Marc; Perez-Torres, Carlos; Pautler, Robia G.; Halas, Naomi J.; Joshi, Amit

    2014-01-01

    Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in ovarian cancer because of its participation in signaling pathway regulating cellular proliferation, differentiation, motility, and survival. Currently, effective diagnostic and therapeutic schemes are lacking for treating ovarian cancer and consequently ovarian cancer has a high mortality rate. While HER2 receptor expression does not usually affect the survival rates of ovarian cancer to the same extent as in breast cancer, it can be employed as a docking site for directed nanotherapies in cases with de novo or acquired chemotherapy resistance. In this study, we have exploited a novel gold nanoshell-based complex (nanocomplex) for targeting, dual modal imaging, and photothermal therapy of HER2 overexpressing and drug resistant ovarian cancer OVCAR3 cells in vitro. The nanocomplexes are engineered to simultaneously provide contrast as fluorescence optical imaging probe and a magnetic resonance imaging (MRI) agent. Both immunofluorescence staining and MRI successfully demonstrate that nanocomplex-anti-HER2 conjugates specifically bind to OVCAR3 cells as opposed to the control, MDA-MB-231 cells, which have low HER2 expression. In addition, nanocomplexes targeted to OVCAR3 cells, when irradiated with near infrared (NIR) laser result in selective destruction of cancer cells through photothermal ablation. We also demonstrate that NIR light therapy and the nanocomplexes by themselves are non-cytotoxic in vitro. To the best of our knowledge, this is the first demonstration of a successful integration of dual modal bioimaging with photothermal cancer therapy for treatment of ovarian cancer. Based on their efficacy in vitro, these nanocomplexes are highly promising for image guided photo-thermal therapy of ovarian cancer as well as other HER2 overexpressing cancers. PMID:20371708

  2. Different effects of laser contrast on proton emission from normal large foils and transverse-size-reduced targets

    NASA Astrophysics Data System (ADS)

    Fang, Yuan; Ge, Xulei; Yang, Su; Wei, Wenqing; Yu, Tongpu; Liu, Feng; Chen, Min; Liu, Jingquan; Yuan, Xiaohui; Sheng, Zhengming; Zhang, Jie

    2016-07-01

    We report experimental results on the effects of laser contrast on beam divergence and energy spectrum of protons emitted from ultrashort intense laser interactions with normal large foils and transverse-size-reduced targets. Correlations between beam divergence and spectral shape are found. Large divergence and near-plateau shape energy spectrum are observed for both types of targets when the laser pulse contrast is low. With high contrast laser irradiation, proton beam divergence is remarkably reduced and the energy spectral shape is changed to exponential for large foil targets. In comparison, a similar large divergence and the near-plateau spectral shape remain for transverse-size-reduced targets. The results could be explained by the preplasma formation and target deformation at different laser contrasts and modified accelerating sheath field evolution in transverse-size-reduced target, which were supported by the 2D hydrodynamic and PIC simulations.

  3. 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.

  4. Phase behavior and molecular mobility of n -octylcyanobiphenyl confined to molecular sieves: Dependence on the pore size

    NASA Astrophysics Data System (ADS)

    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 (Si/Al=14.7) but different pore sizes (diameter between 2.3 and 4.6nm ) was investigated by broadband dielectric spectroscopy (10-2-109Hz) 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.

  5. 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. PMID:19113137

  6. Molecular targets to promote central nervous system regeneration.

    PubMed

    Ferraro, Gino B; Alabed, Yazan Z; Fournier, Alyson E

    2004-01-01

    Trauma in the adult mammalian central nervous system (CNS) results in devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. This regenerative failure can be attributed to both a lack of positive cues and to the presence of inhibitory cues that actively prevent regeneration. Substantial progress has been made in elucidating the molecular identity of negative cues present at the CNS injury site following injury. In the past several years, multiple myelin-associated inhibitors including Nogo, Myelin-associated glycoprotein and Oligodendrocyte-myelin glycoprotein have been characterized. Furthermore a neuronal receptor complex and several intracellular substrates leading to outgrowth inhibition have been identified. Rapid progress has also been made in identifying the role of neurotrophins and other positive cues in promoting axonal regrowth. The most recent advances in our understanding of positive stimuli for axon regeneration come from transplantation studies at the CNS lesion site. A number of artificial substrates, tissues, and cells including fetal cells, neural stem cells, Schwann cells and olfactory-ensheathing cells have been tested in animal models of CNS injury. Based on our expanded knowledge of inhibitory influences and on the positive characteristics of various transplants, a number of interventions have been tested to promote recovery in models of CNS trauma. These advances represent the first steps in developing a viable therapy to promote axon regeneration following CNS trauma. PMID:16181067

  7. 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

    2016-01-01

    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

  8. 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

  9. Implosion of reactor-size, gas-filled spherical shell targets driven by shaped pressure pulses

    SciTech Connect

    Piriz, A.R.; Atzeni, S. )

    1993-05-01

    The implosion of a family of reactor-size targets for inertial confinement fusion (ICF) is studied analytically and numerically. The targets consist of a deuterium--tritium (D--T) shell filled with D--T vapor and they are imploded by a multistep pressure pulse designed in such a way that the final hot spot is formed mainly from the initially gaseous fuel. The formation of the hot spot is described by means of a relatively simple model, and scaling laws for the quantities that characterize the state of the initially gaseous part of the fuel prior to ignition are derived. The results of the model are compared with one-dimensional fluid simulations, and good agreement is found. A parametric study of the fuel energy gain is then presented; the dependence of the gain and of the hot spot convergence ratio on the pulse parameters and on the filling gas density is analyzed. It is also shown that a substantial increase in the gain (for a given target and pulse energy) can be achieved by replacing the last step of the pulse with an exponential ramp.

  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. 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

    2016-01-01

    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

  12. Genotoxicants Target Distinct Molecular Networks in Neonatal Neurons

    PubMed Central

    Kisby, Glen E.; Olivas, Antoinette; Standley, Melissa; Lu, Xinfang; Pattee, Patrick; O’Malley, Jean; Li, Xiaorong; Muniz, Juan; Nagalla, Srinavasa R.

    2006-01-01

    Background Exposure of the brain to environmental agents during critical periods of neuronal development is considered a key factor underlying many neurologic disorders. Objectives In this study we examined the influence of genotoxicants on cerebellar function during early development by measuring global gene expression changes. Methods We measured global gene expression in immature cerebellar neurons (i.e., granule cells) after treatment with two distinct alkylating agents, methylazoxymethanol (MAM) and nitrogen mustard (HN2). Granule cell cultures were treated for 24 hr with MAM (10–1,000 μM) or HN2 (0.1–20 μM) and examined for cell viability, DNA damage, and markers of apoptosis. Results Neuronal viability was significantly reduced (p < 0.01) at concentrations > 500 μM for MAM and > 1.0 μM for HN2; this correlated with an increase in both DNA damage and markers of apoptosis. Neuronal cultures treated with sublethal concentrations of MAM (100 μM) or HN2 (1.0 μM) were then examined for gene expression using large-scale mouse cDNA microarrays (27,648). Gene expression results revealed that a) global gene expression was predominantly up-regulated by both genotoxicants; b) the number of down-regulated genes was approximately 3-fold greater for HN2 than for MAM; and c) distinct classes of molecules were influenced by MAM (i.e, neuronal differentiation, the stress and immune response, and signal transduction) and HN2 (i.e, protein synthesis and apoptosis). Conclusions These studies demonstrate that individual genotoxicants induce distinct gene expression signatures. Further study of these molecular networks may explain the variable response of the developing brain to different types of environmental genotoxicants. PMID:17107856

  13. In vivo molecular imaging using nanomaterials: general in vivo characteristics of nano-sized reagents and applications for cancer diagnosis.

    PubMed

    Rosenblum, Lauren T; Kosaka, Nobuyuki; Mitsunaga, Makoto; Choyke, Peter L; Kobayashi, Hisataka

    2010-10-01

    Nanoparticles present a new collection of contrast agents for the field of in vivo molecular imaging. This review focuses on promising molecular imaging probes for optical and magnetic resonance imaging based on four representative nanomaterial(s) platforms: quantum dots, upconversion phosphors, superparamagnetic iron oxides, and dendrimer-based agents. Quantum dots are extremely efficient fluorescent nanoparticles with size-tunable emission properties, enabling high sensitivity and greater depth penetration. Their heavy metal composition and long retention in the body, however, pose concerns for clinical translational applications. Upconversion phosphors generate excellent signal-to-background contrast because they emit light with higher energy than the excitation photons and autofluorescence signals. For MRI, iron oxide particles also generate excellent signal and have been used in liver imaging and for cell tracking studies. As they are metabolized through endogenous iron salvage pathways, they have already been introduced as clinical contrast agents. Lastly, dendrimers, a 'soft' nanoparticle, can be used as a structural basis for the attachment of small molecule imaging agents and/or targeting groups. This array of nanoparticles should offer insights into the uses and potentials of nanoparticles for the molecular imaging. PMID:20455640

  14. 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

  15. Evaluation of Kirkwood-Buff integrals via finite size scaling: a large scale molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Dednam, W.; Botha, A. E.

    2015-01-01

    Solvation of bio-molecules in water is severely affected by the presence of co-solvent within the hydration shell of the solute structure. Furthermore, since solute molecules can range from small molecules, such as methane, to very large protein structures, it is imperative to understand the detailed structure-function relationship on the microscopic level. For example, it is useful know the conformational transitions that occur in protein structures. Although such an understanding can be obtained through large-scale molecular dynamic simulations, it is often the case that such simulations would require excessively large simulation times. In this context, Kirkwood-Buff theory, which connects the microscopic pair-wise molecular distributions to global thermodynamic properties, together with the recently developed technique, called finite size scaling, may provide a better method to reduce system sizes, and hence also the computational times. In this paper, we present molecular dynamics trial simulations of biologically relevant low-concentration solvents, solvated by aqueous co-solvent solutions. In particular we compare two different methods of calculating the relevant Kirkwood-Buff integrals. The first (traditional) method computes running integrals over the radial distribution functions, which must be obtained from large system-size NVT or NpT simulations. The second, newer method, employs finite size scaling to obtain the Kirkwood-Buff integrals directly by counting the particle number fluctuations in small, open sub-volumes embedded within a larger reservoir that can be well approximated by a much smaller simulation cell. In agreement with previous studies, which made a similar comparison for aqueous co-solvent solutions, without the additional solvent, we conclude that the finite size scaling method is also applicable to the present case, since it can produce computationally more efficient results which are equivalent to the more costly radial distribution

  16. Determination of phytate in high molecular weight, charged organic matrices by two-dimensional size exclusion-ion chromatography.

    PubMed

    Elkin, Kyle R; Slingsby, Rosanne; Bryant, Ray B

    2016-08-15

    A two-dimensional chromatography method for analyzing phytate or other ionic targets in matrices containing high molecular weight, charged organic species is described. Prior to quantification by anion exchange chromatography, the sample matrix was prepared by size exclusion chromatography, which removed the majority of the matrix. Quantification of phytate on the AS11-HC was sensitive (0.25µM, 0.17mg/l) and reproducible (4.6% RSD) allowing this method to provide baseline separation of phytate from a manure extract within 14min. The method is simple, requiring only sample filtering, reproducible (between-run variation 5% RSD) and linear from 0.38 to 76µM (0.25-50mg/l). The method is suitable for routine determination of phytate in high organic matrices such as manure extracts. PMID:27260428

  17. Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds.

    PubMed

    Yang, Yidong; Engkvist, Ola; Llinàs, Antonio; Chen, Hongming

    2012-04-26

    The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a compound is dependent on physicochemical properties such as molecular size, lipophilicity, and ionization state. However, much less is known regarding the relationship between ADMET and the molecular topology. In this study two descriptors related to the molecular topology have been investigated, the fraction of the molecular framework (f(MF)) and the fraction of sp(3)-hybridized carbon atoms (Fsp(3)). f(MF) and Fsp(3), together with standard physicochemical properties (molecular size, ionization state, and lipophilicity), were analyzed for a set of ADMET assays. It is shown that aqueous solubility, Caco-2 permeability, plasma protein binding, human ether-a-go-go-related potassium channel protein inhibition, and CYP3A4 (CYP = cytochrome P450) inhibition are influenced by the molecular topology. These findings are in most cases independent of the already well-established relationships between the properties and molecular size, lipophilicity, and ionization state. PMID:22443161

  18. Ca(2+)-handling proteins and heart failure: novel molecular targets?

    PubMed

    Prestle, J; Quinn, F R; Smith, G L

    2003-06-01

    Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap. PMID:12678683

  19. 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

    2014-03-01

    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. PMID:24407036

  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. Unmixing multiple adjacent fluorescent targets with multispectral excited fluorescence molecular tomography.

    PubMed

    Zhou, Yuan; Guang, Huizhi; Pu, Huangsheng; Zhang, Jiulou; Luo, Jianwen

    2016-06-20

    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 unmix multiple adjacent fluorescent targets that have different functional features but are labeled with the same fluorochrome. A method based on independent component analysis for multispectral excited FMT was proposed in our previous study. It showed that double fluorescent targets with certain edge-to-edge distance (EED) could be unmixed by the method. In this study, the situation is promoted to unmix multiple adjacent fluorescent targets (i.e., more than two fluorescent targets and EED=0). Phantom experiments on the resolving ability of the proposed algorithm demonstrate that the algorithm performs well in unmixing multiple adjacent fluorescent targets in both lateral and axial directions. And also, we recovered the locational information of each independent fluorescent target and described the variable trends of the corresponding fluorescent targets under the excitation spectrum. This method is capable of unmixing multiple fluorescent targets with small EED but labeled with the same fluorochrome, and may be used in imaging of nonspecific probe targeting and metabolism of drugs. PMID:27409108

  2. Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin.

    PubMed

    Dai, Shao-Xing; Li, Wen-Xing; Li, Gong-Hua; Huang, Jing-Fei

    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

  3. 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

  4. Synthetic molecular machines and polymer/monomer size switches that operate through dynamic and non-dynamic covalent changes.

    PubMed

    Stadler, Adrian-Mihail; Ramírez, Juan

    2012-01-01

    The present chapter is focused on how synthetic molecular machines (e.g. shuttles, switches and molecular motors) and size switches (conversions between polymers and their units, i.e., conversions between relatively large and small molecules) can function through covalent changes. Amongst the interesting examples of devices herein presented are molecular motors and size switches based on dynamic covalent chemistry which is an area of constitutional dynamic chemistry. PMID:22169959

  5. 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

  6. Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia

    PubMed Central

    Koonce, Nathan A.; Levy, Joseph; Hardee, Matthew E.; Jamshidi-Parsian, Azemat; Vang, Kieng B.; Sharma, Sunil; Raleigh, James A.; Dings, Ruud P. M.; Griffin, Robert J.

    2015-01-01

    Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be ‘created’ on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions. PMID:26308944

  7. 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. PMID:26776042

  8. 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.

  9. 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

  10. Microscopic mechanisms of laser spallation and ablation of metal targets from large-scale molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Wu, Chengping; Zhigilei, Leonid V.

    2014-01-01

    The microscopic mechanisms of femtosecond laser ablation of an Al target are investigated in large-scale massively parallel atomistic simulations performed with a computational model combining classical molecular dynamics technique with a continuum description of the laser excitation and subsequent relaxation of conduction band electrons. The relatively large lateral size of the computational systems used in the simulations enables a detailed analysis of the evolution of multiple voids generated in a sub-surface region of the irradiated target in the spallation regime, when the material ejection is driven by the relaxation of laser-induced stresses. The nucleation, growth, and coalescence of voids take place within a broad (100 nm) region of the target, leading to the formation of a transient foamy structure of interconnected liquid regions and eventual separation (or spallation) of a thin liquid layer from the bulk of the target. The thickness of the spalled layer is decreasing from the maximum of 50 nm while the temperature and ejection velocity are increasing with increasing fluence. At a fluence of 2.5 times the spallation threshold, the top part of the target reaches the conditions for an explosive decomposition into vapor and small clusters/droplets, marking the transition to the phase explosion regime of laser ablation. This transition is signified by a change in the composition of the ablation plume from large liquid droplets to a mixture of vapor-phase atoms and clusters/droplets of different sizes. The clusters of different sizes are spatially segregated in the expanding ablation plume, where small/medium size clusters present in the middle of the plume are followed by slower (velocities of less than 3 km/s) large droplets consisting of more than 10,000 atoms. The similarity of some of the characteristics of laser ablation of Al targets (e.g., evolution of voids in the spallation regime and cluster size distributions in the phase explosion regime) to the

  11. 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

  12. 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

  13. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies.

    PubMed

    Matsuoka, Tasuku; Yashiro, Masakazu

    2016-01-14

    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. 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.

  15. 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

  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. PMID:25876064

  17. Confirming an integrated pathology of diabetes and its complications by molecular biomarker-target network analysis.

    PubMed

    Zhao, Zide; Zhang, Yingying; Gai, Fengchun; Wang, Ying

    2016-09-01

    Despite ongoing research into diabetes and its complications, the underlying molecular associations remain to be elucidated. The systematic identification of molecular interactions in associated diseases may be approached using a network analysis strategy. The biomarker-target interrelated molecules associated with diabetes and its complications were identified via the Comparative Toxicogenomics Database (CTD); the Search Tool for Recurring Instances of Neighboring Genes was utilized for network construction. Functional enrichment analysis was performed with Database for Annotation, Visualization and Integrated Discovery software to investigate connections between diabetes and its complications. A total of 142 (including 122 biomarkers, 10 therapeutic targets and 10 overlapping molecules) biomarker-target interrelated molecules associated with diabetes and its complications were identified via the CTD database, and analysis of the network yielded 1,087 biological processes and fifteen Kyoto Encyclopedia of Genes and Genomes pathways with significant P‑values. Various critical aspects of the networks were examined in the present study: a) Intermolecular horizontal and vertical combinations in biomarkers and therapeutic targets associated with diabetes and its complicationb) network topology properties associated with molecular pathological responsec) contribution of key molecules to integrated regulation; and d) crosstalk between multiple pathways. Based on a multi-dimensional analysis, it was concluded that the integrated molecular pathological development of diabetes and its complications does not proceed randomly, which suggests a requirement for integrated, multi-target intervention. PMID:27430657

  18. Reversible Masking Using Low-Molecular-Weight Neutral Lipids to Achieve Optimal-Targeted Delivery

    PubMed Central

    Templeton, Nancy Smyth; Senzer, Neil

    2012-01-01

    Intravenous injection of therapeutics is required to effectively treat or cure metastatic cancer, certain cardiovascular diseases, and other acquired or inherited diseases. Using this route of delivery allows potential uptake in all disease targets that are accessed by the bloodstream. However, normal tissues and organs also have the potential for uptake of therapeutic agents. Therefore, investigators have used targeted delivery to attempt delivery solely to the target cells; however, use of ligands on the surface of delivery vehicles to target specific cell surface receptors is not sufficient to avoid nonspecific uptake. PEGylation has been used for decades to try to avoid nonspecific uptake but suffers from many problems known as “The PEGylation Dilemma.” We have solved this dilemma by replacing PEGylation with reversible masking using low-molecular-weight neutral lipids in order to achieve optimal-targeted delivery solely to target cells. Our paper will focus on this topic. PMID:22655199

  19. Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model

    PubMed Central

    Sano, Daisuke; Fooshee, David R.; Zhao, Mei; Andrews, Genevieve A.; Frederick, Mitchell J.; Galer, Chad; Milas, Zvonimir L.; Morrow, Phuong Khanh H.; Myers, Jeffrey N.

    2010-01-01

    Background We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC). Methods The in vitro effects of vandetanib (ZACTIMA™) were assessed in two HNSCC cell lines on cell growth, apoptosis, and receptor and downstream signaling morecule expression and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival. Results In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC. Conclusion Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC. PMID:20629091

  20. X-Ray Dose and Spot Size Calculations for the DARHT-II Distributed Target

    SciTech Connect

    McCarrick, J

    2001-04-05

    The baseline DARHT-II converter target consists of foamed tantalum within a solid-density cylindrical tamper. The baseline design has been modified by D. Ho to further optimize the integrated line density of material in the course of multiple beam pulses. LASNEX simulations of the hydrodynamic expansion of the target have been performed by D. Ho (documented elsewhere). The resulting density profiles have been used as inputs in the MCNP radiation transport code to calculate the X-ray dose and spot size assuming a incoming Gaussian electron beam with {sigma} = 0.65mm, and a PIC-generated beam taking into account the ''swept'' spot emerging from the DARHT-II kicker system. A prerequisite to these calculations is the absorption spectrum of air. In order to obtain this, a separate series of MCNP runs was performed for a set of monoenergetic photon sources, tallying the energy deposited in a volume of air. The forced collision feature was used to improve the statistics since the photon mean free path in air is extremely long at the energies of interest. A sample input file is given below. The resulting data for the MCNP DE and DF cards is shown in the beam-pulse input files, one of which is listed below. Note that the DE and DF cards are entered in column format for easy reading.

  1. Measurements of the molecular size of the simian virus 40 large T antigen.

    PubMed Central

    Griffin, J D; Light, S; Livingston, D M

    1978-01-01

    A measure of the molecular weight of the large simian virus 40 T antigen was sought by SDS-polyacrylamide gel electrophoresis, random-coil chromatography, and sedimentation-velocity analysis in a density gradient. Large T antigen obtained from a simian virus 40-transformed human cell line either by immunoprecipitation or by standard preparatory methods migrated like a 94,000-molecular-weight (approximately 94K) polypeptide in SDS-gels but was found to have an approximate was observed with T antigen obtained from lytically infected monkey cells. In view of the strong theoretical basis for the guanidine method and the agreement with the sedimentation data, these findings suggest that the molecular weight of this protein is approximately 75 to 80K as opposed to 94 to 100K and, therefore, that considerably less than the entire early region of simian virus 40 is required to encode it. This size estimate is in keeping with earlier results which revealed a normal-size T antigen in cells infected with viable deletion mutants lacking as much as 10% of the early region. Images PMID:211251

  2. 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

  3. A titanosilicate molecular sieve with adjustable pores for size-selective adsorption of molecules.

    PubMed

    Kuznicki, S M; Bell, V A; Nair, S; Hillhouse, H W; Jacubinas, R M; Braunbarth, C M; Toby, B H; Tsapatsis, M

    2001-08-16

    Zeolites and related crystalline microporous oxides-tetrahedrally coordinated atoms covalently linked into a porous framework-are of interest for applications ranging from catalysis to adsorption and ion-exchange. In some of these materials (such as zeolite rho) adsorbates, ion-exchange, and dehydration and cation relocation can induce strong framework deformations. Similar framework flexibility has to date not been seen in mixed octahedral/tetrahedral microporous framework materials, a newer and rapidly expanding class of molecular sieves. Here we show that the framework of the titanium silicate ETS-4, the first member of this class of materials, can be systematically contracted through dehydration at elevated temperatures to 'tune' the effective size of the pores giving access to the interior of the crystal. We show that this so-called 'molecular gate' effect can be used to tailor the adsorption properties of the materials to give size-selective adsorbents suitable for commercially important separations of gas mixtures of molecules with similar size in the 4.0 to 3.0 A range, such as that of N2/CH4, Ar/O2 and N2/O2. PMID:11507636

  4. 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

  5. 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).

  6. Targeted PRINT Hydrogels: The Role of Nanoparticle Size and Ligand Density on Cell Association, Biodistribution, and Tumor Accumulation.

    PubMed

    Reuter, Kevin G; Perry, Jillian L; Kim, Dongwook; Luft, J Christopher; Liu, Rihe; DeSimone, Joseph M

    2015-10-14

    In this Letter, we varied targeting ligand density of an EGFR binding affibody on the surface of two different hydrogel PRINT nanoparticles (80 nm × 320 and 55 nm × 60 nm) and monitored effects on target-cell association, off-target phagocytic uptake, biodistribution, and tumor accumulation. Interestingly, variations in ligand density only significantly altered in vitro internalization rates for the 80 nm × 320 nm particle. However, in vivo, both particle sizes experienced significant changes in biodistribution and pharmacokinetics as a function of ligand density. Overall, nanoparticle size and passive accumulation were the dominant factors eliciting tumor sequestration. PMID:26389971

  7. Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules

    PubMed Central

    Cheng, Tiejun; Wang, Yanli; Bryant, Stephen H.

    2010-01-01

    Motivation: Most of the previous data mining studies based on the NCI-60 dataset, due to its intrinsic cell-based nature, can hardly provide insights into the molecular targets for screened compounds. On the other hand, the abundant information of the compound–target associations in PubChem can offer extensive experimental evidence of molecular targets for tested compounds. Therefore, by taking advantages of the data from both public repositories, one may investigate the correlations between the bioactivity profiles of small molecules from the NCI-60 dataset (cellular level) and their patterns of interactions with relevant protein targets from PubChem (molecular level) simultaneously. Results: We investigated a set of 37 small molecules by providing links among their bioactivity profiles, protein targets and chemical structures. Hierarchical clustering of compounds was carried out based on their bioactivity profiles. We found that compounds were clustered into groups with similar mode of actions, which strongly correlated with chemical structures. Furthermore, we observed that compounds similar in bioactivity profiles also shared similar patterns of interactions with relevant protein targets, especially when chemical structures were related. The current work presents a new strategy for combining and data mining the NCI-60 dataset and PubChem. This analysis shows that bioactivity profile comparison can provide insights into the mode of actions at the molecular level, thus will facilitate the knowledge-based discovery of novel compounds with desired pharmacological properties. Availability: The bioactivity profiling data and the target annotation information are publicly available in the PubChem BioAssay database (ftp://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/). Contact: ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov Supplementary information: Supplementary data are available at Bioinformatics online. PMID:20947527

  8. 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.

  9. A Investigation of a Possible Molecular Effect in Ion Atom Collision Using a Gaseous Argon Target

    NASA Astrophysics Data System (ADS)

    Arora, Sanjeev

    1992-01-01

    The present work deals with an investigation of the molecular effect, which is defined as the difference in experimental results using isotachic atomic ion and molecular ion beams in ion atom collisions. Previous studies have dealt almost exclusively with total cross section measurements. This thesis explores the idea that the molecular effect may be more pronounced in the differential ionization probability of the target atoms. Also, a gaseous argon target of sufficiently low density was used in order to ensure that the two correlated protons in the H _2^{+} beam did not interact with two adjacent target atoms simultaneously. We report that, contrary to the expectations noted above, the molecular effect in the K shell differential ionization probability of argon for scattering angles up to 90^circ appears to be no more than the molecular effect in the total ionization probability. The uncertainity in our results is statistical in nature and can be improved upon by running the experiment for a longer duration of time.

  10. 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)

  11. Quality of epitaxial InAs nanowires controlled by catalyst size in molecular beam epitaxy

    SciTech Connect

    Zhang, Zhi; Xu, Hong-Yi; Guo, Ya-Nan; Liao, Zhi-Ming; Lu, Zhen-Yu; Chen, Ping-Ping; Shi, Sui-Xing; Lu, Wei; Zou, Jin

    2013-08-12

    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.

  12. 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.

  13. Automated sampling assessment for molecular simulations using the effective sample size

    PubMed Central

    Zhang, Xin; Bhatt, Divesh; Zuckerman, Daniel M.

    2010-01-01

    To quantify the progress in the development of algorithms and forcefields used in molecular simulations, a general method for the assessment of the sampling quality is needed. Statistical mechanics principles suggest the populations of physical states characterize equilibrium sampling in a fundamental way. We therefore develop an approach for analyzing the variances in state populations, which quantifies the degree of sampling in terms of the effective sample size (ESS). The ESS estimates the number of statistically independent configurations contained in a simulated ensemble. The method is applicable to both traditional dynamics simulations as well as more modern (e.g., multi–canonical) approaches. Our procedure is tested in a variety of systems from toy models to atomistic protein simulations. We also introduce a simple automated procedure to obtain approximate physical states from dynamic trajectories: this allows sample–size estimation in systems for which physical states are not known in advance. PMID:21221418

  14. Repeat Size Determination by Two Molecular Rulers in the Type I-E CRISPR Array.

    PubMed

    Goren, Moran G; Doron, Shany; Globus, Rea; Amitai, Gil; Sorek, Rotem; Qimron, Udi

    2016-09-13

    Prokaryotic adaptive immune systems are composed of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins. These systems adapt to new threats by integrating short nucleic acids, termed spacers, into the CRISPR array. The functional motifs in the repeat and the mechanism by which a constant repeat size is maintained are still elusive. Here, through a series of mutations within the repeat of the CRISPR-Cas type I-E, we identify motifs that are crucial for adaptation and show that they serve as anchor sites for two molecular rulers determining the size of the new repeat. Adaptation products from various repeat mutants support a model in which two motifs in the repeat bind to two different sites in the adaptation complex that are 8 and 16 bp away from the active site. This model significantly extends our understanding of the adaptation process and broadens the scope of its applications. PMID:27626652

  15. Regulating the Rate of Molecular Self-Assembly for Targeting Cancer Cells.

    PubMed

    Zhou, Jie; Du, Xuewen; Xu, Bing

    2016-05-01

    Besides tight and specific ligand-receptor interactions, the rate regulation of the formation of molecular assemblies is one of fundamental features of cells. But the latter receives little exploration for developing anticancer therapeutics. Here we show that a simple molecular design of the substrates of phosphatases-tailoring the number of phosphates on peptidic substrates-is able to regulate the rate of molecular self-assembly of the enzyme reaction product. Such a rate regulation allows selective inhibition of osteosarcoma cells over hepatocytes, which promises to target cancer cells in a specific organ. Moreover, our result reveals that the direct measurement of the rate of the self-assembly in a cell-based assay provides precise assessment of the cell targeting capability of self-assembly. This work, as the first report establishing rate regulation of a multiple-step process to inhibit cells selectively, illustrates a fundamentally new approach for controlling the fate of cells. PMID:27062481

  16. 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

  17. 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

  18. 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.

  19. Fast molecular beacon hybridization in organic solvents with improved target specificity.

    PubMed

    Dave, Neeshma; Liu, Juewen

    2010-12-01

    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. PMID:21062084

  20. Peptide aptamer identified by molecular docking targeting translationally controlled tumor protein in leukemia cells.

    PubMed

    Kadioglu, Onat; Efferth, Thomas

    2016-08-01

    Bioinformatics screening and molecular docking analyses were utilized to select high affinity peptides targeting translationally controlled tumor protein (TCTP). Selected peptide aptamers were tested towards cancer cell lines with different levels of TCTP expression. One peptide (WGQWPYHC) revealed specific cytotoxicity according to the TCTP expression in tumor cells without affecting normal cells. Western blot analysis showed peptide-induced down-regulation of TCTP as primary target as well as of cell-cycle related downstream proteins (CDK2, CDK6, Cyclin D3) in MOLT-4 leukemia cells. "WGQWPYHC" deserves further analysis for targeted therapy of TCTP-expressing tumor cells. Graphical abstract Molecular docking on TCTP, cytotoxicity toward MOLT-4 leukemia cell line and downregulation of CDK2, CDK6, CyclinD3 and TCTP proteins. PMID:26972431

  1. Choice of pore size can introduce artefacts when filtering picoeukaryotes for molecular biodiversity studies.

    PubMed

    Sørensen, Nikolaj; Daugbjerg, Niels; Richardson, Katherine

    2013-05-01

    Published results of studies based on samples size fractionated by sequential filtration (e.g. 0.2-3 μm) indicate that many ciliate, dinoflagellate and rhizarian phylotypes are found among marine picoeukaryotes. This is somewhat surprising as these protists are typically known as being large organisms (often >10 μm) and no picoplanktonic species have so far been identified. Here, the abundances of ciliate and dinoflagellate phylotypes in published molecular studies of picoeukaryotes are shown to correlate negatively with the pore size chosen for the end filter in the sequential filtrations (i.e. the filter used to collect the microbial biomass). This suggests that extracellular DNA adhering to small particles may be the source of ciliate and dinoflagellate phylotypes in picoplanktonic size fractions. This hypothesis was confirmed using real-time qPCR, which revealed significantly less dinoflagellate 18S rDNA in a 0.8-3-μm size fraction compared to 0.2-3 μm. On average, the abundance of putative extracellular phylotypes decreased by 84-89 % when a 0.8- μm end filter was used rather than a 0.2-μm end filter. A 0.8-μm filter is, however, not sufficient to retain all picoeukaryotic cells. Thus, selection of filter pore size involves a trade-off between avoiding artefacts generated by extracellular DNA and sampling the entire picoeukaryotic community. In contrast to ciliate and dinoflagellate phylotypes, rhizarian phylotypes in the picoplankton size range do not display a pattern consistent with an extracellular origin. This is likely due to the documented existence of picoplanktonic swarmer cells within this group. PMID:23325466

  2. New target for high-intensity laser-matter interaction: Gravitational flow of micrometer-sized powders

    SciTech Connect

    Servol, M.; Quere, F.; Bougeard, M.; Monot, P.; Martin, Ph.; Faenov, A.Ya; Pikuz, T.A.; Audebert, P.; Francucci, M.; Petrocelli, G.

    2005-08-15

    The design of efficient targets for high-intensity laser-matter interaction is essential to fully exploit the advantages of laser-induced photons or particles sources. We present an advantageous kind of target, consisting in a free gravitational flow of micrometer-sized powder, and describe its main technical characteristics. We demonstrate a laser-induced keV x-ray source using this target, and show that the photon flux obtained for the K{alpha} line of Si by irradiating different silica powders is comparable to the one obtained with a bulk silica target.

  3. 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. PMID:25655242

  4. Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy.

    PubMed

    Morrell, Eric D; Kellum, John A; Pastor-Soler, Núria M; Hallows, Kenneth R

    2014-01-01

    The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis. PMID:25575158

  5. 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

  6. Targeting the untargeted in molecular phenomics with structurally-selective ion mobility-mass spectrometry.

    PubMed

    May, Jody Christopher; Gant-Branum, Randi Lee; McLean, John Allen

    2016-06-01

    Systems-wide molecular phenomics is rapidly expanding through technological advances in instrumentation and bioinformatics. Strategies such as structural mass spectrometry, which utilizes size and shape measurements with molecular weight, serve to characterize the sum of molecular expression in biological contexts, where broad-scale measurements are made that are interpreted through big data statistical techniques to reveal underlying patterns corresponding to phenotype. The data density, data dimensionality, data projection, and data interrogation are all critical aspects of these approaches to turn data into salient information. Untargeted molecular phenomics is already having a dramatic impact in discovery science from drug discovery to synthetic biology. It is evident that these emerging techniques will integrate closely in broad efforts aimed at precision medicine. PMID:27132126

  7. Molecular beacons with a homo-DNA stem: improving target selectivity

    PubMed Central

    Crey-Desbiolles, Caroline; Ahn, Dae-Ro; Leumann, Christian J.

    2005-01-01

    Molecular beacons (MBs) are stem–loop DNA probes used for identifying and reporting the presence and localization of nucleic acid targets in vitro and in vivo via target-dependent dequenching of fluorescence. A drawback of conventional MB design is present in the stem sequence that is necessary to keep the MBs in a closed conformation in the absence of a target, but that can participate in target binding in the open (target-on) conformation, giving rise to the possibility of false-positive results. In order to circumvent these problems, we designed MBs in which the stem was replaced by an orthogonal DNA analog that does not cross-pair with natural nucleic acids. Homo-DNA seemed to be specially suited, as it forms stable adenine-adenine base pairs of the reversed Hoogsteen type, potentially reducing the number of necessary building blocks for stem design to one. We found that MBs in which the stem part was replaced by homo-adenylate residues can easily be synthesized using conventional automated DNA synthesis. As conventional MBs, such hybrid MBs show cooperative hairpin to coil transitions in the absence of a DNA target, indicating stable homo-DNA base pair formation in the closed conformation. Furthermore, our results show that the homo-adenylate stem is excluded from DNA target binding, which leads to a significant increase in target binding selectivity. PMID:15879349

  8. [Molecular biological foundation of targeted therapy for metastatic renal cell carcinoma].

    PubMed

    Lai, Chong; Teng, Xiaodong

    2016-01-01

    The incidence of renal cell carcinoma (RCC) is increasing. Radical cure by surgery can only be achieved in patients with early stage tumors. How to precisely use antineoplastic agents after surgery is an important problem to be solved. Most metastatic RCCs are pathologically identified as clear cell RCC (ccRCC), thus to develop agents targeting ccRCC is critical. Most clinically available targeted therapies are based on targeting some spots in specific pathways; or based on targeting new anti-tumor mechanisms, such as programmed death-1(PD-1), antibody-drug conjugates (ADC) and stem cells. There is still no targeted therapy having definite effect to most RCC patients. Only von Hippel-Lindau (VHL) pathway so far has been confirmed to be related to ccRCC development and progression; the inactivation of VHL gene causes many significant downstream gene changes. The key proteins involved in VHL pathway may be potential therapeutic targets for ccRCC. In this article, we review the current progress of targeted therapy for RCC, focus on the molecular characteristics of ccRCC, its relation to VHL pathway, the potential therapeutic targets and future clinical application for metastatic ccRCC. PMID:27045248

  9. Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy

    PubMed Central

    Chen, Zhi-Yi; Wang, Yi-Xiang; Lin, Yan; Zhang, Jin-Shan; Yang, Feng; Zhou, Qiu-Lan; Liao, Yang-Ying

    2014-01-01

    Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy. PMID:24689058

  10. Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease

    PubMed Central

    Bansode, Sneha B.; Jana, Asis K.; Batkulwar, Kedar B.; Warkad, Shrikant D.; Joshi, Rakesh S.; Sengupta, Neelanjana; Kulkarni, Mahesh J.

    2014-01-01

    Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), β-secretase (BACE-1), and amyloid β (Aβ) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment. PMID:25141174

  11. In vivo photoacoustic molecular imaging of breast carcinoma with folate receptor-targeted indocyanine green nanoprobes

    NASA Astrophysics Data System (ADS)

    Wang, Huina; Liu, Chengbo; Gong, Xiaojing; Hu, Dehong; Lin, Riqiang; Sheng, Zonghai; Zheng, Cuifang; Yan, Meng; Chen, Jingqin; Cai, Lintao; Song, Liang

    2014-11-01

    As an optical-acoustic hybrid imaging technology, photoacoustic imaging uniquely combines the advantages of rich optical contrast with high ultrasonic resolution in depth, opening up many new possibilities not attainable with conventional pure optical imaging technologies. To perform photoacoustic molecular imaging, optically absorbing exogenous contrast agents are needed to enhance the signals from specifically targeted disease activity. In this work, we designed and developed folate receptor targeted, indocyanine green dye doped poly(d,l-lactide-co-glycolide) lipid nanoparticles (FA-ICG-PLGA-lipid NPs) for molecular photoacoustic imaging of tumor. The fabricated FA-ICG-PLGA-lipid NPs exhibited good aqueous stability, a high folate-receptor targeting efficiency, and remarkable optical absorption in near-infrared wavelengths, providing excellent photoacoustic signals in vitro. Furthermore, after intravenous administration of FA-ICG-PLGA-lipid NPs, mice bearing MCF-7 breast carcinomas showed significantly enhanced photoacoustic signals in vivo in the tumor regions, compared with those using non-targeted ICG-PLGA-lipid NPs. Given the existing wide clinical use of ICG and PLGA, the developed FA-ICG-PLGA-lipid NPs, in conjunction with photoacoustic imaging technology, offer a great potential to be translated into the clinic for non-ionizing molecular imaging of breast cancer in vivo.

  12. Size-exclusion chromatography in the measurements of concentration and molecular weight of some EOR polymers

    SciTech Connect

    Hunt, J.A.; Young, T.S.; Green, D.W.; Willhite, G.P.

    1988-08-01

    Procedures that involve the use of size exclusion chromatography (SEC) for the measurement of concentration and weight-averaged molecular weight, M-bar/sub w/, of some EOR polymers were developed and found to give improved detectability, accuracy, and/or efficiency. The separation of polymer from low-molecular-weight impurities by size allows unambiguous detection of polymer properties such as concentration and M-bar/sub w/. A combination of an SEC column of a pore size small enough to exclude the polymer totally and a mobile phase of ionic strength of 1.5 was found suitable for the separation of polyacrylamide, partially hydrolyzed polyacrylamide, cationic polyacrylamide derivative, and xanthan polysaccharide from impurities. Concentration detection of the separated polymer sample with a variable-wavelength ultraviolet (UV) detector was found to give superior detectability over detection by refractive index difference. A wavelength of 214 nm (2,140 A) was used for the detection of these polymers on the basis of the spectra of samples purified by dialysis. With the active polymer assay determined by reprecipitation into a nonsolvent, the detection limit by UV was determined to be <0.1 ..mu..g/cm/sup 3/ for polyacrylamide and a cationic polyacrylamide derivative, <0.2 ..mu..g/cm/sup 3/ for partially hydrolyzed polyacrylamide, and <0.7 ..mu..g/cm/sup 3/ for a xanthan polysaccharide. The linear calibration range was up to 500 ..mu..g/cm/sup 3/. The precision of the concentration measurement was better than 4% for polyacrylamide and its derivative and 5% for polysaccharide at a 95% confidence level.

  13. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

    PubMed Central

    Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

    2015-01-01

    Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male

  14. Ultrasound Molecular Imaging of Tumor Angiogenesis with a Neuropilin-1-Targeted Microbubble

    PubMed Central

    Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S.; Mahakian, Lisa M.; Lai, Chun-Yen; Tumbale, Spencer K.; Teesalu, Tambet; Hubbard, Neil E.; Borowsky, Alexander D.; Ferrara, Katherine W.

    2015-01-01

    Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ~6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7–21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis. PMID:25934284

  15. Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets.

    PubMed

    Motadi, L R; Misso, N L; Dlamini, Z; Bhoola, K D

    2007-12-20

    Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease. Chemotherapy and radiotherapy produce only a modest improvement in survival of patients with advanced disease. Increased knowledge of molecular mechanisms of lung cancer and apoptosis are providing opportunities for treating lung cancer with new classes of molecularly targeted drugs. These novel therapies should target the abnormalities in lung cancer by maximizing the effects of anti-tumour molecules, with minimal side effects on normal tissues. Of the several molecular targets, those receiving attention are p53 gene replacement, Bcl-2 downregulation, apoptosis by induced by TNF, the FAS/CD95 receptor system and TRAIL, and inhibition of NF-kappaB. Although several studies have shown benefits, there is a need for well planned clinical trials of drugs that target the apoptotic cascade. Stem cell therapy and gene replacement offer the prospect of novel approaches that are likely in the near future to play a definitive role in the treatment of advanced lung cancer. Furthermore, with their apparent minimal toxicity to normal tissues, the newer molecular targets represent attractive investigational directions for innovative cancer therapies. PMID:18039530

  16. Exogenous Molecular Probes for Targeted Imaging in Cancer: Focus on Multi-modal Imaging

    PubMed Central

    Joshi, Bishnu P.; Wang, Thomas D.

    2010-01-01

    Cancer is one of the major causes of mortality and morbidity in our healthcare system. Molecular imaging is an emerging methodology for the early detection of cancer, guidance of therapy, and monitoring of response. The development of new instruments and exogenous molecular probes that can be labeled for multi-modality imaging is critical to this process. Today, molecular imaging is at a crossroad, and new targeted imaging agents are expected to broadly expand our ability to detect and manage cancer. This integrated imaging strategy will permit clinicians to not only localize lesions within the body but also to manage their therapy by visualizing the expression and activity of specific molecules. This information is expected to have a major impact on drug development and understanding of basic cancer biology. At this time, a number of molecular probes have been developed by conjugating various labels to affinity ligands for targeting in different imaging modalities. This review will describe the current status of exogenous molecular probes for optical, scintigraphic, MRI and ultrasound imaging platforms. Furthermore, we will also shed light on how these techniques can be used synergistically in multi-modal platforms and how these techniques are being employed in current research. PMID:22180839

  17. Antagonistic molecular interactions of photosynthetic pigments with molecular disease targets: a new approach to treat AD and ALS.

    PubMed

    Krishnaraj, R Navanietha; Kumari, S S Sreeja; Mukhopadhyay, Sudit Sekhar

    2016-01-01

    Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases that affect the neurons in the brain and the spinal cord. Neuroinflamation and apoptosis are key players in the progressive damage of the neurons in AD and ALS. Currently, there is no drug to offer complete cure for both these diseases. Riluzole is the only available drug that can prolong the life time of the ALS patients for nearly 3 months. Molecules that offer good HIT to the molecular targets of ALS will help to treat AD and ALS patients. P53 kinase receptor (4AT3), EphA4 (3CKH) and histone deacetylase (3SFF) are the promising disease targets of AD and ALS. This paper discusses on a new approach to combat neurodegenerative diseases using photosynthetic pigments. The docking studies were performed with the Autodock Vina algorithm to predict the binding of the natural pigments such as β carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin on these targets. The β carotene, phycoerythrin and phycocyanin had higher binding energies indicating the antagonistic activity to the disease targets. These pigments serve as a potential therapeutic molecule to treat neuroinflammation and apoptosis in the AD and ALS patients. PMID:26053508

  18. 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).

  19. Molecular determinants of plaque size as an indicator of dengue virus attenuation.

    PubMed

    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

  20. 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

  1. 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

  2. Molecular Mechanism and Potential Targets for Blocking HPV-Induced Lesion Development

    PubMed Central

    Guzmán-Olea, E.; Bermúdez-Morales, V. H.; Peralta-Zaragoza, O.; Torres-Poveda, K.; Madrid-Marina, V.

    2012-01-01

    Persistent infection with high-risk HPV is the etiologic agent associated with the development of cervical cancer (CC) development. However, environmental, social, epidemiological, genetic, and host factors may have a joint influence on the risk of disease progression. Cervical lesions caused by HPV infection can be removed naturally by the host immune response and only a small percentage may progress to cancer; thus, the immune response is essential for the control of precursor lesions and CC. We present a review of recent research on the molecular mechanisms that allow HPV-infected cells to evade immune surveillance and potential targets of molecular therapy to inhibit tumor immune escape. PMID:22220169

  3. Molecular Mechanism and Potential Targets for Blocking HPV-Induced Lesion Development.

    PubMed

    Guzmán-Olea, E; Bermúdez-Morales, V H; Peralta-Zaragoza, O; Torres-Poveda, K; Madrid-Marina, V

    2012-01-01

    Persistent infection with high-risk HPV is the etiologic agent associated with the development of cervical cancer (CC) development. However, environmental, social, epidemiological, genetic, and host factors may have a joint influence on the risk of disease progression. Cervical lesions caused by HPV infection can be removed naturally by the host immune response and only a small percentage may progress to cancer; thus, the immune response is essential for the control of precursor lesions and CC. We present a review of recent research on the molecular mechanisms that allow HPV-infected cells to evade immune surveillance and potential targets of molecular therapy to inhibit tumor immune escape. PMID:22220169

  4. Surmounting Chemotherapy and Radioresistance in Chondrosarcoma: Molecular Mechanisms and Therapeutic Targets

    PubMed Central

    Onishi, Anne C.; Hincker, Alexander M.; Lee, Francis Y.

    2011-01-01

    Chondrosarcoma, a primary malignancy of bone, has eluded successful treatment with modern chemotherapeutic and radiation regimens. To date, surgical resection of these tumors remains the only curative treatment offered to patients with this diagnosis. Understanding and exploring the nature of chemotherapy and radiation resistance in chondrosarcoma could lead to new molecular targets and more directed therapy for these notoriously difficult-to-treat tumors. Here we review the most current hypotheses regarding the molecular mechanisms mediating chemotherapy and radiation resistance and the future direction of chondrosarcoma therapy research. PMID:21234363

  5. Molecular targeted therapies in advanced or metastatic chordoma patients: facts and hypotheses.

    PubMed

    Lebellec, Loïc; Aubert, Sébastien; Zaïri, Fahed; Ryckewaert, Thomas; Chauffert, Bruno; Penel, Nicolas

    2015-07-01

    Chordomas, derived from undifferentiated notochordal remnants, represent less than 4% of bone primary tumors. Despite surgery followed by radiotherapy, local and metastatic relapses are frequent. In case of locally advanced or metastatic chordomas, medical treatment is frequently discussed. While chemotherapy is ineffective, it would appear that some molecular targeted therapies, in particular imatinib, could slow down the tumor growth in case-reports, retrospective series, and phase I or II trials. Nineteen publications, between January 1990 and September 2014, have been found describing the activity of these targeted therapies. A systematic analysis of these publications shows that the best objective response with targeted therapies was stabilization in 52 to 69% of chordomas. Given the indolent course of advanced chordoma and because of the absence of randomized trial, the level of evidence to treat chordomas with molecular therapy is low (level III), whatever the drug. Furthermore, we could not draw firm conclusion on the activity of imatinib. Other putative targets have also been described. Therefore, further clinical trials are expected, especially with these targets. Nevertheless, it seems essential, in those future studies, to consider the naturally slow course of the disease. PMID:25682222

  6. MOLECULARLY TARGETED THERAPIES IN NON-SMALL CELL LUNG CANCER ANNUAL UPDATE 2014

    PubMed Central

    Morgensztern, Daniel; Campo, Meghan J.; Dahlberg, Suzanne E.; Doebele, Robert C.; Garon, Edward; Gerber, David E.; Goldberg, Sarah B.; Hammerman, Peter S.; Heist, Rebecca; Hensing, Thomas; Horn, Leora; Ramalingam, Suresh S.; Rudin, Charles M.; Salgia, Ravi; Sequist, Lecia; Shaw, Alice T.; Simon, George R.; Somaiah, Neeta; Spigel, David R.; Wrangle, John; Johnson, David; Herbst, Roy S.; Bunn, Paul; Govindan, Ramaswamy

    2015-01-01

    There have been significant advances in the understanding of the biology and treatment of non-small cell lung cancer (NSCLC) over the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC (Table 1). We are beginning to understand the mechanisms of acquired resistance following exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies and immunotherapy. PMID:25535693

  7. Role of NOM molecular size on iodo-trihalomethane formation during chlorination and chloramination.

    PubMed

    Zhang, Jie; Chen, Dan-Dan; Li, Lei; Li, Wen-Wei; Mu, Yang; Yu, Han-Qing

    2016-10-01

    Natural organic matter (NOM) is the major precursor for the generation of disinfection byproducts (DBPs) during disinfection, but the role of the NOM molecular size on the formation of iodinated DBPs (I-DBPs) is still unclear. The objective of this study was to evaluate the function of the NOM molecular size on the formation of iodo-trihalomethane (I-THMs) during chlorination and chloramination. Humic acid was adopted as the NOM matrix and fractionated into four molecular weight (MW) groups. Various parameters, including iodide, bromide, NOM concentrations, pH, and pre-chlorination time, were investigated for each MW fraction. During chlorination, high MW fractions (i.e., MW > 100 K Da and 50 K < MW < K00 K Da) produced more I-THMs compared with small MW fractions (i.e., MW < 3 K Da and 3 K < MW < 50 K Da). With the increase in the I(-) or NOM concentration, the formation of I-THMs increased for small MW fractions, while a slight reduction occurred for high MW fractions during chlorination. Higher pH resulted in more I-THM formation for small MW fractions, while the opposite was true for high MW fractions during chlorination. Compared to small MW fractions, bromide was relatively more reactive with high MW fractions in the formation of I-THMs during chlorination. During chloramination, the I-THM yields decreased with the increasing NOM concentration for high MW fractions. The concentration of bromine-containing I-THMs decreased with increasing pH for all MW fractions during chloramination. Additionally, with the prolongation of pre-chlorination time, the total amount of I-THMs decreased remarkably for MWs higher than 3 K Da, while a slight change for MW lower than 3 K Da occurred during chloramination. The results from this study suggest that the molecular weight of the NOM plays an important role in the formation of I-THMs during chlorination and chloramination. PMID:27423047

  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

    2015-01-01

    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. PMID:26198223

  9. Does size matter? Study of performance of pseudo-ELISAs based on molecularly imprinted polymer nanoparticles prepared for analytes of different sizes.

    PubMed

    Cáceres, C; Canfarotta, F; Chianella, I; Pereira, E; Moczko, E; Esen, C; Guerreiro, A; Piletska, E; Whitcombe, M J; Piletsky, S A

    2016-02-01

    The aim of this work is to evaluate whether the size of the analyte used as template for the synthesis of molecularly imprinted polymer nanoparticles (nanoMIPs) can affect their performance in pseudo-enzyme linked immunosorbent assays (pseudo-ELISAs). Successful demonstration of a nanoMIPs-based pseudo-ELISA for vancomycin (1449.3 g mol(-1)) was demonstrated earlier. In the present investigation, the following analytes were selected: horseradish peroxidase (HRP, 44 kDa), cytochrome C (Cyt C, 12 kDa) biotin (244.31 g mol(-1)) and melamine (126.12 g mol(-1)). NanoMIPs with a similar composition for all analytes were synthesised by persulfate-initiated polymerisation in water. In addition, core-shell nanoMIPs coated with polyethylene glycol (PEG) and imprinted for melamine were produced in organics and tested. The polymerisation of the nanoparticles was done using a solid-phase approach with the correspondent template immobilised on glass beads. The performance of the nanoMIPs used as replacement for antibodies in direct pseudo-ELISA (for the enzymes) and competitive pseudo-ELISA for the smaller analytes was investigated. For the competitive mode we rely on competition for the binding to the nanoparticles between free analyte and corresponding analyte-HRP conjugate. The results revealed that the best performances were obtained for nanoMIPs synthesised in aqueous media for the larger analytes. In addition, this approach was successful for biotin but completely failed for the smallest template melamine. This problem was solved using nanoMIP prepared by UV polymerisation in an organic media with a PEG shell. This study demonstrates that the preparation of nanoMIP by solid-phase approach can produce material with high affinity and potential to replace antibodies in ELISA tests for both large and small analytes. This makes this technology versatile and applicable to practically any target analyte and diagnostic field. PMID:26796951

  10. Determination of phytate in high molecular weight, charged organic matrices by two-dimensional size exclusion-ion chromatography

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A two-dimensional chromatography method for analyzing anionic targets (specifically phytate) in complex matrices is described. Prior to quantification by anion exchange chromatography, the sample matrix was prepared by size exclusion chromatography, which removed the majority of matrix complexities....

  11. Molecular Classification, Pathway Addiction, and Therapeutic Targeting in Diffuse Large B-cell Lymphoma

    PubMed Central

    Puvvada, Soham; Kendrick, Samantha; Rimsza, Lisa

    2015-01-01

    The rapid emergence of molecularly-based techniques to detect changes in the genetic landscape of diffuse large B-cell lymphoma (DLBCL) including gene expression, DNA and RNA sequencing, and epigenetic profiling, has significantly impacted the understanding and therapeutic targeting of DLBCL. In this review, we will briefly discuss the new methods used in the study of DLBCL. We will describe the influence of the generated data on DLBCL classification and the identification of new entities and altered cell survival strategies with a focus on the renewed interest in some classic oncogenic pathways that are currently targeted for new therapy. Lastly, we will examine the molecular genomic studies that revealed the importance of the tumor microenvironment in the pathogenesis of DLBCL. PMID:24080457

  12. Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis?

    PubMed Central

    Thillai, Kiruthikah; Ross, Paul; Sarker, Debashis

    2016-01-01

    Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC. PMID:26909132

  13. Molecularly-Targeted Gold-Based Nanoparticles for Cancer Imaging and Near-Infrared Photothermal Therapy

    NASA Astrophysics Data System (ADS)

    Day, Emily Shannon

    2011-12-01

    This thesis advances the use of nanoparticles as multifunctional agents for molecularly-targeted cancer imaging and photothermal therapy. Cancer mortality has remained relatively unchanged for several decades, indicating a significant need for improvements in care. Researchers are evaluating strategies incorporating nanoparticles as exogenous energy absorbers to deliver heat capable of inducing cell death selectively to tumors, sparing normal tissue. Molecular targeting of nanoparticles is predicted to improve photothermal therapy by enhancing tumor retention. This hypothesis is evaluated with two types of nanoparticles. The nanoparticles utilized, silica-gold nanoshells and gold-gold sulfide nanoparticles, can convert light energy into heat to damage cancerous cells. For in vivo applications nanoparticles are usually coated with poly(ethylene glycol) (PEG) to increase blood circulation time. Here, heterobifunctional PEG links nanoparticles to targeting agents (antibodies and growth factors) to provide cell-specific binding. This approach is evaluated through a series of experiments. In vitro, antibody-coated nanoparticles can bind breast carcinoma cells expressing the targeted receptor and act as contrast agents for multiphoton microscopy prior to inducing cell death via photoablation. Furthermore, antibody-coated nanoparticles can bind tissue ex vivo at levels corresponding to receptor expression, suggesting they should bind their target even in the complex biological milieu. This is evaluated by comparing the accumulation of antibody-coated and PEG-coated nanoparticles in subcutaneous glioma tumors in mice. Contrary to expectations, antibody targeting did not yield more nanoparticles within tumors. Nevertheless, these studies established the sensitivity of glioma to photothermal therapy; mice treated with PEG-coated nanoshells experienced 57% complete tumor regression versus no regression in control mice. Subsequent experiments employed intracranial tumors to

  14. High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis

    PubMed Central

    Do, Lan; Dahl, Christen P.; Kerje, Susanne; Hansell, Peter; Mörner, Stellan; Lindqvist, Ulla; Engström-Laurent, Anna; Larsson, Göran; Hellman, Urban

    2015-01-01

    Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before. PMID:26448761

  15. Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma.

    PubMed

    Coon, Valerie; Laukert, Tamara; Pedone, Carolyn A; Laterra, John; Kim, K Jin; Fults, Daniel W

    2010-09-01

    The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh + HGF-driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7 + cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7 + 5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7 + cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh + HGF-induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. PMID:20807782

  16. Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

    PubMed Central

    Coon, Valerie; Laukert, Tamara; Pedone, Carolyn A.; Laterra, John; Kim, K. Jin; Fults, Daniel W.

    2010-01-01

    The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic Hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh+HGF–driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7+cyclopamine, or (e) L2G7+5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7+5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7+cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh+HGF induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. PMID:20807782

  17. Functionality in Electrospun Nanofibrous Membranes Based on Fiber's Size, Surface Area, and Molecular Orientation

    PubMed Central

    Matsumoto, Hidetoshi; Tanioka, Akihiko

    2011-01-01

    Electrospinning is a versatile method for forming continuous thin fibers based on an electrohydrodynamic process. This method has the following advantages: (i) the ability to produce thin fibers with diameters in the micrometer and nanometer ranges; (ii) one-step forming of the two- or three-dimensional nanofiber network assemblies (nanofibrous membranes); and (iii) applicability for a broad spectrum of molecules, such as synthetic and biological polymers and polymerless sol-gel systems. Electrospun nanofibrous membranes have received significant attention in terms of their practical applications. The major advantages of nanofibers or nanofibrous membranes are the functionalities based on their nanoscaled-size, highly specific surface area, and highly molecular orientation. These functionalities of the nanofibrous membranes can be controlled by their fiber diameter, surface chemistry and topology, and internal structure of the nanofibers. This report focuses on our studies and describes fundamental aspects and applications of electrospun nanofibrous membranes. PMID:24957735

  18. Size dependence and phase transition during melting of fcc-Fe nanoparticles: A molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Shen, Tong; Meng, Wenjian; Wu, Yongquan; Lu, Xionggang

    2013-07-01

    Continuous melting and cooling of isolated fcc-Fe nanoparticles with 59-9577 atoms are studied by Molecular Dynamics (MD) simulation with Sutton-Chen potential. An energy minimization process was employed to obtain the stable solid structure for simulation of melting. The energy-minimized nanoparticles show lower potential energy and radius compared with the counterparts without energy minimizing. The size dependence of melting point shows perfect linear variation with N-1/3 for particles above a limit of 113 atoms. The bulk melting temperature of 1833.3 K, which is close to the experimental data (1811 K for bcc and 1800.8 K for fcc), has been predicted by a linear relationship. Two different inner structures, including five-fold twinning and lamellar structures, have been found to be the initial stable configurations prior to melting, and both surface premelting and internal defects were verified as the origins for melting behavior.

  19. Fully anharmonic IR and Raman spectra of medium-size molecular systems: accuracy and interpretation†

    PubMed Central

    Barone, Vincenzo; Biczysko, Malgorzata; Bloino, Julien

    2015-01-01

    Computation of full infrared (IR) and Raman spectra (including absolute intensities and transition energies) for medium- and large-sized molecular systems beyond the harmonic approximation is one of the most interesting challenges of contemporary computational chemistry. Contrary to common beliefs, low-order perturbation theory is able to deliver results of high accuracy (actually often better than those issuing from current direct dynamics approaches) provided that anharmonic resonances are properly managed. This perspective sketches the recent developments in our research group toward the development a robust and user-friendly virtual spectrometer rooted into the second-order vibrational perturbation theory (VPT2) and usable also by non-specialists essentially as a black-box procedure. Several examples are explicitly worked out in order to illustrate the features of our computational tool together with the most important ongoing developments. PMID:24346191

  20. Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.

    PubMed

    Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia; Khoshnejad, Makan; Tliba, Samira; Christofidou-Solomidou, Melpo; Muzykantov, Vladimir R

    2016-07-28

    Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively. PMID:27210108

  1. Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and Toxicity

    PubMed Central

    Lee, Young Jin; Savtchenko, Regina; Ostapchenko, Valeriy G.; Makarava, Natallia; Baskakov, Ilia V.

    2011-01-01

    Background According to the prevailing view, soluble oligomers or small fibrillar fragments are considered to be the most toxic species in prion diseases. To test this hypothesis, two conformationally different amyloid states were produced from the same highly pure recombinant full-length prion protein (rPrP). The cytotoxic potential of intact fibrils and fibrillar fragments generated by sonication from these two states was tested using cultured cells. Methodology/Principal Findings For one amyloid state, fibril fragmentation was found to enhance its cytotoxic potential, whereas for another amyloid state formed within the same amino acid sequence, the fragmented fibrils were found to be substantially less toxic than the intact fibrils. Consistent with the previous studies, the toxic effects were more pronounced for cell cultures expressing normal isoform of the prion protein (PrPC) at high levels confirming that cytotoxicity was in part PrPC-dependent. Silencing of PrPC expression by small hairpin RNAs designed to silence expression of human PrPC (shRNA-PrPC) deminished the deleterious effects of the two amyloid states to a different extent, suggesting that the role of PrPC-mediated and PrPC-independent mechanisms depends on the structure of the aggregates. Conclusions/Significance This work provides a direct illustration that the relationship between an amyloid's physical dimension and its toxic potential is not unidirectional but is controlled by the molecular structure of prion protein (PrP) molecules within aggregated states. Depending on the structure, a decrease in size of amyloid fibrils can either enhance or abolish their cytotoxic effect. Regardless of the molecular structure or size of PrP aggregates, silencing of PrPC expression can be exploited to reduce their deleterious effects. PMID:21625461

  2. Molecular magnetic resonance probe targeting VEGF165: preparation and in vitro and in vivo evaluation.

    PubMed

    You, Xiao-Guang; Tu, Rong; Peng, Ming-Li; Bai, Yu-Jie; Tan, Mingqian; Li, Han-Jian; Guan, Jing; Wen, Li-Jun

    2014-01-01

    A new method for imaging the tumor human vascular endothelial growth factor 165 (VEGF 165) is presented. A magnetic resonance imaging (MRI) probe was prepared by crosslinking ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to the aptamer for tumor vascular endothelial growth factor 165 (VEGF165-aptamer). The molecular probe was evaluated for its in vitro and in vivo activities toward VEGF165. Enzyme-linked immunosorbent assay showed that the VEGF165-aptamer-USPIO nanoparticles conjugate specifically binds to VEGF165 in vitro. A cell proliferation test showed that VEGF165-aptamer-USPIO seems to block the proliferation of human umbilical vein endothelial cells induced by free VEGF165, suggesting that VEGF165 is an effective target of this molecular probe. In xenograft mice carrying liver cancer that expresses VEGF165, T2-weighted imaging of the tumor displayed marked negative enhancement 3 h after the intravenous administration of VEGF165-aptamer-USPIO. The enhancement disappeared 6 h after administration of the probe. These results suggest the targeted imaging effect of VEGF165-aptamer-USPIO probe in vivo for VEGF165-expressing tumors. This is the first report of a targeted MRI molecular probe based on USPIO and VEGF165-aptamer. PMID:24729581

  3. Recent advances in developing molecular tools for targeted genome engineering of mammalian cells.

    PubMed

    Lim, Kwang-il

    2015-01-01

    Various biological molecules naturally existing in diversified species including fungi, bacteria, and bacteriophage have functionalities for DNA binding and processing. The biological molecules have been recently actively engineered for use in customized genome editing of mammalian cells as the molecule-encoding DNA sequence information and the underlying mechanisms how the molecules work are unveiled. Excitingly, multiple novel methods based on the newly constructed artificial molecular tools have enabled modifications of specific endogenous genetic elements in the genome context at efficiencies that are much higher than that of the conventional homologous recombination based methods. This minireview introduces the most recently spotlighted molecular genome engineering tools with their key features and ongoing modifications for better performance. Such ongoing efforts have mainly focused on the removal of the inherent DNA sequence recognition rigidity from the original molecular platforms, the addition of newly tailored targeting functions into the engineered molecules, and the enhancement of their targeting specificity. Effective targeted genome engineering of mammalian cells will enable not only sophisticated genetic studies in the context of the genome, but also widely-applicable universal therapeutics based on the pinpointing and correction of the disease-causing genetic elements within the genome in the near future. PMID:25104401

  4. Breast Cancer Detection by B7-H3 Targeted Ultrasound Molecular Imaging

    PubMed Central

    Bachawal, Sunitha V.; Jensen, Kristin C.; Wilson, Katheryne E.; Tian, Lu; Lutz, Amelie M.; Willmann, Jürgen K.

    2015-01-01

    Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T cell co-regulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor and malignant breast pathologies for diagnostic purposes. Through an immunohistochemical analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients. PMID:25899053

  5. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets.

    PubMed

    Medico, Enzo; Russo, Mariangela; Picco, Gabriele; Cancelliere, Carlotta; Valtorta, Emanuele; Corti, Giorgio; Buscarino, Michela; Isella, Claudio; Lamba, Simona; Martinoglio, Barbara; Veronese, Silvio; Siena, Salvatore; Sartore-Bianchi, Andrea; Beccuti, Marco; Mottolese, Marcella; Linnebacher, Michael; Cordero, Francesca; Di Nicolantonio, Federica; Bardelli, Alberto

    2015-01-01

    The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available. PMID:25926053

  6. Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions

    PubMed Central

    Hirabara, Sandro M.; Gorjão, Renata; Vinolo, Marco A.; Rodrigues, Alice C.; Nachbar, Renato T.; Curi, Rui

    2012-01-01

    Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions. PMID:23049242

  7. An improved approach for predicting drug-target interaction: proteochemometrics to molecular docking.

    PubMed

    Shaikh, Naeem; Sharma, Mahesh; Garg, Prabha

    2016-02-23

    Proteochemometric (PCM) methods, which use descriptors of both the interacting species, i.e. drug and the target, are being successfully employed for the prediction of drug-target interactions (DTI). However, unavailability of non-interacting dataset and determining the applicability domain (AD) of model are a main concern in PCM modeling. In the present study, traditional PCM modeling was improved by devising novel methodologies for reliable negative dataset generation and fingerprint based AD analysis. In addition, various types of descriptors and classifiers were evaluated for their performance. The Random Forest and Support Vector Machine models outperformed the other classifiers (accuracies >98% and >89% for 10-fold cross validation and external validation, respectively). The type of protein descriptors had negligible effect on the developed models, encouraging the use of sequence-based descriptors over the structure-based descriptors. To establish the practical utility of built models, targets were predicted for approved anticancer drugs of natural origin. The molecular recognition interactions between the predicted drug-target pair were quantified with the help of a reverse molecular docking approach. The majority of predicted targets are known for anticancer therapy. These results thus correlate well with anticancer potential of the selected drugs. Interestingly, out of all predicted DTIs, thirty were found to be reported in the ChEMBL database, further validating the adopted methodology. The outcome of this study suggests that the proposed approach, involving use of the improved PCM methodology and molecular docking, can be successfully employed to elucidate the intricate mode of action for drug molecules as well as repositioning them for new therapeutic applications. PMID:26822863

  8. Discrete Step Sizes of Molecular Motors Lead to Bimodal Non-Gaussian Velocity Distributions under Force.

    PubMed

    Vu, Huong T; Chakrabarti, Shaon; Hinczewski, Michael; Thirumalai, D

    2016-08-12

    Fluctuations in the physical properties of biological machines are inextricably linked to their functions. Distributions of run lengths and velocities of processive molecular motors, like kinesin-1, are accessible through single-molecule techniques, but rigorous theoretical models for these probabilities are lacking. Here, we derive exact analytic results for a kinetic model to predict the resistive force (F)-dependent velocity [P(v)] and run length [P(n)] distribution functions of generic finitely processive molecular motors. Our theory quantitatively explains the zero force kinesin-1 data for both P(n) and P(v) using the detachment rate as the only parameter. In addition, we predict the F dependence of these quantities. At nonzero F, P(v) is non-Gaussian and is bimodal with peaks at positive and negative values of v, which is due to the discrete step size of kinesin-1. Although the predictions are based on analyses of kinesin-1 data, our results are general and should hold for any processive motor, which walks on a track by taking discrete steps. PMID:27564000

  9. Discrete Step Sizes of Molecular Motors Lead to Bimodal Non-Gaussian Velocity Distributions under Force

    NASA Astrophysics Data System (ADS)

    Vu, Huong T.; Chakrabarti, Shaon; Hinczewski, Michael; Thirumalai, D.

    2016-08-01

    Fluctuations in the physical properties of biological machines are inextricably linked to their functions. Distributions of run lengths and velocities of processive molecular motors, like kinesin-1, are accessible through single-molecule techniques, but rigorous theoretical models for these probabilities are lacking. Here, we derive exact analytic results for a kinetic model to predict the resistive force (F )-dependent velocity [P (v )] and run length [P (n )] distribution functions of generic finitely processive molecular motors. Our theory quantitatively explains the zero force kinesin-1 data for both P (n ) and P (v ) using the detachment rate as the only parameter. In addition, we predict the F dependence of these quantities. At nonzero F , P (v ) is non-Gaussian and is bimodal with peaks at positive and negative values of v , which is due to the discrete step size of kinesin-1. Although the predictions are based on analyses of kinesin-1 data, our results are general and should hold for any processive motor, which walks on a track by taking discrete steps.

  10. Molecular size of benzodiazepine receptor in rat brain in situ: evidence for a functional dimer?

    NASA Astrophysics Data System (ADS)

    Doble, A.; Iversen, L. L.

    1982-02-01

    Benzodiazepine tranquillizers such as diazepam and chlordiazepoxide interact with high-affinity binding sites in nervous tissue1,2. The correlation between the affinities of various benzodiazepines for these sites with their clinical potencies and activity in behavioural and electrophysiological tests in animals suggests that the sites represent the functional `receptor' whereby benzodiazepines exert their effects3. The intimate involvement of benzodiazepines with γ-aminobutyric acid (GABA) and chloride channels raised the possibility that the benzodiazepine binding site (BDZ-R) may be a protein in the GABA receptor-effector complex4,5. GABA agonists enhance the affinity of BDZ-R for benzodiazepines6, although BDZ-R is distinct from the GABA receptor itself3. However, electrophysiological evidence suggests that the action of benzodiazepines is chloride channel, rather than receptor, directed7-10. Several attempts have been made to measure the molecular weight (Mr) of BDZ-R after solubilization from brain membranes: treatment with 1% Triton X-100 followed by assay of binding activity in solute fractions separated according to molecular weight suggested11 a value of ~200,000, photoaffinity labelling of BDZ-R with 3H-flunitrazepam (3H-FNZ) followed by more rigorous solubilization and gel chromatography indicated12,13 an apparent Mr of ~55,000 and a third approach14 a value of ~100,000. The measured molecular weight seems to depend critically on the solubilization procedure used. Chang et al.15 recently described the use of radiation inactivation to determine the size of BDZ-R in situ in calf brain membranes, and estimated a Mr, of 216,000. We have also used this approach; the results reported here indicate a Mr of between 90,000 and 100,000, but this is reduced to 60,000-63,000 in membranes pretreated with GABA, suggesting the disaggregation of a normally dimeric form.

  11. Ionic size effects to molecular solvation energy and to ion current across a channel resulted from the nonuniform size-modified PNP equations

    NASA Astrophysics Data System (ADS)

    Qiao, Yu; Tu, Bin; Lu, Benzhuo

    2014-05-01

    Ionic finite size can impose considerable effects to both the equilibrium and non-equilibrium properties of a solvated molecular system, such as the solvation energy, ionic concentration, and transport in a channel. As discussed in our former work [B. Lu and Y. C. Zhou, Biophys. J. 100, 2475 (2011)], a class of size-modified Poisson-Boltzmann (PB)/Poisson-Nernst-Planck (PNP) models can be uniformly studied through the general nonuniform size-modified PNP (SMPNP) equations deduced from the extended free energy functional of Borukhov et al. [I. Borukhov, D. Andelman, and H. Orland, Phys. Rev. Lett. 79, 435 (1997)] This work focuses on the nonuniform size effects to molecular solvation energy and to ion current across a channel for real biomolecular systems. The main contributions are: (1) we prove that for solvation energy calculation with nonuniform size effects (through equilibrium SMPNP simulation), there exists a simplified approximation formulation which is the same as the widely used one in PB community. This approximate form avoids integration over the whole domain and makes energy calculations convenient. (2) Numerical calculations show that ionic size effects tend to negate the solvation effects, which indicates that a higher molecular solvation energy (lower absolute value) is to be predicted when ionic size effects are considered. For both calculations on a protein and a DNA fragment systems in a 0.5M 1:1 ionic solution, a difference about 10 kcal/mol in solvation energies is found between the PB and the SMPNP predictions. Moreover, it is observed that the solvation energy decreases as ionic strength increases, which behavior is similar as those predicted by the traditional PB equation (without size effect) and by the uniform size-modified Poisson-Boltzmann equation. (3) Nonequilibrium SMPNP simulations of ion permeation through a gramicidin A channel show that the ionic size effects lead to reduced ion current inside the channel compared with the results

  12. Ionic size effects to molecular solvation energy and to ion current across a channel resulted from the nonuniform size-modified PNP equations.

    PubMed

    Qiao, Yu; Tu, Bin; Lu, Benzhuo

    2014-05-01

    Ionic finite size can impose considerable effects to both the equilibrium and non-equilibrium properties of a solvated molecular system, such as the solvation energy, ionic concentration, and transport in a channel. As discussed in our former work [B. Lu and Y. C. Zhou, Biophys. J. 100, 2475 (2011)], a class of size-modified Poisson-Boltzmann (PB)/Poisson-Nernst-Planck (PNP) models can be uniformly studied through the general nonuniform size-modified PNP (SMPNP) equations deduced from the extended free energy functional of Borukhov et al. [I. Borukhov, D. Andelman, and H. Orland, Phys. Rev. Lett. 79, 435 (1997)] This work focuses on the nonuniform size effects to molecular solvation energy and to ion current across a channel for real biomolecular systems. The main contributions are: (1) we prove that for solvation energy calculation with nonuniform size effects (through equilibrium SMPNP simulation), there exists a simplified approximation formulation which is the same as the widely used one in PB community. This approximate form avoids integration over the whole domain and makes energy calculations convenient. (2) Numerical calculations show that ionic size effects tend to negate the solvation effects, which indicates that a higher molecular solvation energy (lower absolute value) is to be predicted when ionic size effects are considered. For both calculations on a protein and a DNA fragment systems in a 0.5M 1:1 ionic solution, a difference about 10 kcal/mol in solvation energies is found between the PB and the SMPNP predictions. Moreover, it is observed that the solvation energy decreases as ionic strength increases, which behavior is similar as those predicted by the traditional PB equation (without size effect) and by the uniform size-modified Poisson-Boltzmann equation. (3) Nonequilibrium SMPNP simulations of ion permeation through a gramicidin A channel show that the ionic size effects lead to reduced ion current inside the channel compared with the results

  13. Target size analysis of serotonin 5-HT/sub 1/ and 5-HT/sub 2/ receptors in bovine brain membranes

    SciTech Connect

    Nishino, N.; Tanaka, C.

    1985-09-23

    Freeze-dried crude synaptic membranes prepared from bovine cerebral cortex and striatum were exposed to high energy gamma ray from the source of /sup 60/Co. The size of serotonin 5-HT/sub 1/ receptors labeled by (/sup 3/H)serotonin and that of 5-HT/sub 2/ receptors labeled by (/sup 3/H)spiperone or (/sup 3/H)ketanserin was determined by target size analyses. The values were 57,000 daltons, 145,000 daltons and 152,000 daltons for the cerebral cortex and 56,000 daltons, 141,000 daltons and 150,000 daltons for the striatum, respectively. The estimated sizes were deduced by reference to enzyme standards with known molecular masses and which were irradiated in parallel. These results demonstrate that the molecular entities in situ for 5-HT/sub 1/ receptors are distinct from those for 5-HT/sub 2/ receptors, thus supporting data on the existence of two distinct populations of serotonin receptors, hitherto evidenced physiopharmacologically.

  14. High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging

    PubMed Central

    Xiao, Yunbin; Lin, Zuan Tao; Chen, Yanmei; Wang, He; Deng, Ya Li; Le, D Elizabeth; Bin, Jianguo; Li, Meiyu; Liao, Yulin; Liu, Yili; Jiang, Gangbiao; Bin, Jianping

    2015-01-01

    Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors. PMID:25709439

  15. Dependable and Efficient Clinical Molecular Diagnosis of Chinese RP Patient with Targeted Exon Sequencing

    PubMed Central

    Yin, Xiaobei; Dou, Hongliang; Zhao, Lin; Chen, Ningning; Zhang, Jinlu; Zhang, Huirong; Li, Genlin; Ma, Zhizhong

    2015-01-01

    Retinitis pigmentosa (RP) is the most common inherited retinal disease. It is a clinically and genetically heterogeneous disorder, which is why it is particularly challenging to diagnose. The aim of this study was to establish a targeted next-generation sequencing (NGS) approach for the comprehensive, rapid, and cost-effective clinical molecular diagnosis of RP. A specific hereditary eye disease enrichment panel (HEDEP) based on exome capture technology was used to collect the protein coding regions of 371 targeted hereditary eye disease genes, followed by high-throughput sequencing on the Illumina HiSeq2000 platform. From a cohort of 34 Chinese RP families, 13 families were successfully diagnosed; thus, the method achieves a diagnostic rate of approximately 40%. Of 16 pathogenic mutations identified, 11 were novel. Our study demonstrates that targeted capture sequencing offers a rapid and effective method for the molecular diagnosis of RP, which helps to provide a more accurate clinical diagnosis and paves the way for genetic counseling, family planning, and future gene-targeted treatment. PMID:26496393

  16. Molecular Targeted Therapies for the Treatment of Leptomeningeal Carcinomatosis: Current Evidence and Future Directions

    PubMed Central

    Lee, Dae-Won; Lee, Kyung-Hun; Kim, Jin Wook; Keam, Bhumsuk

    2016-01-01

    Leptomeningeal carcinomatosis (LMC) is the multifocal seeding of cerebrospinal fluid and leptomeninges by malignant cells. The incidence of LMC is approximately 5% in patients with malignant tumors overall and the rate is increasing due to increasing survival time of cancer patients. Eradication of the disease is not yet possible, so the treatment goals of LMC are to improve neurologic symptoms and to prolong survival. A standard treatment for LMC has not been established due to low incidences of LMC, the rapidly progressing nature of the disease, heterogeneous populations with LMC, and a lack of randomized clinical trial results. Treatment options for LMC include intrathecal chemotherapy, systemic chemotherapy, and radiation therapy, but the prognoses remain poor with a median survival of <3 months. Recently, molecular targeted agents have been applied in the clinic and have shown groundbreaking results in specific patient groups epidermal growth factor receptor (EGFR)-targeted therapy or an anaplastic lymphoma kinase (ALK) inhibitor in lung cancer, human epidermal growth factor receptor 2 (HER2)-directed therapy in breast cancer, and CD20-targeted therapy in B cell lymphoma). Moreover, there are results indicating that the use of these agents under proper dose and administration routes can be effective for managing LMC. In this article, we review molecular targeted agents for managing LMC. PMID:27399673

  17. Magnetic trapping with simultaneous photoacoustic detection of molecularly targeted rare circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Wei, Chen-Wei; Xia, Jinjun; Pelivanov, Ivan M.; Hu, Xiaoge; Gao, Xiaohu; O'Donnell, Matthew

    2013-03-01

    Photoacoustic (PA) imaging has been widely used in molecular imaging to detect diseased cells by targeting them with nanoparticle-based contrast agents. However, the sensitivity and specificity are easily degraded because contrast agent signals can be masked by the background. Magnetomotive photoacoustic imaging uses a new type of multifunctional composite particle combining an optically absorptive gold nanorod core and magnetic nanospheres, which can potentially accumulate and concentrate targeted cells while simultaneously enhancing their specific contrast compared to background signals. In this study, HeLa cells molecularly targeted using nanocomposites with folic acid mimicking targeted rare circulating tumor cells (CTCs) were circulated at a 6 ml/min flow rate for trapping and imaging studies. Preliminary results show that the cells accumulate rapidly in the presence of an externally applied magnetic field produced by a dual magnet system. The sensitivity of the current system can reach up to 1 cell/ml in clear water. By manipulating the trapped cells magnetically, the specificity of detecting cells in highly absorptive ink solution can be enhanced with 16.98 dB background suppression by applying motion filtering on PA signals to remove unwanted background signals insensitive to the magnetic field. The results appear promising for future preclinical studies on a small animal model and ultimate clinical detection of rare CTCs in the vasculature.

  18. De novo synthesis of a narrow size distribution low-molecular-weight heparin

    PubMed Central

    Chandarajoti, Kasemsiri; Xu, Yongmei; Sparkenbaugh, Erica; Key, Nigel S; Pawlinski, Rafal; Liu, Jian

    2014-01-01

    Heparin, a commonly used anticoagulant drug, is a mixture of highly sulfated polysaccharides with various molecular weights (MWs). The unique sulfation pattern dictates the anticoagulant activity of heparin. Commercial heparins are categorized into three forms according to their average MW: unfractionated heparin (UFH, MWavg 14,000), low-MW heparin (LMWH, MWavg 3500–6500) and the synthetic pentasaccharide (fondaparinux, MW 1508.3). UFH is isolated from porcine intestine while LMWH is derived from UFH by various methods of depolymerization, which generate a wide range of oligosaccharide chain lengths. Different degradation methods result in structurally distinct LMWH products, displaying different pharmacological and pharmacokinetic properties. In this report, we utilized a chemoenzymatic method to synthesize LMWH with the emphasis on controlling the size distribution of the oligosaccharides. A tetrasaccharide primer and a controlled enzyme-based polymerization were employed to build a narrow size oligosaccharide backbone. The oligosaccharide backbones were further modified by a series of sulfation and epimerization steps in order to obtain a full anticoagulation activity. Determination of the anticoagulation activity in vitro and ex vivo indicated that the synthetic LMWH has higher potency than enoxaparin, a commercial LMWH drug in clinical usage. PMID:24626379

  19. Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.

    PubMed

    Evans, Patrick D; Vallender, Eric J; Lahn, Bruce T

    2006-06-21

    Primary microcephaly is a developmental defect of the brain characterized by severely reduced brain size but an absence of other overt abnormalities. Mutations in several loci have been linked to primary microcephaly. The underlying genes for two of these were recently identified as CDK5RAP2 and CENPJ. Here, we focus on CDK5RAP2 and show that the protein evolutionary rate of this gene is significantly higher in primates than rodents or carnivores. We further show that the evolutionary rate within primates is particularly high in the human and chimpanzee terminal branches. Thus, the pattern of molecular evolution seen in CDK5RAP2 appears to parallel, at least approximately, that seen in two other previously identified primary microcephaly genes, microcephalin and ASPM. We also briefly discuss CENPJ, which similarly exhibits higher rate of protein evolution in primates as compared to rodents and carnivores. Together, the evolutionary patterns of all four presently known primary microcephaly genes are consistent with the hypothesis that genes regulating brain size during development might also play a role in brain evolution in primates and especially humans. PMID:16631324

  20. Original triazine inductor of new specific molecular targets, with antitumor activity against nonsmall cell lung cancer.

    PubMed

    Moreau, Dimitri; Jacquot, Catherine; Tsita, Polyxeni; Chinou, Ioanna; Tomasoni, Cristophe; Juge, Marcel; Antoniadou-Vyza, Ekaterini; Martignat, Lionel; Pineau, Alain; Roussakis, Christos

    2008-12-01

    Despite our growing insight into carcinogenesis, treatment of tumors, especially nonsmall cell lung cancer (NSCLC), remains limited and it is urgent to develop strategies that target tumor cells and their genetic features. Drug discovery efforts have historically focused on the search for compounds that modulate the protein products of genes. Current drug therapy targets only a few hundred endogenous targets, mainly proteins, such as receptors and enzymes. But now, the interest in specifically targeting RNA is increasing, both for target validation and/or therapeutic purposes. In this regard, our work was concerned with the induction of new molecular targets correlated to a cytostatic effect on NSCLC cell line, after treatment with a new triazin named A190. The in vitro study of cell cycle and apoptosis induction demonstrated the antiproliferative potential of this new compounds, and the use of quantitative RT-PCR analysis permit to display an original mechanism of action involving 2 genes: HEF1 and B2. The antitumor effect was also confirmed by the good results in vivo on nude mice xenografts. PMID:18798255

  1. Predicting Molecular Targets for Small-Molecule Drugs with a Ligand-Based Interaction Fingerprint Approach.

    PubMed

    Cao, Ran; Wang, Yanli

    2016-06-20

    The computational prediction of molecular targets for small-molecule drugs remains a great challenge. Herein we describe a ligand-based interaction fingerprint (LIFt) approach for target prediction. Together with physics-based docking and sampling methods, we assessed the performance systematically by modeling the polypharmacology of 12 kinase inhibitors in three stages. First, we examined the capacity of this approach to differentiate true targets from false targets with the promiscuous binder staurosporine, based on native complex structures. Second, we performed large-scale profiling of kinase selectivity on the clinical drug sunitinib by means of computational simulation. Third, we extended the study beyond kinases by modeling the cross-inhibition of bromodomain-containing protein 4 (BRD4) for 10 well-established kinase inhibitors. On this basis, we made prospective predictions by exploring new kinase targets for the anticancer drug candidate TN-16, originally known as a colchicine site binder and microtubule disruptor. As a result, p38α was highlighted from a panel of 187 different kinases. Encouragingly, our prediction was validated by an in vitro kinase assay, which showed TN-16 as a low-micromolar p38α inhibitor. Collectively, our results suggest the promise of the LIFt approach in predicting potential targets for small-molecule drugs. PMID:26222196

  2. Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy

    SciTech Connect

    Kim, Dong Wook; Huamani, Jessica; Fu, Allie; Hallahan, Dennis E. . E-mail: dennis.hallahan@vanderbilt.edu

    2006-01-01

    The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer.

  3. The development of molecularly targeted anticancer therapies: an Eli Lilly and Company perspective.

    PubMed

    Perry, William L; Weitzman, Aaron

    2005-03-01

    The ability to identify activated pathways that drive the growth and progression of cancer and to develop specific and potent inhibitors of key proteins in these pathways promises to dramatically change the treatment of cancer: A patient's cancer could be characterized at the molecular level and the information used to select the best treatment options. The development of successful therapies not only requires extensive target validation, but also new approaches to evaluating drug efficacy in animal models and in the clinic compared to the development of traditional cytotoxic agents. This article highlights Eli Lilly and Company's approach to developing targeted therapies, from target identification and validation through evaluation in the clinic. A selection of drugs in the Lilly Oncology pipeline is also discussed. PMID:16166991

  4. Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

    PubMed Central

    Bayraktar, Soley; Rocha-Lima, Caio M

    2013-01-01

    Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents. PMID:23696960

  5. Effects of Microbubble Size on Ultrasound-Induced Transdermal Delivery of High-Molecular-Weight Drugs

    PubMed Central

    Liao, Ai-Ho; Ho, Hsin-Chiao; Lin, Yi-Chun; Chen, Hang-Kang; Wang, Chih-Hung

    2015-01-01

    The transdermal delivery of a wide range of high-molecular-weight drugs is limited by the stratum corneum layer of the epidermis representing a significant barrier to penetration across the skin. This study first determined the different effects of different-size ultrasound (US) contrast agents and microbubbles (MBs) for enhancing the transdermal delivery of high-molecular-weight drugs. The effects of US-mediated different-size (1.4, 2.1, and 3.5 μm) MBs (as a contrast agent) and ascorbyl tetraisopalmitate (VC-IP) on enhancing skin transdermal delivery were demonstrated both in vitro and in vivo. The results indicated that at a power density of 3 W/cm2 the penetration depth in group US combined with 3.5-μm MBs and penetrating VC-IP (U+3.5) was 34% and 14% higher than those in groups US combined with 1.4-μm MBs and penetrating VC-IP (U+1.4) and US combined with 2.1-μm MBs and penetrating VC-IP (U+2.1), respectively, for the agarose phantoms, while the corresponding increases for pigskin were 37% and 19%.In terms of the skin permeation of VC-IP, the VC-IP concentration in group U+3.5 was 23% and 10% higher in than those in groups U+1.4 and U+2.1, respectively. The whitening effect (luminosity index) of mice skin in group U+3.5 had increased (significantly) by 28% after 1 week, by 34% after 2 weeks, and tended to stabilize after 3 weeks (45%) in C57BL/6J mice over a 4-week experimental period. The results obtained in this study indicate that combining US with MBs of different sizes can produce different degrees of skin permeability so as to enhance the delivery of VC-IP to inhibit melanogenesis, without damaging the skin in mice. PMID:26390051

  6. Effects of Microbubble Size on Ultrasound-Induced Transdermal Delivery of High-Molecular-Weight Drugs.

    PubMed

    Liao, Ai-Ho; Ho, Hsin-Chiao; Lin, Yi-Chun; Chen, Hang-Kang; Wang, Chih-Hung

    2015-01-01

    The transdermal delivery of a wide range of high-molecular-weight drugs is limited by the stratum corneum layer of the epidermis representing a significant barrier to penetration across the skin. This study first determined the different effects of different-size ultrasound (US) contrast agents and microbubbles (MBs) for enhancing the transdermal delivery of high-molecular-weight drugs. The effects of US-mediated different-size (1.4, 2.1, and 3.5 μm) MBs (as a contrast agent) and ascorbyl tetraisopalmitate (VC-IP) on enhancing skin transdermal delivery were demonstrated both in vitro and in vivo. The results indicated that at a power density of 3 W/cm2 the penetration depth in group US combined with 3.5-μm MBs and penetrating VC-IP (U+3.5) was 34% and 14% higher than those in groups US combined with 1.4-μm MBs and penetrating VC-IP (U+1.4) and US combined with 2.1-μm MBs and penetrating VC-IP (U+2.1), respectively, for the agarose phantoms, while the corresponding increases for pigskin were 37% and 19%.In terms of the skin permeation of VC-IP, the VC-IP concentration in group U+3.5 was 23% and 10% higher in than those in groups U+1.4 and U+2.1, respectively. The whitening effect (luminosity index) of mice skin in group U+3.5 had increased (significantly) by 28% after 1 week, by 34% after 2 weeks, and tended to stabilize after 3 weeks (45%) in C57BL/6J mice over a 4-week experimental period. The results obtained in this study indicate that combining US with MBs of different sizes can produce different degrees of skin permeability so as to enhance the delivery of VC-IP to inhibit melanogenesis, without damaging the skin in mice. PMID:26390051

  7. A comparative analysis of different molecular targets using PCR for diagnosis of old world leishmaniasis.

    PubMed

    Koltas, Ismail S; Eroglu, Fadime; Uzun, Soner; Alabaz, Derya

    2016-05-01

    The different sensitivity values were obtained in each study conducted for the diagnosis of leishmaniasis with the polymerase chain reaction (PCR). However, a standardized PCR target for the diagnosis of leishmaniasis does not exist. The aim of the current study, the most ideal PCR target was determined for diagnosis of leishmaniasis. A total of 72 smear and 48 bone marrow samples were analyzed with six different molecular targets to determine their potential as a tool for the specific molecular diagnosis of leishmaniasis using PCR. The positivity-negativity value and the sensitivity-specificity of each PCR targets were calculated. The positivity value of PCR targets were sequenced in different levels in the diagnosis of leishmaniasis from highest to lowest in the order of kDNA-PCR > SSU rRNA-PCR > ITS2-PCR > ITS1-PCR > ME-PCR > HSP70-PCR. The sensitivities of PCR targets except ITS1-PCR, ME-PCR and HSP70-PCR were found to be 100% in cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) cases as compared to microscopic examination accepted as a gold standard. The sensitivities of ITS1-PCR, ME-PCR and HSP70-PCR were found 96.6%, 90.0% and 86.6%, respectively, in CL-cases. In addition, the sensitivities of ITS1-PCR, ME-PCR and HSP70-PCR were found 90.0%, 70.0% and 60.0%, respectively, in VL-cases. The kDNA genomic region was the most sensitive for routine diagnosis of leishmaniasis. ITS1-PCR restriction fragment length polymorphism, the alternative method for the identification of Old World Leishmania species, did not require culturing of the parasites. PMID:26896641

  8. Locally Targeted Delivery of a Micron-Size Radiation Therapy Source Using Temperature-Sensitive Hydrogel

    SciTech Connect

    Kim, Yusung; Seol, Dong Rim; Mohapatra, Sucheta; Sunderland, John J.; Schultz, Michael K.; Domann, Frederick E.; Lim, Tae-Hong

    2014-04-01

    Purpose: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Methods and Materials: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. Results: RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). Conclusions: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the

  9. The molecular basis of multiple vector insertion by gene targeting in mammalian cells.

    PubMed Central

    Ng, P; Baker, M D

    1999-01-01

    Gene targeting using sequence insertion vectors generally results in integration of one copy of the targeting vector generating a tandem duplication of the cognate chromosomal region of homology. However, occasionally the target locus is found to contain >1 copy of the integrated vector. The mechanism by which the latter recombinants arise is not known. In the present study, we investigated the molecular basis by which multiple vectors become integrated at the chromosomal immunoglobulin mu locus in a murine hybridoma. To accomplish this, specially designed insertion vectors were constructed that included six diagnostic restriction enzyme markers in the Cmu region of homology to the target chromosomal mu locus. This enabled contributions by the vector-borne and chromosomal Cmu sequences at the recombinant locus to be ascertained. Targeted recombinants were isolated and analyzed to determine the number of vector copies integrated at the chromosomal immunoglobulin mu locus. Targeted recombinants identified as bearing >1 copy of the integrated vector resulted from a Cmu triplication formed by two vector copies in tandem. Examination of the fate of the Cmu region markers suggested that this class of recombinant was generated predominantly, if not exclusively, by two targeted vector integration events, each involving insertion of a single copy of the vector. Both vector insertion events into the chromosomal mu locus were consistent with the double-strand-break repair mechanism of homologous recombination. We interpret our results, taken together, to mean that a proportion of recipient cells is in a predetermined state that is amenable to targeted but not random vector integration. PMID:10049930

  10. Biomarker Tests for Molecularly Targeted Therapies: Laying the Foundation and Fulfilling the Dream.

    PubMed

    Lyman, Gary H; Moses, Harold L

    2016-06-10

    Precision medicine focuses on the management of individual patients on the basis of biomarkers and other distinguishing characteristics, with the overarching objective of improving clinical outcomes. The rapid proliferation of biomarker tests and targeted therapies has revolutionized patient care in a variety of serious disorders. Targeted cancer therapies interrupt oncogenic molecular pathways driven by mutations, overexpression, or translocation of specific genes. However, there is concern that the emergence of large-scale genomic data is exceeding our capacity to appropriately analyze and interpret the results.In 2014, the Institute of Medicine convened the Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies. This committee conducted a study to develop recommendations to address diverse and interconnected development, regulatory, clinical practice, and reimbursement issues. The committee conducted an extensive search of the relevant literature and invited testimony from a wide range of experts in the field. The final report of the committee's study and deliberations was released on March 4, 2016, focusing on ways to achieve 10 goals to further advance the development and appropriate clinical use of biomarker tests for molecularly targeted therapies.This article presents an overview of the committee's study and resulting recommendations, which cover establishment of clinical utility, regulatory oversight, coverage and reimbursement, health system data integration, as well as education and access. The committee's recommendations presented and discussed here are fundamentally grounded in the understanding that, when properly validated and appropriately implemented, these assays and corresponding therapies hold considerable promise to enhance the quality of patient care and improve meaningful clinical outcomes. PMID:27069080

  11. Ultrasound Molecular Imaging of Tumor Angiogenesis with an Integrin Targeted Microbubble Contrast Agent

    PubMed Central

    Anderson, Christopher R.; Hu, Xiaowen; Tlaxca, Jose; Decleves, Anne-Emilie; Houghtaling, Robert; Sharma, Kumar; Lawrence, Michael; Ferrara, Katherine; Rychak, Joshua J.

    2010-01-01

    Rationale and Objectives Ultrasound molecular imaging is an emerging technique for sensitive detection of intravascular targets. Molecular imaging of angiogenesis has strong potential for both clinical use and as a research tool in tumor biology and the development of anti-angiogenic therapies. Our objective is to develop a robust microbubble (MB) ultrasound contrast agent platform to which targeting ligands can be conjugated by biocompatible, covalent conjugation chemistry, and to develop a pure low mechanical index imaging processing method and corresponding quantifying method. The microbubbles and the imaging methods were evaluated in a mouse model of breast cancer in vivo. Materials and Methods We utilized a cyclic RGD (cRGD) pentapeptide containing a terminal cysteine group conjugated to the surface of MB bearing pyridyldithio-propionate (PDP) for targeting αvβ3 integrins. As negative controls, MB without a ligand or MB bearing a scrambled sequence (cRAD) were prepared. To enable characterization of peptides bound to MB surfaces, the cRGD peptide was labeled with FITC and detected by plate fluorometry, flow cytometry, and fluorescence microscopy. Targeted adhesion of cRGD-MB was demonstrated in an in vitro flow adhesion assay against recombinant murine αvβ3 integrin protein and αvβ3 integrin-expressing endothelial cells (bEnd.3). The specificity of cRGD-MB for αvβ3 integrin was demonstrated by treating bEnd.3 EC with a blocking antibody. A murine model of mammary carcinoma was used to assess targeted adhesion and ultrasound molecular imaging in vivo. The targeted microbubbles were visualized using a low mechanical index contrast imaging pulse sequence, and quantified by intensity normalization and two-dimensional Fourier transform analysis, Results The cRGD ligand concentration on the MB surface was ~8.2 × 106 molecules/MB. At a wall shear stress of 1.0 dynes/cm2, cRGD-MB exhibited 5-fold higher adhesion to immobilized recombinant αvβ3 integrin

  12. Specific binding of molecularly targeted agents to pancreas tumors and impact on observed optical contrast

    NASA Astrophysics Data System (ADS)

    Samkoe, Kimberley S.; Hextrum, Shannon K.; Pardesi, Omar; O'Hara, Julia A.; Hasan, Tayyaba; Pogue, Brian W.

    2010-02-01

    In optical imaging it is thought that optimum tumor contrast can be achieved with the use of small-labeled molecular tracers that have high affinity to their targets and fast clearance rates from the blood stream and healthy tissues. An example of this is fluorescently tagged EGF to monitor the molecular activity of tumors, such as pancreatic cancer. Extensive fluorescence contrast analysis for fluorescence molecular tomography has been performed on the AsPC-1 pancreas tumor, grown orthotopically in mice; yet, the binding dynamics of the EGF-fluorescent agent in vivo is not completely known. The bulk pancreatic tumor displays 3:1 contrast relative to the normal pancreas at long times after injection; however, even higher levels of fluorescence in the liver, kidney and intestine suggest that molecular specificity for the tumor may be low. Mice were administered a fluorescently labeled EGF agent and were sacrificed at various time points post-injection. To analyze the amount of specific binding at each time point frozen tissue samples were fluorescently imaged, washed with saline to remove the interstitially distributed contrast agent, and then imaged again. This technique demonstrated that approximately ~10% of the molecular target was firmly bound to the cell, while 90% was mobile or unbound. This low binding ratio suggests that the contrast observed is from inherent properties of the tumor (i.e. enhanced permeability and retention effect) and not from specific bound contrast as previously anticipated. The use of EGF contrast agents in MRI-guided fluorescence tomography and the impact of low binding specificity are discussed.

  13. Target-protecting dumbbell molecular probe against exonucleases digestion for sensitive detection of ATP and streptavidin.

    PubMed

    Chen, Jinyang; Liu, Yucheng; Ji, Xinghu; He, Zhike

    2016-09-15

    In this work, a versatile dumbbell molecular (DM) probe was designed and employed in the sensitively homogeneous bioassay. In the presence of target molecule, the DM probe was protected from the digestion of exonucleases. Subsequently, the protected DM probe specifically bound to the intercalation dye and resulted in obvious fluorescence signal which was used to determine the target molecule in return. This design allows specific and versatile detection of diverse targets with easy operation and no sophisticated fluorescence labeling. Integrating the idea of target-protecting DM probe with adenosine triphosphate (ATP) involved ligation reaction, the DM probe with 5'-end phosphorylation was successfully constructed for ATP detection, and the limitation of detection was found to be 4.8 pM. Thanks to its excellent selectivity and sensitivity, this sensing strategy was used to detect ATP spiked in human serum as well as cellular ATP. Moreover, the proposed strategy was also applied in the visual detection of ATP in droplet-based microfluidic platform with satisfactory results. Similarly, combining the principle of target-protecting DM probe with streptavidin (SA)-biotin interaction, the DM probe with 3'-end biotinylation was developed for selective and sensitive SA determination, which demonstrated the robustness and versatility of this design. PMID:27131994

  14. Site-targeted acoustic contrast agent detects molecular expression of tissue factor after balloon angioplasty

    NASA Astrophysics Data System (ADS)

    Hall, Christopher S.; Abendschein, Dana R.; Scherrer, David E.; Scott, Michael J.; Marsh, Jon N.; Wickline, Samuel A.; Lanza, Gregory M.

    2000-04-01

    Complex molecular signaling heralds the early stages of pathologies such as angiogenesis, inflammation, and cellular responses to mechanically damaged coronary arteries after balloon angioplasty. In previous studies, we have demonstrated acoustic enhancement of blood clot morphology with the use of a nongaseous, ligand-targeted acoustic nanoparticle emulsion delivered to areas of thrombosis both in vitro and in vivo. In this paper, we characterize the early expression of tissue factor which contributes to subsequent arterial restenosis. Tissue factor is a 42kd glycoprotein responsible for blood coagulation but also plays a well-described role in cancer metastasis, angiogenesis, and vascular restenosis. This study was designed to determine whether the targeted contrast agent could localize tissue factor expressed within the wall of balloon-injured arteries. Both carotid arteries of five pigs (20 kg) were injured using an 8 X 20 mm angioplasty balloon. The carotids were treated in situ with a perfluorocarbon nanoparticle emulsion covalently complexed to either specific anti-tissue factor polyclonal F(ab) fragments (treatment) or non-specific IgG F(ab) fragments (control). Intravascular ultrasound (30 MHz) images of the arteries were obtained before and after exposure to the emulsions. Tissue- factor targeted ultrasonic contrast agent acoustically enhanced the subintima and media at the site of balloon- induced injury compared with control contrast arteries (p less than 0.05). Immunohistochemical staining confirmed the presence of increased tissue factor at the sites of acoustic enhancement. Binding of the targeted agents was demonstrated in vitro by scanning electron microscope images of cultured smooth muscle cells that constitutively express tissue factor. This study demonstrates the concept of molecular imaging and localization of carotid arteries' tissue factor in vivo using a new, nanoparticulate emulsion. Enhancement of the visualization of the molecular

  15. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

    PubMed Central

    Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin

    2014-01-01

    The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

  16. The Molecular Phenotype of Endocapillary Proliferation: Novel Therapeutic Targets for IgA Nephropathy

    PubMed Central

    John, Rohan; Grone, Elisabeth; Porubsky, Stefan; Gröne, Hermann-Josef; Herzenberg, Andrew M.; Scholey, James W.; Hladunewich, Michelle; Cattran, Daniel C.

    2014-01-01

    IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN. PMID:25133636

  17. Molecular crowding effect on dynamics of DNA-binding proteins search for their targets

    NASA Astrophysics Data System (ADS)

    Liu, Lin; Luo, Kaifu

    2014-12-01

    DNA-binding proteins locate and bind their target sequences positioned on DNA in crowded environments, but the molecular crowding effect on this search process is not clear. Using analytical techniques and Langevin dynamics simulations in two dimensions (2D), we find that the essential physics for facilitated diffusion in 2D search and 3D search is the same. We observe that the average search times have minima at the same optimal nonspecific binding energy for the cases with and without the crowding particle. Moreover, the molecular crowding increases the search time by increasing the average search rounds and the one-dimensional (1D) sliding time of a round, but almost not changing the average 2D diffusion time of a round. In addition, the fraction of 1D sliding time out of the total search time increases with increasing the concentration of crowders. For 2D diffusion, the molecular crowding decreases the jumping length and narrows its distribution due to the cage effect from crowders. These results shed light on the role of facilitated diffusion in DNA targeting kinetics in living cells.

  18. Target Product Profile of a Molecular Drug-Susceptibility Test for Use in Microscopy Centers

    PubMed Central

    Denkinger, Claudia M.; Dolinger, David; Schito, Marco; Wells, William; Cobelens, Frank; Pai, Madhukar; Zignol, Matteo; Cirillo, Daniela Maria; Alland, David; Casenghi, Martina; Gallarda, Jim; Boehme, Catharina C.; Perkins, Mark D.

    2015-01-01

    Background. Current phenotypic testing for drug resistance in patients with tuberculosis is inadequate primarily with respect to turnaround time. Molecular tests hold the promise of an improved time to diagnosis. Methods. A target product profile for a molecular drug-susceptibility test (DST) was developed on the basis of a collaborative effort that included opinions gathered from researchers, clinicians, policy makers, and test developers on optimal clinical and operational characteristics in settings of intended use. In addition, the current diagnostic ecosystem and the diagnostic development landscape were mapped. Results. Molecular DSTs for detecting tuberculosis in microscopy centers should ideally evaluate for resistance to rifampin, fluoroquinolones, isoniazid, and pyrazinamide and enable the selection of the most appropriate treatment regimen. Performance characteristics of DSTs need to be optimized, but compromises can be made that depend on the trade-off between a false-positive result and a false-negative result. The operational requirements of a test will vary depending on the site of implementation. However, the most-important considerations pertain to quality control, maintenance and calibration, and the ability to export data. Conclusion. This target product profile defines the needs as perceived by the tuberculosis stakeholder community and attempts to provide a means of communication with test developers to ensure that fit-for-purpose DSTs are being developed. PMID:25765105

  19. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets.

    PubMed

    Safi, Sher Zaman; Qvist, Rajes; Kumar, Selva; Batumalaie, Kalaivani; Ismail, Ikram Shah Bin

    2014-01-01

    The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

  20. Searching for life on Mars: selection of molecular targets for ESA's aurora ExoMars mission.

    PubMed

    Parnell, John; Cullen, David; Sims, Mark R; Bowden, Stephen; Cockell, Charles S; Court, Richard; Ehrenfreund, Pascale; Gaubert, Francois; Grant, William; Parro, Victor; Rohmer, Michel; Sephton, Mark; Stan-Lotter, Helga; Steele, Andrew; Toporski, Jan; Vago, Jorge

    2007-08-01

    The European Space Agency's ExoMars mission will seek evidence of organic compounds of biological and non-biological origin at the martian surface. One of the instruments in the Pasteur payload may be a Life Marker Chip that utilizes an immunoassay approach to detect specific organic molecules or classes of molecules. Therefore, it is necessary to define and prioritize specific molecular targets for antibody development. Target compounds have been selected to represent meteoritic input, fossil organic matter, extant (living, recently dead) organic matter, and contamination. Once organic molecules are detected on Mars, further information is likely to derive from the detailed distribution of compounds rather than from single molecular identification. This will include concentration gradients beneath the surface and gradients from generic to specific compounds. The choice of biomarkers is informed by terrestrial biology but is wide ranging, and nonterrestrial biology may be evident from unexpected molecular distributions. One of the most important requirements is to sample where irradiation and oxidation are minimized, either by drilling or by using naturally excavated exposures. Analyzing regolith samples will allow for the search of both extant and fossil biomarkers, but sequential extraction would be required to optimize the analysis of each of these in turn. PMID:17723091

  1. Cell size control in yeast

    PubMed Central

    Turner, Jonathan J.; Ewald, Jennifer C.; Skotheim, Jan M.

    2012-01-01

    Cell size is an important adaptive trait that influences nearly all aspects of cellular physiology. Despite extensive characterization of the cell cycle regulatory network, the molecular mechanismscoupling growth to division, and thereby controlling cell size, have remained elusive. Recent workin yeast has reinvigorated the size control field and suggested provocative mechanisms forthe distinct functions of setting and sensing cell size. Further examination of size sensing models based on spatial gradients and molecular titration, coupled with elucidation of the pathways responsible for nutrient-modulated target size, may reveal the fundamental principles of eukaryotic cell size control. PMID:22575477

  2. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets.

    PubMed

    Chan, K Ming; Gordon, Tessa; Zochodne, Douglas W; Power, Hollie A

    2014-11-01

    Peripheral nerve injury is common especially among young individuals. Although injured neurons have the ability to regenerate, the rate is slow and functional outcomes are often poor. Several potential therapeutic agents have shown considerable promise for improving the survival and regenerative capacity of injured neurons. These agents are reviewed within the context of their molecular mechanisms. The PI3K/Akt and Ras/ERK signaling cascades play a key role in neuronal survival. A number of agents that target these pathways, including erythropoietin, tacrolimus, acetyl-l-carnitine, n-acetylcysteine and geldanamycin have been shown to be effective. Trk receptor signaling events that up-regulate cAMP play an important role in enhancing the rate of axonal outgrowth. Agents that target this pathway including rolipram, testosterone, fasudil, ibuprofen and chondroitinase ABC hold considerable promise for human application. A tantalizing prospect is to combine different molecular targeting strategies in complementary pathways to optimize their therapeutic effects. Although further study is needed prior to human trials, these modalities could open a new horizon in the clinical arena that has so far been elusive. PMID:25220611

  3. Targeted next-generation sequencing for the detection of ciprofloxacin resistance markers using molecular inversion probes

    PubMed Central

    Stefan, Christopher P.; Koehler, Jeffrey W.; Minogue, Timothy D.

    2016-01-01

    Antibiotic resistance (AR) is an epidemic of increasing magnitude requiring rapid identification and profiling for appropriate and timely therapeutic measures and containment strategies. In this context, ciprofloxacin is part of the first-line of countermeasures against numerous high consequence bacteria. Significant resistance can occur via single nucleotide polymorphisms (SNP) and deletions within ciprofloxacin targeted genes. Ideally, use of ciprofloxacin would be prefaced with AR determination to avoid overuse or misuse of the antibiotic. Here, we describe the development and evaluation of a panel of 44 single-stranded molecular inversion probes (MIPs) coupled to next-generation sequencing (NGS) for the detection of genetic variants known to confer ciprofloxacin resistance in Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Sequencing results demonstrate MIPs capture and amplify targeted regions of interest at significant levels of coverage. Depending on the genetic variant, limits of detection (LOD) for high-throughput pooled sequencing ranged from approximately 300–1800 input genome copies. LODs increased 10-fold in the presence of contaminating human genome DNA. In addition, we show that MIPs can be used as an enrichment step with high resolution melt (HRM) real-time PCR which is a sensitive assay with a rapid time-to-answer. Overall, this technology is a multiplexable upfront enrichment applicable with multiple downstream molecular assays for the detection of targeted genetic regions. PMID:27174456

  4. Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review.

    PubMed

    Craig, Sonya E L; Wright, James; Sloan, Andrew E; Brady-Kalnay, Susann M

    2016-06-01

    The median life expectancy after a diagnosis of glioblastoma is 15 months. Although chemotherapeutics may someday cure glioblastoma by killing the highly dispersive malignant cells, the most important contribution that clinicians can currently offer to improve survival is by maximizing the extent of resection and providing concurrent chemo-radiation, which has become standard. Strides have been made in this area with the advent and implementation of methods of improved intraoperative tumor visualization. One of these techniques, optical fluorescent imaging with targeted molecular imaging agents, allows the surgeon to view fluorescently labeled tumor tissue during surgery with the use of special microscopy, thereby highlighting where to resect and indicating when tumor-free margins have been obtained. This advantage is especially important at the difficult-to-observe margins where tumor cells infiltrate normal tissue. Targeted fluorescent agents also may be valuable for identifying tumor versus nontumor tissue. In this review, we briefly summarize nontargeted fluorescent tumor imaging agents before discussing several novel targeted fluorescent agents being developed for glioma imaging in the context of fluorescent-guided surgery or live molecular navigation. Many of these agents are currently undergoing preclinical testing. As the agents become available, however, it is necessary to understand the strengths and weaknesses of each. PMID:26915698

  5. Target Definition in Salvage Radiotherapy for Recurrent Prostate Cancer: The Role of Advanced Molecular Imaging

    PubMed Central

    Amzalag, Gaël; Rager, Olivier; Tabouret-Viaud, Claire; Wissmeyer, Michael; Sfakianaki, Electra; de Perrot, Thomas; Ratib, Osman; Miralbell, Raymond; Giovacchini, Giampiero; Garibotto, Valentina; Zilli, Thomas

    2016-01-01

    Salvage radiotherapy (SRT) represents the main treatment option for relapsing prostate cancer in patients after radical prostatectomy. Several open questions remain unanswered in terms of target volumes definition and delivered doses for SRT: the effective dose necessary to achieve biochemical control in the SRT setting may be different if the tumor recurrence is micro- or macroscopic. At the same time, irradiation of only the prostatic bed or of the whole pelvis will depend on the localization of the recurrence, local or locoregional. In the “theragnostic imaging” era, molecular imaging using positron emission tomography (PET) constitutes a useful tool for clinicians to define the site of the recurrence, the extent of disease, and individualize salvage treatments. The best option currently available in clinical routine is the combination of radiolabeled choline PET imaging and multiparametric magnetic resonance imaging (MRI), associating the nodal and distant metastases identification based on PET with the local assessment by MRI. A new generation of targeted tracers, namely, prostate-specific membrane antigen, show promising results, with a contrast superior to choline imaging and a higher detection rate even for low prostate-specific antigen levels; validation studies are ongoing. Finally, imaging targeting bone remodeling, using whole-body SPECT–CT, is a relevant complement to molecular/metabolic PET imaging when bone involvement is suspected. PMID:27065024

  6. Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

    PubMed Central

    Sahin, Ibrahim H; Iacobuzio-Donahue, Christine A; O’Reilly, Eileen M

    2016-01-01

    Introduction Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. Areas covered In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. Expert opinion Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a ‘precision medicine’ approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes. PMID:26439702

  7. Targeted next-generation sequencing for the detection of ciprofloxacin resistance markers using molecular inversion probes.

    PubMed

    Stefan, Christopher P; Koehler, Jeffrey W; Minogue, Timothy D

    2016-01-01

    Antibiotic resistance (AR) is an epidemic of increasing magnitude requiring rapid identification and profiling for appropriate and timely therapeutic measures and containment strategies. In this context, ciprofloxacin is part of the first-line of countermeasures against numerous high consequence bacteria. Significant resistance can occur via single nucleotide polymorphisms (SNP) and deletions within ciprofloxacin targeted genes. Ideally, use of ciprofloxacin would be prefaced with AR determination to avoid overuse or misuse of the antibiotic. Here, we describe the development and evaluation of a panel of 44 single-stranded molecular inversion probes (MIPs) coupled to next-generation sequencing (NGS) for the detection of genetic variants known to confer ciprofloxacin resistance in Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Sequencing results demonstrate MIPs capture and amplify targeted regions of interest at significant levels of coverage. Depending on the genetic variant, limits of detection (LOD) for high-throughput pooled sequencing ranged from approximately 300-1800 input genome copies. LODs increased 10-fold in the presence of contaminating human genome DNA. In addition, we show that MIPs can be used as an enrichment step with high resolution melt (HRM) real-time PCR which is a sensitive assay with a rapid time-to-answer. Overall, this technology is a multiplexable upfront enrichment applicable with multiple downstream molecular assays for the detection of targeted genetic regions. PMID:27174456

  8. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy

    PubMed Central

    Hu, Yongfei; Li, Xiaobo; Wang, Xishan; Fan, Huihui; Wang, Guiyu; Wang, Dong

    2015-01-01

    Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers. PMID:26461477

  9. Trypanosoma cruzi Invasion into Host Cells: A Complex Molecular Targets Interplay.

    PubMed

    Campo, Vanessa Leiria; Martins-Teixeira, Maristela Braga; Carvalho, Ivone

    2016-01-01

    Chagas' disease is still a worldwide threat, with estimated from 6 to 7 million infected people, mainly in Latin America. Despite all efforts, especially from international consortia (DNDi, NMTrypI), to develop an innovative therapeutic strategy against this disease, no candidate has achieved full requirements for clinical use yet. In this review, we point out the general molecular and cellular mechanisms involved in T. cruzi cell invasion and elucidate the roles of specific parasite and host targets in the progress of Chagas' disease. Among these molecular targets are Gp85/transsialidase, mucins, cruzipain and oligopeptidase B, found in parasite cell surface, and Galectin-3 and Toll-like receptors present in host cells. Thus, the deep understanding of their interplay and involvement on T. cruzi host cell adhesion, invasion and evasion from host immune may expand the chances for discovering new therapeutic agents against this neglected disease. Additionally, these targets may represent a remarkable strategy to block parasite invasion in the early stages of infection. PMID:27281167

  10. Size of lethality target in mouse immature oocytes determined with accelerated heavy ions.

    PubMed

    Straume, T; Dobson, R L; Kwan, T C

    1989-01-01

    Mouse immature oocytes were irradiated in vivo with highly charged, heavy ions from the Bevalac accelerator at the Lawrence Berkeley Laboratory. The particles used were 670-MeV/nucleon Si14+, 570-MeV/nucleon Ar18+, and 450-MeV/nucleon Fe26+. The cross-sectional area of the lethality target in these extremely radiosensitive cells was determined from fluence-response curves and information on energy deposition by delta rays. Results indicate a target cross-section larger than that of the nucleus, one which closely approximates the cross-sectional area of the entire oocyte. For 450-MeV/nucleon Fe26+ particles, the predicted target cross-sectional area is 120 +/- 16 microns2, comparing well with the microscopically determined cross-sectional area of 111 +/- 12 microns2 for these cells. The present results are in agreement with our previous target studies which implicate the oocyte plasma membrane. PMID:2657842

  11. Five miRNAs Considered as Molecular Targets for Predicting Esophageal Cancer

    PubMed Central

    Zhao, Jia-ying; Wang, Fei; Li, Yi; Zhang, Xing-bo; Yang, Lei; Wang, Wei; Xu, Hao; Liu, Da-zhong; Zhang, Lin-you

    2015-01-01

    Background Esophageal cancer (EC) is one of the most aggressive malignant gastrointestinal tumors; however the traditional therapies for EC are not effective enough. Great improvements are needed to explore new and valid treatments for EC. We aimed to screen the differentially expressed miRNAs (DEMs) in esophageal cancer and explore the pathogenesis of esophageal cancer along with functions and pathways of the target genes. Material/Methods miRNA high-throughput sequencing data were downloaded from The Cancer Genome Atlas (TCGA), then the DEMs underwent principal component analysis (PCA) based on their expression value. Following that, TargetScan software was used to predict the target genes, and enrichment analysis and pathway annotation of these target genes were done by DAVID and KEGG, respectively. Finally, survival analysis between the DEMs and patient survival time was done, and the miRNAs with prediction potential were identified. Results A total of 140 DEMs were obtained, 113 miRNAs were up-regulated including hsa-mir-153-2, hsa-mir-92a-1 and hsa-mir-182; while 27 miRNAs were down-regulated including hsa-mir comprising 29a, hsa-mir-100 and hsa-mir-139 and so on. Five miRNAs (hsa-mir-103-1, hsa-mir-18a, hsa-mir-324, hsa-mir-369 and hsa-mir-320b-2) with diagnostic and preventive potential were significantly correlated with survival time. Conclusions The crucial molecular targets such as p53 may provide great clinical value in treatment, as well to provide new ideas for esophageal cancer therapy. The target genes of miRNA were found to play key roles in protein phosphorylation, and the functions of the target genes during protein phosphorylation should be further studied to explore novel treatment of EC. PMID:26498375

  12. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents

    PubMed Central

    Walker, Sarah R.; Chaudhury, Mousumi; Frank, David A.

    2011-01-01

    To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies. PMID:21949561

  13. Sampling Enrichment toward Target Structures Using Hybrid Molecular Dynamics-Monte Carlo Simulations

    PubMed Central

    Yang, Kecheng; Różycki, Bartosz; Cui, Fengchao; Shi, Ce; Chen, Wenduo; Li, Yunqi

    2016-01-01

    Sampling enrichment toward a target state, an analogue of the improvement of sampling efficiency (SE), is critical in both the refinement of protein structures and the generation of near-native structure ensembles for the exploration of structure-function relationships. We developed a hybrid molecular dynamics (MD)-Monte Carlo (MC) approach to enrich the sampling toward the target structures. In this approach, the higher SE is achieved by perturbing the conventional MD simulations with a MC structure-acceptance judgment, which is based on the coincidence degree of small angle x-ray scattering (SAXS) intensity profiles between the simulation structures and the target structure. We found that the hybrid simulations could significantly improve SE by making the top-ranked models much closer to the target structures both in the secondary and tertiary structures. Specifically, for the 20 mono-residue peptides, when the initial structures had the root-mean-squared deviation (RMSD) from the target structure smaller than 7 Å, the hybrid MD-MC simulations afforded, on average, 0.83 Å and 1.73 Å in RMSD closer to the target than the parallel MD simulations at 310K and 370K, respectively. Meanwhile, the average SE values are also increased by 13.2% and 15.7%. The enrichment of sampling becomes more significant when the target states are gradually detectable in the MD-MC simulations in comparison with the parallel MD simulations, and provide >200% improvement in SE. We also performed a test of the hybrid MD-MC approach in the real protein system, the results showed that the SE for 3 out of 5 real proteins are improved. Overall, this work presents an efficient way of utilizing solution SAXS to improve protein structure prediction and refinement, as well as the generation of near native structures for function annotation. PMID:27227775

  14. In situ relations of target strength to fish size for Great Lakes pelagic planktivores

    USGS Publications Warehouse

    Fleischer, Guy W.; Argyle, Ray L.; Curtis, Gary L.

    1997-01-01

    We found mean target strength to be a reliable in situ predictor of fish weight, which allows direct estimation of the pelagic planktivore fish biomass from target strength measurements. Fish were collected by midwater trawling concurrent with target strength measurements (120-kHz frequency) in Lake Michigan. The mean weight of fish caught ranged from 2 to 71 g and mean target strength ranged from –54.9 to –38.0 decibels. Changes in mean target strength explained 73% of the variability in mean weight for combinations of various planktivore species, principally rainbow smelt Osrnerus mordax, bloaters Coregonus hovi, and alewives Alosa pseudoharengus. Bloaters were found to be less acoustically reflective than the other pelagic species, and a linear regression model with a classification variable was used to predict weight from target strength for bloaters and for the other species. We demonstrated that variations in the backscattering properties of different fish species must be considered to obtain accurate acoustic-based estimates of fish biomass.

  15. Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

    PubMed Central

    Luis, Michael; Tavares, Ana; Carvalho, Liliana S; Lara-Santos, Lúcio; Araújo, António; de Mello, Ramon Andrade

    2013-01-01

    Globally, gastric cancer is the 4th most frequently diagnosed cancer and the 2nd leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved. PMID:24151357

  16. Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

    PubMed Central

    Lopez, Juanita; Harris, Sam; Roda, Desam; Yap, Timothy A

    2015-01-01

    Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies. PMID:26609214

  17. FXR is a molecular target for the effects of vertical sleeve gastrectomy

    PubMed Central

    Ryan, Karen K.; Tremaroli, Valentina; Clemmensen, Christoffer; Kovatcheva-Datchary, Petia; Myronovych, Andriy; Karns, Rebekah; Wilson-Pérez, Hilary E.; Sandoval, Darleen A.; Kohli, Rohit; Bäckhed, Fredrik; Seeley, Randy J.

    2014-01-01

    SUMMARY Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are currently the most effective therapy for the treatment of obesity, and are associated with substantial improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention. The present study demonstrates that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, we report that VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of this weight-loss surgery. PMID:24670636

  18. Molecularly targeted agents and immunotherapy for the treatment of head and neck squamous cell cancer (HNSCC).

    PubMed

    Azoury, SaÏd C; Gilmore, Richard C; Shukla, Vivek

    2016-06-01

    Squamous cell carcinoma is one of the most frequent tumors of the head and neck and often presents at an advanced-stage. Traditionally, treatment for head and neck squamous cell carcinoma (HNSCC) has included surgery, radiation, and chemotherapy depending on both the site and stage of disease. Although the treatment approach for local disease is often standardized, the management of recurrent and advanced disease is evolving. A better understanding of the molecular mechanisms of HNSCC has led to numerous promising investigations and the push for the development of novel therapies. Similarly, over the past several decades, growing data supports the notion that an individual's immune system can be manipulated in such a way to help eradicate cancer. The success of immunotherapeutic agents such as interleukin therapy and immune checkpoint inhibitor blockade in cancer, particularly advanced-stage melanoma, has stimulated researchers to uncover similar success stories in HNSCC. Examples of immunotherapeutics that are being studied for the treatment of HNSCC include adoptive T-cell therapy, vaccines, and immune checkpoint inhibitor proteins (e.g., anti-CTLA-4, -PD-1, -PD-L1). Molecularly targeted agents of interest include inhibitors of transmembrane growth factor receptors, angiogenesis, and PI3K/AKT/mTOR and NOTCH signaling pathways. To date, cetuximab, an epidermal growth factor receptor inhibitor, is the only targeted agent for HNSCC that was approved by the Federal Food and Drug Administration (FDA) on the basis that it improves overall survival when combined with chemotherapy or radiation. Herein, the authors provide an up-to-date review of immunotherapeutic and molecularly targeted agents for the treatment of HNSCC. PMID:27448787

  19. Molecular targets of dietary agents for prevention and therapy of cancer.

    PubMed

    Aggarwal, Bharat B; Shishodia, Shishir

    2006-05-14

    While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food. PMID:16563357

  20. Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer

    PubMed Central

    Balasundaram, Ghayathri; Ho, Chris Jun Hui; Li, Kai; Driessen, Wouter; Dinish, US; Wong, Chi Lok; Ntziachristos, Vasilis; Liu, Bin; Olivo, Malini

    2015-01-01

    Conjugated polymers (CPs) are upcoming optical contrast agents in view of their unique optical properties and versatile synthetic chemistry. Biofunctionalization of these polymer-based nanoparticles enables molecular imaging of biological processes. In this work, we propose the concept of using a biofunctionalized CP for noninvasive photoacoustic (PA) molecular imaging of breast cancer. In particular, after verifying the PA activity of a CP nanoparticle (CP dots) in phantoms and the targeting efficacy of a folate-functionalized version of the same (folate-CP dots) in vitro, we systemically administered the probe into a folate receptor-positive (FR+ve) MCF-7 breast cancer xenograft model to demonstrate the possible application of folate-CP dots for imaging FR+ve breast cancers in comparison to CP dots with no folate moieties. We observed a strong PA signal at the tumor site of folate-CP dots-administered mice as early as 1 hour after administration as a result of the active targeting of the folate-CP dots to the FR+ve tumor cells but a weak PA signal at the tumor site of CP-dots-administered mice as a result of the passive accumulation of the probe by enhanced permeability and retention effect. We also observed that folate-CP dots produced ~4-fold enhancement in the PA signal in the tumor, when compared to CP dots. These observations demonstrate the great potential of this active-targeting CP to be used as a contrast agent for molecular PA diagnostic imaging in various biomedical applications. PMID:25609951

  1. Molecular Design of Bisphosphonate-Modified Proteins for Efficient Bone Targeting In Vivo

    PubMed Central

    Katsumi, Hidemasa; Sano, Jun-ichi; Nishikawa, Makiya; Hanzawa, Keiko; Sakane, Toshiyasu; Yamamoto, Akira

    2015-01-01

    To establish a rational molecular design for bisphosphonate (BP)-modified proteins for efficient bone targeting, a pharmacokinetic study was performed using a series of alendronate (ALN), a nitrogen-containing BP, modified proteins with various molecular weights and varying degrees of modification. Four proteins with different molecular weight—yeast glutathione reductase (GR; MW: 112,000 Da), bovine serum albumin (BSA; MW: 67,000 Da), recombinant human superoxide dismutase (SOD; MW: 32,000 Da), and chicken egg white lysozyme (LZM; MW: 14,000 Da)—were modified with ALN to obtain ALN-modified proteins. Pharmacokinetic analysis of the tissue distribution of the ALN-modified and unmodified proteins was performed after radiolabeling them with indium-111 (111In) by using a bifunctional chelating agent. Calculation of tissue uptake clearances revealed that the bone uptake clearances of 111In-ALN-modified proteins were proportional to the degree of ALN modification. 111In-GR-ALN and BSA-ALN, the two high-molecular-weight proteins, efficiently accumulated in bones, regardless of the degree of ALN modification. Approximately 36 and 34% of the dose, respectively, was calculated to be delivered to the bones. In contrast, the maximum amounts taken up by bone were 18 and 13% of the dose for 111In-SOD-ALN(32) and LZM-ALN(9), respectively, because of their high renal clearance. 111In-SOD modified with both polyethylene glycol (PEG) and ALN (111In-PEG-SOD-ALN) was efficiently delivered to the bone. Approximately 36% of the dose was estimated to be delivered to the bones. In an experimental bone metastasis mouse model, treatment with PEG-SOD-ALN significantly reduced the number of tumor cells in the bone of the mice. These results indicate that the combination of PEG and ALN modification is a promising approach for efficient bone targeting of proteins with a high total-body clearance. PMID:26287482

  2. Molecular phylogeny and genome size evolution of the genus Betula (Betulaceae)

    PubMed Central

    Wang, Nian; McAllister, Hugh A.; Bartlett, Paul R.; Buggs, Richard J. A.

    2016-01-01

    Background and Aims Betula L. (birch) is a genus of approx. 60 species, subspecies or varieties with a wide distribution in the northern hemisphere, of ecological and economic importance. A new classification of Betula has recently been proposed based on morphological characters. This classification differs somewhat from previously published molecular phylogenies, which may be due to factors such as convergent evolution, hybridization, incomplete taxon sampling or misidentification of samples. While chromosome counts have been made for many species, few have had their genome size measured. The aim of this study is to produce a new phylogenetic and genome size analysis of the genus. Methods Internal transcribed spacer (ITS) regions of nuclear ribosomal DNA were sequenced for 76 Betula samples verified by taxonomic experts, representing approx. 60 taxa, of which approx. 24 taxa have not been included in previous phylogenetic analyses. A further 49 samples from other collections were also sequenced, and 108 ITS sequences were downloaded from GenBank. Phylogenetic trees were built for these sequences. The genome sizes of 103 accessions representing nearly all described species were estimated using flow cytometry. Key Results As expected for a gene tree of a genus where hybridization and allopolyploidy occur, the ITS tree shows clustering, but not resolved monophyly, for the morphological subgenera recently proposed. Most sections show some clustering, but species of the dwarf section Apterocaryon are unusually scattered. Betula corylifolia (subgenus Nipponobetula) unexpectedly clusters with species of subgenus Aspera. Unexpected placements are also found for B. maximowicziana, B. bomiensis, B. nigra and B. grossa. Biogeographical disjunctions were found within Betula between Europe and North America, and also disjunctions between North-east and South-west Asia. The 2C-values for Betula ranged from 0·88 to 5·33 pg, and polyploids are scattered widely throughout the

  3. Molecular control of brain size: Regulators of neural stem cell life, death and beyond

    SciTech Connect

    Joseph, Bertrand; Hermanson, Ola

    2010-05-01

    The proper development of the brain and other organs depends on multiple parameters, including strictly controlled expansion of specific progenitor pools. The regulation of such expansion events includes enzymatic activities that govern the correct number of specific cells to be generated via an orchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteins in turn exert direct control of these enzymatic activities and thus progenitor pool expansion and organ size. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators of cell cycle exit that interact with and inhibit the activity of cyclin-CDK complexes, whereas members of the p53/p63/p73 family are traditionally associated with regulation of cell death. It has however become clear that the roles for these proteins are not as clear-cut as initially thought. In this review, we discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cycle control, differentiation, and death of neural stem cells. We suggest that these proteins act as molecular interfaces, or 'pilots', to assure the correct assembly of protein complexes with enzymatic activities at the right place at the right time, thereby regulating essential decisions in multiple cellular events.

  4. Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice.

    PubMed

    Zhang, Zui; Ohtake-Niimi, Shiori; Kadomatsu, Kenji; Uchimura, Kenji

    2016-08-01

    Alzheimer's disease (AD) is a progressive disorder leading to cognitive impairment and neuronal loss. Cerebral extracellular accumulation and deposition of amyloid ß plaques is a pathological hallmark of AD. Chondroitin sulfate (CS) is an extracellular component abundant in the brain. CS is a sulfated glycosaminoglycan covalently attached to a core protein, forming chondroitin sulfate proteoglycan. The structure of CS is heterogeneous with sulfation modification and elongation of the chain. The structural diversity of CS allows it to play various roles in the brain. Increasing evidence has shown that CS promotes aggregation of amyloid ß peptides into higher-order species such as insoluble amyloid ß fibrils. Difficulties in the structural analysis of brain CS, as well as its heterogeneity, limit the study of potential roles of CS in AD pathology. Here we established a microanalysis method with reversed-phase ion-pair high performance liquid chromatography and found that CS in the brains of Tg2576 AD model mice show a lower molecular size and an increased ratio of CS-B motif di-sulfated disaccharide. Our findings provide insight into the structural changes of cerebral CS upon Alzheimer's pathogenesis. PMID:27578913

  5. Influence of carp intestinal mucus molecular size and glycosylation on bacterial adhesion.

    PubMed

    Schroers, V; Van Der Marel, M; Steinhagen, D

    2008-08-27

    The first step of the pathogenesis of many infectious diseases is the colonisation of the mucosal surface by the pathogen. Bacterial colonisation of the mucosal surface is promoted by adherence to high molecular weight mucus glycoproteins. We examined the effect of carp intestinal mucus glycoproteins on the adhesion of different bacteria. The bacteria used were 3 strains of Aeromonas hydrophila, and A. salmonicida, Edwardsiella tarda and Yersinia ruckeri. All bacteria adhered to mucus, but at varying intensities. All tested bacteria adhered best to molecules of 670 to 2000 kDa in size, less to molecules larger than 2000 kDa and weakest to molecules of 30 to 670 kDa. In general, bacteria that showed a stronger adhesion to intestinal mucus were cytotoxic to cells in vitro, and bacteria that showed a weaker adhesion to intestinal mucus did not lead to alterations of monolayers of EPC-cells. Furthermore, the involvement of glycan side chains of the glycoproteins for bacterial adhesion was analysed for one A. hydrophila strain. After cleavage of terminal sugar residues by treatment of mucus glycoproteins with different glycosidases, binding of bacteria was modulated. When mannose was cleaved off, adhesion significantly increased. Blocking of glycan receptors by incubation of bacteria with different oligosaccharides had no clear effect on bacterial binding to mucus glycoproteins. Our results suggest that bacteria interact with carbohydrate side chains of mucus glycoproteins, and that the carbohydrates of the core region are involved in bacterial binding. PMID:18924378

  6. Size effect on cold-welding of gold nanowires investigated using molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Wu, Cheng-Da; Fang, Te-Hua; Wu, Chung-Chin

    2016-03-01

    The size effect on the cold-welding mechanism and mechanical properties of Au nanowires (NWs) in head-to-head contact are studied using molecular dynamics simulations based on the second-moment approximation of the many-body tight-binding potential. The results are discussed in terms of atomic trajectories, slip vectors, stress, radial distribution function, and weld strength ratio. Simulation results show that during the cold-welding process, a few disordered atoms/defects in the jointing area rearrange themselves and transform into a face-centered cubic crystalline structure. With an increase in contact between the two NWs, dislocations gradually form on the (111) slip plane and then on a twin plane, leading to an increase in the lateral deformation of 4-nm-wide NWs. The effect of structural instability increases with decreasing NW width, making the alignment of the two NWs more difficult. The elongation ability of the welded NWs increases with increasing NW width. Smaller NWs have better weld strength.

  7. Magnetic Resonance Spectroscopy and Imaging Guidance in Molecular Medicine: Targeting and Monitoring of Choline and Glucose Metabolism in Cancer

    PubMed Central

    Glunde, Kristine; Jiang, Lu; Moestue, Siver A.; Gribbestad, Ingrid S.

    2011-01-01

    Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) are valuable tools to detect metabolic changes in tumors. The currently emerging era of molecular medicine, which is shaped by molecularly targeted anticancer therapies combined with molecular imaging of the effects of such therapies, requires powerful imaging technologies that are able to detect molecular information. MRS and MRSI (MRS/I) are such technologies that are able to detect metabolites arising from glucose and choline metabolism in noninvasive in vivo settings and at higher resolution in tissue samples. The roles that MRS/I plays in diagnosing different types of cancer as well as in early monitoring of tumor response to traditional chemotherapies are reviewed. Emerging roles of MRS/I in the development and detection of novel targeted anticancer therapies that target oncogenic signaling pathways or targets in choline or glucose metabolism are discussed. PMID:21793073

  8. Targeting damage-associated molecular pattern molecules (DAMPs) and DAMP receptors in melanoma.

    PubMed

    Boone, Brian A; Lotze, Michael T

    2014-01-01

    Damage-associated molecular pattern molecules (DAMPs) are proteins released from cells under stress due to nutrient deprivation, hypoxia, trauma, or treatment with chemotherapy, among a variety of other causes. When released, DAMPs activate innate immunity, providing a pathway to a systemic inflammatory response in the absence of infection. By regulating inflammation in the tumor microenvironment, promoting angiogenesis, and increasing autophagy with evasion of apoptosis, DAMPs facilitate cancer growth. DAMPs and DAMP receptors have a key role in melanoma pathogenesis. Due to their crucial role in the development of melanoma and chemoresistance, DAMPs represent intriguing targets at a time when novel treatments are desperately needed. PMID:24258998

  9. Formation of target-specific binding sites in enzymes: solid-phase molecular imprinting of HRP

    NASA Astrophysics Data System (ADS)

    Czulak, J.; Guerreiro, A.; Metran, K.; Canfarotta, F.; Goddard, A.; Cowan, R. H.; Trochimczuk, A. W.; Piletsky, S.

    2016-05-01

    Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike complex protein engineering approaches commonly employed to generate affinity proteins, the method proposed can be used to produce protein-based ligands in a short time period using native protein molecules. These affinity materials are potentially useful tools especially for assays since they combine the catalytic properties of enzymes (for signaling) and molecular recognition properties of antibodies. We demonstrate this concept in an ELISA-format assay where HRP imprinted with vancomycin and ampicillin replaced traditional enzyme-antibody conjugates for selective detection of templates at micromolar concentrations. This approach can potentially provide a fast alternative to raising antibodies for targets that do not require high assay sensitivities; it can also find uses as a biochemical research tool, as a possible replacement for immunoperoxidase-conjugates.Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike

  10. Molecular-receptor-specific, non-toxic, near-infrared-emitting Au cluster-protein nanoconjugates for targeted cancer imaging

    NASA Astrophysics Data System (ADS)

    Retnakumari, Archana; Setua, Sonali; Menon, Deepthy; Ravindran, Prasanth; Muhammed, Habeeb; Pradeep, Thalappil; Nair, Shantikumar; Koyakutty, Manzoor

    2010-02-01

    Molecular-receptor-targeted imaging of folate receptor positive oral carcinoma cells using folic-acid-conjugated fluorescent Au25 nanoclusters (Au NCs) is reported. Highly fluorescent Au25 clusters were synthesized by controlled reduction of Au+ ions, stabilized in bovine serum albumin (BSA), using a green-chemical reducing agent, ascorbic acid (vitamin-C). For targeted-imaging-based detection of cancer cells, the clusters were conjugated with folic acid (FA) through amide linkage with the BSA shell. The bioconjugated clusters show excellent stability over a wide range of pH from 4 to 14 and fluorescence efficiency of ~5.7% at pH 7.4 in phosphate buffer saline (PBS), indicating effective protection of nanoclusters by serum albumin during the bioconjugation reaction and cell-cluster interaction. The nanoclusters were characterized for their physico-chemical properties, toxicity and cancer targeting efficacy in vitro. X-ray photoelectron spectroscopy (XPS) suggests binding energies correlating to metal Au 4f7/2~83.97 eV and Au 4f5/2~87.768 eV. Transmission electron microscopy and atomic force microscopy revealed the formation of individual nanoclusters of size ~1 nm and protein cluster aggregates of size ~8 nm. Photoluminescence studies show bright fluorescence with peak maximum at ~674 nm with the spectral profile covering the near-infrared (NIR) region, making it possible to image clusters at the 700-800 nm emission window where the tissue absorption of light is minimum. The cell viability and reactive oxygen toxicity studies indicate the non-toxic nature of the Au clusters up to relatively higher concentrations of 500 µg ml-1. Receptor-targeted cancer detection using Au clusters is demonstrated on FR+ve oral squamous cell carcinoma (KB) and breast adenocarcinoma cell MCF-7, where the FA-conjugated Au25 clusters were found internalized in significantly higher concentrations compared to the negative control cell lines. This study demonstrates the potential of using

  11. Molecular-receptor-specific, non-toxic, near-infrared-emitting Au cluster-protein nanoconjugates for targeted cancer imaging.

    PubMed

    Retnakumari, Archana; Setua, Sonali; Menon, Deepthy; Ravindran, Prasanth; Muhammed, Habeeb; Pradeep, Thalappil; Nair, Shantikumar; Koyakutty, Manzoor

    2010-02-01

    Molecular-receptor-targeted imaging of folate receptor positive oral carcinoma cells using folic-acid-conjugated fluorescent Au(25) nanoclusters (Au NCs) is reported. Highly fluorescent Au(25) clusters were synthesized by controlled reduction of Au(+) ions, stabilized in bovine serum albumin (BSA), using a green-chemical reducing agent, ascorbic acid (vitamin-C). For targeted-imaging-based detection of cancer cells, the clusters were conjugated with folic acid (FA) through amide linkage with the BSA shell. The bioconjugated clusters show excellent stability over a wide range of pH from 4 to 14 and fluorescence efficiency of approximately 5.7% at pH 7.4 in phosphate buffer saline (PBS), indicating effective protection of nanoclusters by serum albumin during the bioconjugation reaction and cell-cluster interaction. The nanoclusters were characterized for their physico-chemical properties, toxicity and cancer targeting efficacy in vitro. X-ray photoelectron spectroscopy (XPS) suggests binding energies correlating to metal Au 4f(7/2) approximately 83.97 eV and Au 4f(5/2) approximately 87.768 eV. Transmission electron microscopy and atomic force microscopy revealed the formation of individual nanoclusters of size approximately 1 nm and protein cluster aggregates of size approximately 8 nm. Photoluminescence studies show bright fluorescence with peak maximum at approximately 674 nm with the spectral profile covering the near-infrared (NIR) region, making it possible to image clusters at the 700-800 nm emission window where the tissue absorption of light is minimum. The cell viability and reactive oxygen toxicity studies indicate the non-toxic nature of the Au clusters up to relatively higher concentrations of 500 microg ml(-1). Receptor-targeted cancer detection using Au clusters is demonstrated on FR(+ve) oral squamous cell carcinoma (KB) and breast adenocarcinoma cell MCF-7, where the FA-conjugated Au(25) clusters were found internalized in significantly higher

  12. The Size of the Internal Loop in DNA Hairpins Influences Their Targeting with Partially Complementary Strands

    PubMed Central

    2015-01-01

    Targeting of noncanonical DNA structures, such as hairpin loops, may have significant diagnostic and therapeutic potential. Oligonucleotides can be used for binding to mRNA, forming a DNA/RNA hybrid duplex that inhibits translation. This kind of modulation of gene expression is called the antisense approach. In order to determine the best strategy to target a common structural motif in mRNA, we have designed a set of stem-loop DNA molecules with sequence: d(GCGCTnGTAAT5GTTACTnGCGC), where n = 1, 3, or 5, “T5” is an end loop of five thymines. We used a combination of calorimetric and spectroscopy techniques to determine the thermodynamics for the reaction of a set of hairpins containing internal loops with their respective partially complementary strands. Our aim was to determine if internal- and end-loops are promising regions for targeting with their corresponding complementary strands. Indeed, all targeting reactions were accompanied by negative changes in free energy, indicating that reactions proceed spontaneously. Further investigation showed that these negative free energy terms result from a net balance of unfavorable entropy and favorable enthalpy contributions. In particular, unfolding of hairpins and duplexes is accompanied by positive changes in heat capacity, which may be a result of exposure of hydrophobic groups to the solvent. This study provides a new method for the targeting of mRNA in order to control gene expression. PMID:25486129

  13. Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma

    PubMed Central

    ADACHI, Mami; HOSHINO, Yuki; IZUMI, Yusuke; TAKAGI, Satoshi

    2015-01-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

  14. Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs.

    PubMed

    Bayliss, Richard; Choi, Jene; Fennell, Dean A; Fry, Andrew M; Richards, Mark W

    2016-03-01

    A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90. PMID:26755435

  15. Molecular Targets of β-Lactam-Based Antimicrobials: Beyond the Usual Suspects

    PubMed Central

    Konaklieva, Monika I.

    2014-01-01

    The common practice in antibacterial drug development has been to rapidly make an attempt to find ever-more stable and broad-spectrum variants for a particular antibiotic, once a drug resistance for that antibiotic is detected. We are now facing bacterial resistance toward our clinically relevant antibiotics of such a magnitude that the conversation for antimicrobial drug development ought to include effective new antibiotics with alternative mechanisms of action. The electrophilic β-lactam ring is amenable for the inhibition of different enzyme classes by a suitable decoration of the core scaffold. Monocyclic β-lactams lacking an ionizable group at the lactam nitrogen exhibit target preferences toward bacterial enzymes important for resistance and virulence. The present review intends to draw attention to the versatility of the β-lactams as antimicrobials with “unusual” molecular targets. PMID:27025739

  16. Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma.

    PubMed

    Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Takagi, Satoshi

    2016-05-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

  17. Type IV traffic ATPase TrwD as molecular target to inhibit bacterial conjugation.

    PubMed

    Ripoll-Rozada, Jorge; García-Cazorla, Yolanda; Getino, María; Machón, Cristina; Sanabria-Ríos, David; de la Cruz, Fernando; Cabezón, Elena; Arechaga, Ignacio

    2016-06-01

    Bacterial conjugation is the main mechanism responsible for the dissemination of antibiotic resistance genes. Hence, the search for specific conjugation inhibitors is paramount in the fight against the spread of these genes. In this pursuit, unsaturated fatty acids have been found to specifically inhibit bacterial conjugation. Despite the growing interest on these compounds, their mode of action and their specific target remain unknown. Here, we identified TrwD, a Type IV secretion traffic ATPase, as the molecular target for fatty acid-mediated inhibition of conjugation. Moreover, 2-alkynoic fatty acids, which are also potent inhibitors of bacterial conjugation, are also powerful inhibitors of the ATPase activity of TrwD. Characterization of the kinetic parameters of ATPase inhibition has led us to identify the catalytic mechanism by which fatty acids exert their activity. These results open a new avenue for the rational design of inhibitors of bacterial conjugation in the fight against the dissemination of antibiotic resistance genes. PMID:26915347

  18. Inflammatory therapeutic targets in coronary atherosclerosis—from molecular biology to clinical application

    PubMed Central

    Linden, Fabian; Domschke, Gabriele; Erbel, Christian; Akhavanpoor, Mohammadreza; Katus, Hugo A.; Gleissner, Christian A.

    2014-01-01

    Atherosclerosis is the leading cause of death worldwide. Over the past two decades, it has been clearly recognized that atherosclerosis is an inflammatory disease of the arterial wall. Accumulating data from animal experiments have supported this hypothesis, however, clinical applications making use of this knowledge remain scarce. In spite of optimal interventional and medical therapy, the risk for recurrent myocardial infarction remains by about 20% over 3 years after acute coronary syndromes, novel therapies to prevent atherogenesis or treat atherosclerosis are urgently needed. This review summarizes selected potential molecular inflammatory targets that may be of clinical relevance. We also review recent and ongoing clinical trails that target inflammatory processes aiming at preventing adverse cardiovascular events. Overall, it seems surprising that translation of basic science into clinical practice has not been a great success. In conclusion, we propose to focus on specific efforts that promote translational science in order to improve outcome and prognosis of patients suffering from atherosclerosis. PMID:25484870

  19. New molecular targeted therapies for advanced non-small-cell lung cancer

    PubMed Central

    Méndez, Míriam; Custodio, Ana; Provencio, Mariano

    2011-01-01

    Non-small-cell lung cancer (NSCLC) is a uniformly fatal disease and most patients will present with advanced stage. Treatment outcomes remain unsatisfactory, with low long-term survival rates. Standard treatment, such as palliative chemotherapy and radiotherapy, offers a median survival not exceeding 1 year. Hence, considerable efforts have started to be made in order to identify new biological agents which may safely and effectively be administered to advanced NSCLC patients. Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. However, novel targeted therapies that interfere with other dysregulated pathways in lung cancer are already in the clinic. This review outlines the most promising research approaches to the treatment of NSCLC, discussed according to the specific molecular pathway targeted. PMID:22263060

  20. Discrete Molecular Dynamics Distinguishes Nativelike Binding Poses from Decoys in Difficult Targets

    PubMed Central

    Proctor, Elizabeth A.; Yin, Shuangye; Tropsha, Alexander; Dokholyan, Nikolay V.

    2012-01-01

    Virtual screening is one of the major tools used in computer-aided drug discovery. In structure-based virtual screening, the scoring function is critical to identifying the correct docking pose and accurately predicting the binding affinities of compounds. However, the performance of existing scoring functions has been shown to be uneven for different targets, and some important drug targets have proven especially challenging. In these targets, scoring functions cannot accurately identify the native or near-native binding pose of the ligand from among decoy poses, which affects both the accuracy of the binding affinity prediction and the ability of virtual screening to identify true binders in chemical libraries. Here, we present an approach to discriminating native poses from decoys in difficult targets for which several scoring functions failed to correctly identify the native pose. Our approach employs Discrete Molecular Dynamics simulations to incorporate protein-ligand dynamics and the entropic effects of binding. We analyze a collection of poses generated by docking and find that the residence time of the ligand in the native and nativelike binding poses is distinctly longer than that in decoy poses. This finding suggests that molecular simulations offer a unique approach to distinguishing the native (or nativelike) binding pose from decoy poses that cannot be distinguished using scoring functions that evaluate static structures. The success of our method emphasizes the importance of protein-ligand dynamics in the accurate determination of the binding pose, an aspect that is not addressed in typical docking and scoring protocols. PMID:22225808

  1. Molecular Inversion Probes for targeted resequencing in non-model organisms

    PubMed Central

    Niedzicka, M.; Fijarczyk, A.; Dudek, K.; Stuglik, M.; Babik, W.

    2016-01-01

    Applications that require resequencing of hundreds or thousands of predefined genomic regions in numerous samples are common in studies of non-model organisms. However few approaches at the scale intermediate between multiplex PCR and sequence capture methods are available. Here we explored the utility of Molecular Inversion Probes (MIPs) for the medium-scale targeted resequencing in a non-model system. Markers targeting 112 bp of exonic sequence were designed from transcriptome of Lissotriton newts. We assessed performance of 248 MIP markers in a sample of 85 individuals. Among the 234 (94.4%) successfully amplified markers 80% had median coverage within one order of magnitude, indicating relatively uniform performance; coverage uniformity across individuals was also high. In the analysis of polymorphism and segregation within family, 77% of 248 tested MIPs were confirmed as single copy Mendelian markers. Genotyping concordance assessed using replicate samples exceeded 99%. MIP markers for targeted resequencing have a number of advantages: high specificity, high multiplexing level, low sample requirement, straightforward laboratory protocol, no need for preparation of genomic libraries and no ascertainment bias. We conclude that MIP markers provide an effective solution for resequencing targets of tens or hundreds of kb in any organism and in a large number of samples. PMID:27046329

  2. Molecular Inversion Probes for targeted resequencing in non-model organisms.

    PubMed

    Niedzicka, M; Fijarczyk, A; Dudek, K; Stuglik, M; Babik, W

    2016-01-01

    Applications that require resequencing of hundreds or thousands of predefined genomic regions in numerous samples are common in studies of non-model organisms. However few approaches at the scale intermediate between multiplex PCR and sequence capture methods are available. Here we explored the utility of Molecular Inversion Probes (MIPs) for the medium-scale targeted resequencing in a non-model system. Markers targeting 112 bp of exonic sequence were designed from transcriptome of Lissotriton newts. We assessed performance of 248 MIP markers in a sample of 85 individuals. Among the 234 (94.4%) successfully amplified markers 80% had median coverage within one order of magnitude, indicating relatively uniform performance; coverage uniformity across individuals was also high. In the analysis of polymorphism and segregation within family, 77% of 248 tested MIPs were confirmed as single copy Mendelian markers. Genotyping concordance assessed using replicate samples exceeded 99%. MIP markers for targeted resequencing have a number of advantages: high specificity, high multiplexing level, low sample requirement, straightforward laboratory protocol, no need for preparation of genomic libraries and no ascertainment bias. We conclude that MIP markers provide an effective solution for resequencing targets of tens or hundreds of kb in any organism and in a large number of samples. PMID:27046329

  3. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.

    PubMed

    Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Geschwind, Jean-Francois

    2013-01-01

    The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic. PMID:23267123

  4. Molecular Platform for Design and Synthesis of Targeted Dual-Modality Imaging Probes

    PubMed Central

    2015-01-01

    We report a versatile dendritic structure based platform for construction of targeted dual-modality imaging probes. The platform contains multiple copies of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) branching out from a 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) core. The specific coordination chemistries of the NOTA and DOTA moieties offer specific loading of 68/67Ga3+ and Gd3+, respectively, into a common molecular scaffold. The platform also contains three amino groups which can potentiate targeted dual-modality imaging of PET/MRI or SPECT/MRI (PET: positron emission tomography; SPECT: single photon emission computed tomography; MRI: magnetic resonance imaging) when further functionalized by targeting vectors of interest. To validate this design concept, a bimetallic complex was synthesized with six peripheral Gd-DOTA units and one Ga-NOTA core at the center, whose ion T1 relaxivity per gadolinium atom was measured to be 15.99 mM–1 s–1 at 20 MHz. Further, the bimetallic agent demonstrated its anticipated in vivo stability, tissue distribution, and pharmacokinetic profile when labeled with 67Ga. When conjugated with a model targeting peptide sequence, the trivalent construct was able to visualize tumors in a mouse xenograft model by both PET and MRI via a single dose injection. PMID:25615011

  5. Effects of thermomechanical processing on the recrystallization texture and grain size of Al-1%Si sputtering target material

    NASA Astrophysics Data System (ADS)

    Li, X. R.; Xu, C. L.; Huang, T. L.; Luo, Y.; Wu, G. L.; Liu, Q.; Huang, X.

    2015-04-01

    An Al-1%Si alloy was solution treated and deformed by conventional cold rolling to different strains, followed by annealing at various temperatures until complete recrystallization. The microstructures of annealed samples were characterized by electron backscatter diffraction. It is found that under optimal conditions of cold rolling and annealing, the microstructure desired for sputtering target materials with fine, uniformly sized and randomly textured grains can be obtained for the Al-1%Si alloy.

  6. Manipulating target size influences perceptions of success when learning a dart-throwing skill but does not impact retention.

    PubMed

    Ong, Nicole T; Lohse, Keith R; Hodges, Nicola J

    2015-01-01

    Positive feedback or experiences of success during skill acquisition have been shown to benefit motor skill learning. In this study, our aim was to manipulate learners' success perceptions through a minor adjustment to goal criterion (target size) in a dart-throwing task. Two groups of novice participants practiced throwing at a large (easy) or a small (difficult) target from the same distance. In reference to the origin/center of the target, the practice targets were alike in objective difficulty and indeed participants in both groups were not different in their objective practice performance (i.e., radial error from the center). Although the groups experienced markedly different success rates, with the large target group experiencing more hits and reporting greater confidence (or self-efficacy) than the small target group, these practice effects were not carried into longer-term retention, which was assessed after a 1-week delay. For success perceptions to moderate or benefit motor learning, we argue that unambiguous indicators of positive performance are necessary, especially for tasks where intrinsic feedback about objective error is salient. PMID:26441753

  7. Manipulating target size influences perceptions of success when learning a dart-throwing skill but does not impact retention

    PubMed Central

    Ong, Nicole T.; Lohse, Keith R.; Hodges, Nicola J.

    2015-01-01

    Positive feedback or experiences of success during skill acquisition have been shown to benefit motor skill learning. In this study, our aim was to manipulate learners’ success perceptions through a minor adjustment to goal criterion (target size) in a dart-throwing task. Two groups of novice participants practiced throwing at a large (easy) or a small (difficult) target from the same distance. In reference to the origin/center of the target, the practice targets were alike in objective difficulty and indeed participants in both groups were not different in their objective practice performance (i.e., radial error from the center). Although the groups experienced markedly different success rates, with the large target group experiencing more hits and reporting greater confidence (or self-efficacy) than the small target group, these practice effects were not carried into longer-term retention, which was assessed after a 1-week delay. For success perceptions to moderate or benefit motor learning, we argue that unambiguous indicators of positive performance are necessary, especially for tasks where intrinsic feedback about objective error is salient. PMID:26441753

  8. Evaluating Three Programs Using a School Effectiveness Model: Direct Instruction, Target Teach, and Class Size Reduction

    ERIC Educational Resources Information Center

    Thompson, Bruce

    2006-01-01

    Value-added models, which rate schools for effectiveness while taking into account the poverty and other socioeconomic status of the students, are generating increased interest. This paper describes the use of one such model to evaluate whether school ratings changed when three new programs were introduced: the "Target Teach" curriculum alignment,…

  9. CD22ΔE12 as a molecular target for RNAi therapy

    PubMed Central

    Uckun, Fatih M.; Ma, Hong; Cheng, Jianjun; Myers, Dorothea E.; Qazi, Sanjive

    2015-01-01

    B-precursor acute lymphoblastic leukemia (BPL) is the most common form of cancer in children and adolescents. Our recent studies have demonstrated that CD22ΔE12 is a characteristic genetic defect of therapy-refractory clones in pediatric BPL and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to evaluate the biologic significance of the CD22ΔE12 molecular lesion in BPL and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. Here we report a previously unrecognized causal link between CD22ΔE12 and aggressive biology of human BPL cells by demonstrating that siRNA-mediated knockdown of CD22ΔE12 in primary leukemic B-cell precursors is associated with a marked inhibition of their clonogenicity. Additionally, we report a nanoscale liposomal formulation of CD22ΔE12-specific siRNA with potent in vitro and in vivo anti-leukemic activity against primary human BPL cells as a first-in-class RNAi therapeutic candidate targeting CD22ΔE12. PMID:25659406

  10. Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

    PubMed Central

    Chen, Chuan; Wang, Ge

    2015-01-01

    The incidence and mortality of hepatocellular carcinoma (HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics. PMID:26244070

  11. Formation of target-specific binding sites in enzymes: solid-phase molecular imprinting of HRP.

    PubMed

    Czulak, J; Guerreiro, A; Metran, K; Canfarotta, F; Goddard, A; Cowan, R H; Trochimczuk, A W; Piletsky, S

    2016-06-01

    Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike complex protein engineering approaches commonly employed to generate affinity proteins, the method proposed can be used to produce protein-based ligands in a short time period using native protein molecules. These affinity materials are potentially useful tools especially for assays since they combine the catalytic properties of enzymes (for signaling) and molecular recognition properties of antibodies. We demonstrate this concept in an ELISA-format assay where HRP imprinted with vancomycin and ampicillin replaced traditional enzyme-antibody conjugates for selective detection of templates at micromolar concentrations. This approach can potentially provide a fast alternative to raising antibodies for targets that do not require high assay sensitivities; it can also find uses as a biochemical research tool, as a possible replacement for immunoperoxidase-conjugates. PMID:27174700

  12. [Economic Loss of Remaining Contents in Molecular Target Drug Preparation and the Simulation for Cost Saving].

    PubMed

    Usami, Eiseki; Kimura, Michio; Fukuoka, Tomohiro; Okada, Kazutomo; Yoshimura, Tomoaki

    2016-06-01

    While preparing an anticancer drug, even if it is an expensive molecular target drug, the remainder is not divided and saved for use in other patients; instead, it is discarded, resulting in waste of medical resources. In this study, we examined the economic loss in terms of medical costs by calculating the discarded amounts of 12 commonly used molecular target drugs at Ogaki Municipal Hospital, Japan between January 2012 and December 2014. We found, on average, that drugs valued at ¥ 52,593,182 were discarded annually. In particular, the discarded amounts of relatively expensive drugs, such as bevacizumab, bortezomib, and rituximab, were valued at ¥ 16,646,300, ¥ 15,866,289, and ¥ 8,401,324, respectively. Among these, the average amount of waste per administration of bortezomib was particularly expensive, at a cost of ¥ 67,325. Bortezomib is a commonly used treatment, resulting in excessive cumulative discarded cost. In an effort to save cost, we should consider using small capacity standard injections. Development of a simulation that used the remaining drug contents from only 1 day showed that bevacizumab alone accounts for an average cost saving of ¥1 2,542,191(75.3%) per year. This study suggests that effectively utilizing the remaining drug contents would ensure efficient use of medical resources, thereby reducing economic losses. PMID:27306812

  13. Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology.

    PubMed

    Gao, Li; Wang, Xiao-Dong; Niu, Yang-Yang; Duan, Dan-Dan; Yang, Xue; Hao, Jian; Zhu, Cui-Hong; Chen, Dan; Wang, Ke-Xin; Qin, Xue-Mei; Wu, Xiong-Zhi

    2016-01-01

    Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan-Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc. PMID:27143508

  14. Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy

    PubMed Central

    2013-01-01

    The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8–9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy. PMID:23503600

  15. An Overview on the Marine Neurotoxin, Saxitoxin: Genetics, Molecular Targets, Methods of Detection and Ecological Functions

    PubMed Central

    Cusick, Kathleen D.; Sayler, Gary S.

    2013-01-01

    Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin’s ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxin research are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed. PMID:23535394

  16. Computer-aided Molecular Design of Compounds Targeting Histone Modifying Enzymes

    PubMed Central

    Andreoli, Federico; Del Rio, Alberto

    2015-01-01

    Growing evidences show that epigenetic mechanisms play crucial roles in the genesis and progression of many physiopathological processes. As a result, research in epigenetic grew at a fast pace in the last decade. In particular, the study of histone post-translational modifications encountered an extraordinary progression and many modifications have been characterized and associated to fundamental biological processes and pathological conditions. Histone modifications are the catalytic result of a large set of enzyme families that operate covalent modifications on specific residues at the histone tails. Taken together, these modifications elicit a complex and concerted processing that greatly contribute to the chromatin remodeling and may drive different pathological conditions, especially cancer. For this reason, several epigenetic targets are currently under validation for drug discovery purposes and different academic and industrial programs have been already launched to produce the first pre-clinical and clinical outcomes. In this scenario, computer-aided molecular design techniques are offering important tools, mainly as a consequence of the increasing structural information available for these targets. In this mini-review we will briefly discuss the most common types of known histone modifications and the corresponding operating enzymes by emphasizing the computer-aided molecular design approaches that can be of use to speed-up the efforts to generate new pharmaceutically relevant compounds. PMID:26082827

  17. Molecular targets of naturopathy in cancer research: bridge to modern medicine.

    PubMed

    Ahmad, Aamir; Ginnebaugh, Kevin R; Li, Yiwei; Padhye, Subhash B; Sarkar, Fazlul H

    2015-01-01

    The relevance of naturopathy (defined as the practice of medicine for the treatment of human diseases with natural agents) in human cancer is beginning to be appreciated, as documented by renewed interest in nutraceutical research, the natural anticancer agents of dietary origin. Because of their pleiotropic effects and the ability to modulate multiple signaling pathways, which is a good attribute of natural agents, nutraceuticals have frequently been demonstrated to re-sensitize drug-resistant cancers. The effectiveness of nutraceuticals can be further enhanced if the tools for the relative assessment of their molecular targets are readily available. Such information can be critical for determining their most effective uses. Here, we discuss the anticancer potential of nutraceuticals and the associated challenges that have interfered with their translational potential as a naturopathic approach for the management of cancers. In the years to come, an efficient screening and assessment of molecular targets will be the key to make rapid progress in the area of drug design and discovery, especially focusing on evidence-based development of naturopathy for the treatment of human malignancies. PMID:25569626

  18. Development of molecularly targeted agents and immunotherapies in small cell lung cancer.

    PubMed

    Sharp, Adam; Bhosle, Jaishree; Abdelraouf, Fatma; Popat, Sanjay; O'Brien, Mary; Yap, Timothy A

    2016-06-01

    Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC. PMID:27060747

  19. Metal ion mediated synthesis of molecularly imprinted polymers targeting tetracyclines in aqueous samples.

    PubMed

    Qu, Guorun; Zheng, Sulian; Liu, Yumin; Xie, Wei; Wu, Aibo; Zhang, Dabing

    2009-10-01

    Molecularly imprinted polymers (MIPs) prepared in water-containing systems are more appropriate as adsorption materials in analyte extraction from biological samples. However, water as a polar solvent involved in the synthesis of MIPs frequently disrupts non-covalent interactions, and causes non-specific binding. In this study Fe(2+) was used as mediator to prepare MIPs, targeting tetracyclines (TCs) of tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC), with TC as template molecule and methacrylic acid (MAA) as functional monomer. The subsequent binding assay indicated that Fe(2+) was responsible for substantially improved specific binding in recognition of TCs by decreasing the non-specific binding. Spectrophotometric analysis suggested the existence of the strong interactions among TC, metal ions and MAA in the mixture of methanol and water. Moreover, mass spectrometric measurements verified that Fe(2+) could bridge between TC and MAA to form a ternary complex of one TC, one Fe(2+) and four MAAs with a mass of 844.857. Furthermore, combined with molecularly imprinted solid-phase extraction (MISPE) for sample pretreatment, HPLC-UV analysis data revealed good performance of the obtained MIPs as adsorbents. The recoveries of TC, OTC and CTC in urine samples were 80.1-91.6%, 78.4-89.3% and 78.2-86.2%, respectively. This research strategy provides an example for preparation of desirable water-compatible MIPs extracting target drugs from aqueous samples by introducing metal ion as mediator into conventional polymerization system. PMID:19726243

  20. Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary

    PubMed Central

    KOBAYASHI, HIROSHI; SHIGETOMI, HIROSHI; YOSHIMOTO, CHIHARU

    2015-01-01

    In clear cell carcinoma of the ovary, chemoresistance frequently results in treatment failure. The present study aimed to review the potential association of transcription factor hepatocyte nuclear factor (HNF)-1β with cell cycle checkpoint machinery, as a mechanism for chemoresistance. The English-language literature on the subject was reviewed to identify genomic alterations and aberrant molecular pathways interacting with chemoresistance in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage induces greater susceptibility of endometriotic cells to DNA damage, and subsequent malignant transformation results in endometriosis-associated ovarian cancer. Molecular changes, including those in HNF-1β and checkpoint kinase 1 (Chk1), may be a manifestation of essential alterations in cell cycle regulation, detoxification and chemoresistance in clear cell carcinoma. Chk1 is a critical signal transducer in the cell cycle checkpoint machinery. DNA damage, in turn, increases persistent phosphorylation of Chk1 and induction of G2/M phase cell cycle arrest in cells overexpressing HNF-1β. HNF-1β deletion induces apoptosis, suggesting that enhanced levels of HNF-1β may be associated with chemoresistance. Targeted therapy with Chk1 inhibitors may be explored as a potential treatment modality for patients with clear cell carcinoma. This provides a novel direction for combination therapy, including targeting of Chk1, which may overcome drug resistance and improve treatment efficacy. PMID:26622535

  1. Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology

    PubMed Central

    Gao, Li; Wang, Xiao-dong; Niu, Yang-yang; Duan, Dan-dan; Yang, Xue; Hao, Jian; Zhu, Cui-hong; Chen, Dan; Wang, Ke-xin; Qin, Xue-mei; Wu, Xiong-zhi

    2016-01-01

    Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan–Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc. PMID:27143508

  2. Adequately-Sized Nanocarriers Allow Sustained Targeted Drug Delivery to Neointimal Lesions in Rat Arteries.

    PubMed

    Taniguchi, Ryosuke; Miura, Yutaka; Koyama, Hiroyuki; Chida, Tsukasa; Anraku, Yasutaka; Kishimura, Akihiro; Shigematsu, Kunihiro; Kataoka, Kazunori; Watanabe, Toshiaki

    2016-06-01

    In atherosclerotic lesions, the endothelial barrier against the bloodstream can become compromised, resulting in the exposure of the extracellular matrix (ECM) and intimal cells beneath. In theory, this allows adequately sized nanocarriers in circulation to infiltrate into the intimal lesion intravascularly. We sought to evaluate this possibility using rat carotid arteries with induced neointima. Cy5-labeled polyethylene glycol-conjugated polyion complex (PIC) micelles and vesicles, with diameters of 40, 100, or 200 nm (PICs-40, PICs-100, and PICs-200, respectively) were intravenously administered to rats after injury to the carotid artery using a balloon catheter. High accumulation and long retention of PICs-40 in the induced neointima was confirmed by in vivo imaging, while the accumulation of PICs-100 and PICs-200 was limited, indicating that the size of nanocarriers is a crucial factor for efficient delivery. Furthermore, epirubicin-incorporated polymeric micelles with a diameter similar to that of PICs-40 showed significant curative effects in rats with induced neointima, in terms of lesion size and cell number. Specific and effective drug delivery to pre-existing neointimal lesions was demonstrated with adequate size control of the nanocarriers. We consider that this nanocarrier-based drug delivery system could be utilized for the treatment of atherosclerosis. PMID:27183493

  3. Molecular target discovery for neural repair in the functional genomics era.

    PubMed

    Verhaagen, Joost; Van Kesteren, Ronald E; Bossers, Koen A M; Macgillavry, Harold D; Mason, Matthew R; Smit, August B

    2012-01-01

    A comprehensive understanding of the molecular pathways activated by traumatic neural injury is of major importance for the development of treatments for spinal cord injury (SCI). High-throughput gene expression profiling is a powerful approach to reveal genome-wide changes in gene expression during a specific biological process. Microarray analysis of injured nerves or neurons would ideally generate new hypotheses concerning the progression or deregulation of injury- and repair-related biological processes, such as neural scar formation and axon regeneration. These hypotheses should subsequently be tested experimentally and would eventually provide the molecular substrates for the development of novel therapeutics. Over the last decade, this approach has elucidated numerous extrinsic (mostly neural scar-associated) as well as neuron-intrinsic genes that are regulated following an injury. To date, the main challenge is to translate the observed injury-induced gene expression changes into a mechanistic framework to understand their functional implications. To achieve this, research on neural repair will have to adopt the conceptual advances and analytical tools provided by the functional genomics and systems biology revolution. Based on progress made in bioinformatics, high-throughput and high-content functional cellular screening, and in vivo gene transfer technology, we propose a multistep "roadmap" that provides an integrated strategy for molecular target discovery for repair of the injured spinal cord. PMID:23098739

  4. Trigger of autoimmune diseases (SLE): identification of LINE transposition based novel therapeutic molecular targets.

    PubMed

    Tiwari, Anupama; Soni, Upendra Kumar

    2014-12-01

    Autoimmune diseases are the highly heterogeneous at cellular and molecular level. The causes and consequences of most of the autoimmune diseases are not well explored. However the researches focusing on the development of biomarkers for the diagnosis of autoimmune diseases are seems to be inadequate and given treatment are insufficient to control or cure the disease properly. It is a big obstacle to develop any therapy without knowing the actual cause and molecular event playing role in disease onset. In this article we are raising the involvement of LINE or other transposition as a first trigger and cause for autoimmune disease. Further we are proposing a novel hybrid aptamers based biocapturing model which would help in the investigation of genome-wide LINE transposition in pristane induced SLE mice model. Importantly the effect of new LINE movements at the expression pattern of neighboring genes would be used as novel molecular prognostic biomarkers for onset of SLE and related autoimmune diseases. We are also proposing that the differential expression either inductive or suppressive pattern of expected several candidate genes would be implicated in the defective biochemical or cellular defects, and targeted therapy would be employed to such life threatening disease. PMID:25468787

  5. Invariance of molecular charge transport upon changes of extended molecule size and several related issues.

    PubMed

    Bâldea, Ioan

    2016-01-01

    As a sanity test for the theoretical method employed, studies on (steady-state) charge transport through molecular devices usually confine themselves to check whether the method in question satisfies the charge conservation. Another important test of the theory's correctness is to check that the computed current does not depend on the choice of the central region (also referred to as the "extended molecule"). This work addresses this issue and demonstrates that the relevant transport and transport-related properties are indeed invariant upon changing the size of the extended molecule, when the embedded molecule can be described within a general single-particle picture (namely, a second-quantized Hamiltonian bilinear in the creation and annihilation operators). It is also demonstrates that the invariance of nonequilibrium properties is exhibited by the exact results but not by those computed approximately within ubiquitous wide- and flat-band limits (WBL and FBL, respectively). To exemplify the limitations of the latter, the phenomenon of negative differential resistance (NDR) is considered. It is shown that the exactly computed current may exhibit a substantial NDR, while the NDR effect is absent or drastically suppressed within the WBL and FBL approximations. The analysis done in conjunction with the WBLs and FBLs reveals why general studies on nonequilibrium properties require a more elaborate theoretical than studies on linear response properties (e.g., ohmic conductance and thermopower) at zero temperature. Furthermore, examples are presented that demonstrate that treating parts of electrodes adjacent to the embedded molecule and the remaining semi-infinite electrodes at different levels of theory (which is exactly what most NEGF-DFT approaches do) is a procedure that yields spurious structures in nonlinear ranges of current-voltage curves. PMID:27335734

  6. Dense molecular cloud cores as a source of micrometer-sized grains in galaxies

    NASA Astrophysics Data System (ADS)

    Hirashita, Hiroyuki; Asano, Ryosuke S.; Nozawa, Takaya; Li, Zhi-Yun; Liu, Ming-Chang

    2014-10-01

    Coreshine in dense molecular cloud cores (dense cores) is interpreted as evidence for micrometer-sized grains (referred to as very large grains, VLGs). VLGs may have a significant influence on the total dust amount and the extinction curve. We estimate the total abundance of VLGs in the Galaxy, assuming that dense cores are the site of VLG formation. We find that the VLG abundance relative to the total dust mass is roughly ϕVLG~0.01(1-ε)/ε((fVLG/0.5)(tshat/108 year), where ε is the star formation efficiency in dense cores, τSF is the timescale of gas consumption by star formation, fVLG is the fraction of dust mass eventually coagulated into VLGs in dense cores, and tshat is the lifetime of VLGs (determined by shattering). Adopting their typical values for the Galaxy, we obtain ϕVLG~0.02-0.09. This abundance is well below the value detected in the heliosphere by Ulysses and Galileo, which means that local enhancement of VLG abundance in the solar neighborhood is required if the VLGs originate from dense cores. We also show that the effects of VLGs on the extinction curve are negligible even with the upper value of the above range, ϕVLG~0.09. If we adopt an extreme value, ϕVLG~0.5, close to that inferred from the above spacecraft data, the extinction curve is still in the range of the variation in Galactic extinction curves, but is not typical of the diffuse ISM.

  7. Invariance of molecular charge transport upon changes of extended molecule size and several related issues

    PubMed Central

    2016-01-01

    Summary As a sanity test for the theoretical method employed, studies on (steady-state) charge transport through molecular devices usually confine themselves to check whether the method in question satisfies the charge conservation. Another important test of the theory’s correctness is to check that the computed current does not depend on the choice of the central region (also referred to as the “extended molecule”). This work addresses this issue and demonstrates that the relevant transport and transport-related properties are indeed invariant upon changing the size of the extended molecule, when the embedded molecule can be described within a general single-particle picture (namely, a second-quantized Hamiltonian bilinear in the creation and annihilation operators). It is also demonstrates that the invariance of nonequilibrium properties is exhibited by the exact results but not by those computed approximately within ubiquitous wide- and flat-band limits (WBL and FBL, respectively). To exemplify the limitations of the latter, the phenomenon of negative differential resistance (NDR) is considered. It is shown that the exactly computed current may exhibit a substantial NDR, while the NDR effect is absent or drastically suppressed within the WBL and FBL approximations. The analysis done in conjunction with the WBLs and FBLs reveals why general studies on nonequilibrium properties require a more elaborate theoretical than studies on linear response properties (e.g., ohmic conductance and thermopower) at zero temperature. Furthermore, examples are presented that demonstrate that treating parts of electrodes adjacent to the embedded molecule and the remaining semi-infinite electrodes at different levels of theory (which is exactly what most NEGF-DFT approaches do) is a procedure that yields spurious structures in nonlinear ranges of current–voltage curves. PMID:27335734

  8. Relationship between the size of the bottleneck 15 A from iron in the main channel and the reactivity of catalase corresponding to the molecular size of substrates.

    PubMed

    Hara, Isao; Ichise, Nobutoshi; Kojima, Kiyoshi; Kondo, Hidemasa; Ohgiya, Satoru; Matsuyama, Hidetoshi; Yumoto, Isao

    2007-01-01

    A catalase that exhibits a high level of activity and a rapid reaction with organic peroxides has been purified from Exiguobacterium oxidotolerans T-2-2T (EKTA catalase). The amino acid sequence of EKTA catalase revealed that it is a novel clade 1 catalase. Amino acid residues in the active site around the protoheme are conserved in the primary structure of EKTA catalase. Although the general interactions of molecules larger than hydrogen peroxide with catalases are strongly inhibited because of the selection role of long and narrow channels in the substrate reaching the active site, the formation rate of reactive intermediates (compound I) in the reaction of EKTA catalase with peracetic acid is 77 times higher than that of bovine liver catalase (BLC) and 1200 times higher than that of Micrococcus luteus catalase (MLC). The crystal structure of EKTA catalase has been determined and refined to 2.4 A resolution. The main channel structure of EKTA catalase is different from those of BLC and MLC. The rate constant of compound I formation in catalases decreased with an increase in the molecular size of the substrate. For EKTA catalase with a larger bottleneck 15 A from the iron (entrance of narrow channel) in the main channel, a lower rate of reduction in compound I formation rate with an increase in the molecular size of substrates was found. The increase in the rate constant of compound I formation in these catalases was directly proportional to the increase in the size of the bottleneck in the main channel when molecules of substrates larger than H2O2, such as organic peroxides, are used in the reaction. The results indicate that the size of the bottleneck in the main channel in catalase is an important factor in defining the rate of compound I formation corresponding to the molecular size of the substrates, and this was demonstrated. The Leu149-Ile180 and Asp109-Met167 combinations at the entrance of the narrow channel in EKTA catalase determine the size of the

  9. Exosomes and Microvesicles: Identification and Targeting By Particle Size and Lipid Chemical Probes

    PubMed Central

    Kastelowitz, Noah

    2014-01-01

    Exosomes and microvesicles are two classes of submicroscopic vesicle released by cells into the extracellular space. Collectively referred to as extracellular vesicles, these membrane containers facilitate important cell-cell communication by carrying a diverse array of signaling molecules, including nucleic acids, proteins, and lipids. Recently, the role of extracellular vesicle signaling in cancer progression has become a topic of significant interest. Methods to detect and target exosomes and microvesicles are needed to realize applications of extracellular vesicles as biomarkers and, perhaps, therapeutic targets. Detection of exosomes and microvesicles is a complex problem as they are both submicroscopic and of heterogeneous cellular origins. In this Minireview, we highlight the basic biology of extracellular vesicles, and address available biochemical and biophysical detection methods. Detectible characteristics described here include lipid and protein composition, and physical properties such as the vesicle membrane shape and diffusion coefficient. In particular, we propose that detection of exosome and microvesicle membrane curvature with lipid chemical probes that sense membrane shape is a distinctly promising method for identifying and targeting these vesicles. PMID:24740901

  10. Determination of molecular size of alpha-1 and alpha-2 adrenoceptors in rat mesenteric artery by radiation inactivation

    SciTech Connect

    Agrawal, D.K.; Grover, A.K.; Daniel, E.E.; Jung, C.Y.

    1986-03-01

    Radiation inactivation of alpha-1 and alpha-2 adrenoceptors in the purified plasma membranes of rat mesenteric artery has been performed with high energy electrons at -45 to -55 degrees C. Alpha-1 and alpha-2 adrenoceptor inactivation was monitored with (3H) prazosin and (3H)yohimbine binding, respectively. Internal endogenous and external standards of known molecular weight were used in these studies to determine the molecular size. The average value of D37 for the (3H)prazosin binding site was 6.75 +/- 0.62 Mrad (n = 4) with an estimated molecular size of 122,921 +/- 11,329 Daltons. However, the average value of D37 for the (3H) yohimbine binding site was higher (D37 = 10.05 +/- 0.91 Mrad) and accordingly the molecular size of this binding site was less than the (3H)prazosin binding sites (molecular weight = 82,540 +/- 7478 Daltons; n = 4). Irradiation did not change the dissociation constant of either radioligand, suggesting that the loss of the radioligand binding sites after radiation is due to receptor protein inactivation. These results confirm our earlier finding that (3H)prazosin and (3H)yohimbine bind to two distinct sites in the plasma membranes of rat mesenteric artery. Whether both of these sites are the subunits of a common macromolecule of alpha adrenoceptor on vascular smooth muscle in rat mesenteric artery cannot be concluded from these results. This report is the first one in the literature on the molecular size of alpha-1 and alpha-2 binding sites in vascular smooth muscle.

  11. Mechanism of MicroRNA-Target Interaction: Molecular Dynamics Simulations and Thermodynamics Analysis

    PubMed Central

    Wang, Yonghua; Li, Yan; Ma, Zhi; Yang, Wei; Ai, Chunzhi

    2010-01-01

    MicroRNAs (miRNAs) are endogenously produced ∼21-nt riboregulators that associate with Argonaute (Ago) proteins to direct mRNA cleavage or repress the translation of complementary RNAs. Capturing the molecular mechanisms of miRNA interacting with its target will not only reinforce the understanding of underlying RNA interference but also fuel the design of more effective small-interfering RNA strands. To address this, in the present work the RNA-bound (Ago-miRNA, Ago-miRNA-target) and RNA-free Ago forms were analyzed by performing both molecular dynamics simulations and thermodynamic analysis. Based on the principal component analysis results of the simulation trajectories as well as the correlation analysis in fluctuations of residues, we discover that: 1) three important (PAZ, Mid and PIWI) domains exist in Argonaute which define the global dynamics of the protein; 2) the interdomain correlated movements are so crucial for the interaction of Ago-RNAs that they not only facilitate the relaxation of the interactions between residues surrounding the RNA binding channel but also induce certain conformational changes; and 3) it is just these conformational changes that expand the cavity of the active site and open putative pathways for both the substrate uptake and product release. In addition, by thermodynamic analysis we also discover that for both the guide RNA 5′-end recognition and the facilitated site-specific cleavage of the target, the presence of two metal ions (of Mg2+) plays a predominant role, and this conclusion is consistent with the observed enzyme catalytic cleavage activity in the ternary complex (Ago-miRNA-mRNA). Our results find that it is the set of arginine amino acids concentrated in the nucleotide-binding channel in Ago, instead of the conventionally-deemed seed base-paring, that makes greater contributions in stabilizing the binding of the nucleic acids to Ago. PMID:20686687

  12. Molecular and biochemical characterization of methionine aminopeptidase of Babesia bovis as a potent drug target.

    PubMed

    Munkhjargal, Tserendorj; Ishizaki, Takahiro; Guswanto, Azirwan; Takemae, Hitoshi; Yokoyama, Naoaki; Igarashi, Ikuo

    2016-05-15

    Aminopeptidases are increasingly being investigated as therapeutic targets in various diseases. In this study, we cloned, expressed, and biochemically characterized a member of the methionine aminopeptidase (MAP) family from Babesia bovis (B. bovis) to develop a potential molecular drug target. Recombinant B. bovis MAP (rBvMAP) was expressed in Escherichia coli (E. coli) as a glutathione S-transferase (GST)-fusion protein, and we found that it was antigenic. An antiserum against the rBvMAP protein was generated in mice, and then a native B. bovis MAP was identified in B. bovis by Western blot assay. Further, an immunolocalization assay showed that MAP is present in the cytoplasm of the B. bovis merozoite. Analysis of the biochemical properties of rBvMAP revealed that it was enzymatically active, with optimum activity at pH 7.5. Enhanced enzymatic activity was observed in the presence of divalent manganese cations and was effectively inhibited by a metal chelator, ethylenediaminetetraacetic acid (EDTA). Moreover, the enzymatic activity of BvMAP was inhibited by amastatin and bestatin as inhibitors of MAP (MAPi) in a dose-dependent manner. Importantly, MAPi was also found to significantly inhibit the growth of Babesia parasites both in vitro and in vivo; additionally, they induced high levels of cytokines and immunoglobulin (IgG) titers in the host. Therefore, our results suggest that BvMAP is a molecular target of amastatin and bestatin, and those inhibitors may be drug candidates for the treatment of babesiosis, though more studies are required to confirm this. PMID:27084466

  13. Nitric Oxide Improves Molecular Imaging of Inflammatory Atheroma using Targeted Echogenic Immunoliposomes

    PubMed Central

    Kim, Hyunggun; Kee, Patrick H.; Rim, Yonghoon; Moody, Melanie R.; Klegerman, Melvin E.; Vela, Deborah; Huang, Shao-Ling; McPherson, David D.; Laing, Susan T.

    2013-01-01

    Objective: This study aimed to demonstrate whether pretreatment with nitric oxide (NO) loaded into echogenic immunoliposomes (ELIP) plus ultrasound, applied before injection of molecularly targeted ELIP can promote penetration of the targeted contrast agent and improve visualization of atheroma components. Methods: ELIP were prepared using the pressurization-freeze method. Atherosclerosis was induced in Yucatan miniswine by balloon denudation and a hyperlipidemic diet. The animals were randomized to receive anti-intercellular adhesion molecule-1 (ICAM-1) ELIP or immunoglobulin (IgG)-ELIP, and were subdivided to receive pretreatment with standard ELIP plus ultrasound, NO-loaded ELIP, or NO-loaded ELIP plus ultrasound. Intravascular ultrasound (IVUS) data were collected before and after treatment. Results: Pretreatment with standard ELIP plus ultrasound or NO-loaded ELIP without ultrasound resulted in 9.2 ± 0.7% and 9.2 ± 0.8% increase in mean gray scale values, respectively, compared to baseline (p<0.001 vs. control). Pretreatment with NO-loaded ELIP plus ultrasound activation resulted in a further increase in highlighting with a change in mean gray scale value to 14.7 ± 1.0% compared to baseline (p<0.001 vs. control). These differences were best appreciated when acoustic backscatter data values (RF signal) were used [22.7 ± 2.0% and 22.4 ± 2.2% increase in RF signals for pretreatment with standard ELIP plus ultrasound and NO-loaded ELIP without ultrasound respectively (p<0.001 vs. control), and 40.0 ± 2.9% increase in RF signal for pretreatment with NO-loaded ELIP plus ultrasound (p<0.001 vs. control)]. Conclusion: NO-loaded ELIP plus ultrasound activation can facilitate anti-ICAM-1 conjugated ELIP delivery to inflammatory components in the arterial wall. This NO pretreatment strategy has potential to improve targeted molecular imaging of atheroma for eventual true tailored and personalized management of cardiovascular diseases. PMID:24267236

  14. Attentional focus, perceived target size, and movement kinematics under performance pressure.

    PubMed

    Gray, Rob; Cañal-Bruland, Rouwen

    2015-12-01

    The present study examined the relationship between attentional focus, perceived hole size, and radial putting error in a golf task. Twenty-five experienced golfers were asked to produce size estimates immediately after completing a putt. To assess their attentional focus, one of two secondary tasks (chosen randomly) was performed next. In the Hole task, participants were asked to indicate whether a sound played during their putting stroke was presented to the left or right of the hole. In the Club task, they were asked to indicate whether the sound occurred closer to the beginning or end of their backswing. Participants completed three phases: a no pressure pretest, a pressure phase, and a no pressure posttest. There were substantial individual differences in the effects of pressure on putting kinematics: 11 golfers (designated the Choke group) showed significant changes in kinematic variables and heart rate, and 14 golfers (designated the Clutch group) showed no significant change in these variables. For the Choke group, putting error and the accuracy on the Club task significantly increased during the pressure phase while size estimates and accuracy on the Hole task significantly decreased. There were no significant changes in any of these variables for the Clutch group. These findings provide further evidence for the attentional accentuation hypothesis of action-specific effects. PMID:25933628

  15. Sodium modulates opioid receptors through a membrane component different from G-proteins. Demonstration by target size analysis

    SciTech Connect

    Ott, S.; Costa, T.; Herz, A.

    1988-07-25

    The target size for opioid receptor binding was studied after manipulations known to affect the interactions between receptor and GTP-binding regulatory proteins (G-proteins). Addition of GTP or its analogs to the binding reaction, exposure of intact cells to pertussis toxin prior to irradiation, or treatment of irradiated membranes with N-ethylmaleimide did not change the target size (approximately equal to 100 kDa) for opioid receptors in NG 108-15 cells and rat brain. These data suggest that the 100-kDa species does not include an active subunit of a G-protein or alternatively that GTP does not promote the dissociation of the receptor-G-protein complex. The presence of Na+ (100 mM) in the radioligand binding assay induced a biphasic decay curve for agonist binding and a flattening of the monoexponential decay curve for a partial agonist. In both cases the effect was explained by an irradiation-induced loss of the low affinity state of the opioid receptor produced by the addition of Na+. This suggests that an allosteric inhibitor that mediates the effect of sodium on the receptor is destroyed at low doses of irradiation, leaving receptors which are no longer regulated by sodium. The effect of Na+ on target size was slightly increased by the simultaneous addition of GTP but was not altered by pertussis toxin treatment. Thus, the sodium unit is distinct from G-proteins and may represent a new component of the opioid receptor complex. Assuming a simple bimolecular model of one Na+ unit/receptor, the size of this inhibitor can be measured as 168 kDa.

  16. Molecular-targeted therapy for chemotherapy-refractory gastric cancer: a case report and literature review.

    PubMed

    Kuo, Hung-Yang; Yeh, Kun-Huei

    2014-07-01

    The prognosis of advanced gastric cancer (AGC) remains poor despite therapeutic advances in recent decades. Several recent positive phase III trials established the efficacy of second-line chemotherapy for metastatic gastric cancer in prolonging overall survival. However, malnutrition and poor performance of AGC in late stages usually preclude such patients from intensive treatment. Many targeted-therapies failed to show a significant survival benefit in AGC, but have regained attention after the positive result of ramucirumab was announced last year. Among all targeted agents, only trastuzumab, a monoclonal antibody against Human epidermal growth factor receptor-2 (HER2) protein, has been proven as having survival benefit by addition to first-line chemotherapy. Herein we reported a patient who benefited from adding trastuzumab to the same second-line combination chemotherapy (paclitaxel, 5-fluorouracil, and leucovorin) upon progression of bulky liver metastases. At least five months of progression-free survival were achieved without any additional toxicity. We also reviewed literature of molecularly-targeted therapy for chemotherapy-refractory gastric cancer, including several large phase III trials (REGARD, GRANITE-1, EXPAND, and REAL-3) published in 2013-2014. PMID:24982389

  17. New Synaptic and Molecular Targets for Neuroprotection in Parkinson’s Disease

    PubMed Central

    Calabresi, Paolo; Di Filippo, Massimiliano; Gallina, Antongiulio; Wang, Yingfei; Stankowski, Jeannette N.; Picconi, Barbara; Dawson, Valina L.; Dawson, Ted M.

    2014-01-01

    The defining anatomical feature of Parkinson’s disease (PD) is the degeneration of substantia nigra pars compacta (SNc) neurons, resulting in striatal dopamine (DA) deficiency and in the subsequent alteration of basal ganglia physiology. Treatments targeting the dopaminergic system alleviate PD symptoms but are not able to slow the neurodegenerative process that underlies PD progression. The nucleus striatum comprises a complex network of projecting neurons and interneurons that integrates different neural signals to modulate the activity of the basal ganglia circuitry. In this review we describe new potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD. In particular, we focus on the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway. Moreover, we also discuss the possibility to target the cell death program parthanatos and the kinase LRRK2 in order to develop new putative neuroprotective agents for PD acting on dopaminergic nigral neurons as well as on other basal ganglia structures. PMID:22927178

  18. Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension

    PubMed Central

    Morrell, Nicholas W.; Archer, Stephen L.; DeFelice, Albert; Evans, Steven; Fiszman, Monica; Martin, Thomas; Saulnier, Muriel; Rabinovitch, Marlene; Schermuly, Ralph; Stewart, Duncan; Truebel, Hubert; Walker, Gennyne; Stenmark, Kurt R.

    2013-01-01

    Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years. This research has identified important new targets that could be explored as potential therapies for PAH. In this review we discuss whether further exploitation of vasoactive agents could bring additional benefits over existing approaches. Approaches to enhance smooth muscle cell apotosis and the potential of receptor tyrosine kinase inhibition are summarised. We evaluate the role of inflammation, epigenetic changes and altered glycolytic metabolism as potential targets for therapy, and whether inherited genetic mutations in PAH have revealed druggable targets. The potential of cell based therapies and gene therapy are also discussed. Potential candidate pathways that could be explored in the context of experimental medicine are identified. PMID:23662201

  19. The Killer Fly Hunger Games: Target Size and Speed Predict Decision to Pursuit

    PubMed Central

    Wardill, Trevor J.; Knowles, Katie; Barlow, Laura; Tapia, Gervasio; Nordström, Karin; Olberg, Robert M.; Gonzalez-Bellido, Paloma T.

    2015-01-01

    Predatory animals have evolved to optimally detect their prey using exquisite sensory systems such as vision, olfaction and hearing. It may not be so surprising that vertebrates, with large central nervous systems, excel at predatory behaviors. More striking is the fact that many tiny insects, with their miniscule brains and scaled down nerve cords, are also ferocious, highly successful predators. For predation, it is important to determine whether a prey is suitable before initiating pursuit. This is paramount since pursuing a prey that is too large to capture, subdue or dispatch will generate a substantial metabolic cost (in the form of muscle output) without any chance of metabolic gain (in the form of food). In addition, during all pursuits, the predator breaks its potential camouflage and thus runs the risk of becoming prey itself. Many insects use their eyes to initially detect and subsequently pursue prey. Dragonflies, which are extremely efficient predators, therefore have huge eyes with relatively high spatial resolution that allow efficient prey size estimation before initiating pursuit. However, much smaller insects, such as killer flies, also visualize and successfully pursue prey. This is an impressive behavior since the small size of the killer fly naturally limits the neural capacity and also the spatial resolution provided by the compound eye. Despite this, we here show that killer flies efficiently pursue natural (Drosophila melanogaster) and artificial (beads) prey. The natural pursuits are initiated at a distance of 7.9 ± 2.9 cm, which we show is too far away to allow for distance estimation using binocular disparities. Moreover, we show that rather than estimating absolute prey size prior to launching the attack, as dragonflies do, killer flies attack with high probability when the ratio of the prey's subtended retinal velocity and retinal size is 0.37. We also show that killer flies will respond to a stimulus of an angular size that is smaller

  20. Estimation of turbulent kinetic energy using 4D phase-contrast MRI: Effect of scan parameters and target vessel size.

    PubMed

    Ha, Hojin; Hwang, Dongha; Kim, Guk Bae; Kweon, Jihoon; Lee, Sang Joon; Baek, Jehyun; Kim, Young-Hak; Kim, Namkug; Yang, Dong Hyun

    2016-07-01

    Quantifying turbulence velocity fluctuation is important because it indicates the fluid energy dissipation of the blood flow, which is closely related to the pressure drop along the blood vessel. This study aims to evaluate the effects of scan parameters and the target vessel size of 4D phase-contrast (PC)-MRI on quantification of turbulent kinetic energy (TKE). Comprehensive 4D PC-MRI measurements with various velocity-encoding (VENC), echo time (TE), and voxel size values were carried out to estimate TKE distribution in stenotic flow. The total TKE (TKEsum), maximum TKE (TKEmax), and background noise level (TKEnoise) were compared for each scan parameter. The feasibility of TKE estimation in small vessels was also investigated. Results show that the optimum VENC for stenotic flow with a peak velocity of 125cm/s was 70cm/s. Higher VENC values overestimated the TKEsum by up to six-fold due to increased TKEnoise, whereas lower VENC values (30cm/s) underestimated it by 57.1%. TE and voxel size did not significantly influence the TKEsum and TKEnoise, although the TKEmax significantly increased as the voxel size increased. TKE quantification in small-sized vessels (3-5-mm diameter) was feasible unless high-velocity turbulence caused severe phase dispersion in the reference image. PMID:26968139

  1. Size- and condition-dependent predation: a seabird disproportionately targets substandard individual juvenile salmon.

    PubMed

    Tucker, Strahan; Hipfner, J Mark; Trudel, Marc

    2016-02-01

    Selection of prey that are small and in poor body condition is a widespread phenomenon in terrestrial predator-prey systems and may benefit prey populations by removing substandard individuals. Similar selection is widely assumed to operate in aquatic systems. Indeed, size-selective predation is a longstanding and central tenet of aquatic food web theory. However, it is not known if aquatic predators select prey based on their condition or state, compared to their size. Surprisingly, no comparable information is available for marine systems because it is exceedingly difficult to make direct observations in this realm. Thus the role of body condition in regulating susceptibility to predation remains a black box in the marine environment. Here we have exploited an ideal model system to evaluate selective predation on pelagic marine fish: comparing characteristics (fork length, mass corrected for fork length) of fresh, whole, intact juvenile Pacific salmon delivered by a seabird to its single nestling with salmon collected concurrently in coastal trawl surveys. Three species of juvenile salmon (Oncorhynchus spp.) are consumed by provisioning Rhinoceros Auklets (Cerorhinca nionocerata); an abundant, colonial, pursuit-diving seabird. Samples were collected from multiple colonies and fisheries surveys in coastal British Columbia in two years. As predicted, Auklets preyed on small individuals in poor condition and consistently selected them at levels higher than their relative availability. This is the first study to provide direct evidence for both size- and condition-selective predation on marine fish in the wild. We anticipate that our results will be a starting point in evaluating how selective predation may structure or influence marine fish populations and bridges a fundamental incongruity between ecological theory and application; although "bigger is better" is considered a fundamental tenet of marine food webs, marine predators are often assumed to consume

  2. Dosimetric Verification by Using the ArcCHECK System and 3DVH Software for Various Target Sizes

    PubMed Central

    Song, Jin Ho; Shin, Hun-Joo; Kay, Chul Seung; Son, Seok Hyun

    2015-01-01

    Objective To investigate the usefulness of the 3DVH software with an ArcCHECK 3D diode array detector in newly designed plans with various target sizes. Methods The isocenter dose was measured with an ion-chamber and was compared with the planned and 3DVH predicted doses. The 2D gamma passing rates were evaluated at the diode level by using the ArcCHECK detector. The 3D gamma passing rates for specific regions of interest (ROIs) were also evaluated by using the 3DVH software. Several dose-volume histograms (DVH)-based predicted metrics for all structures were also obtained by using the 3DVH software. Results The isocenter dose deviation was <1% in all plans except in the case of a 1 cm target. Besides the gamma passing rate at the diode level, the 3D gamma passing rate for specific ROIs tended to decrease with increasing target size; this was more noticeable when a more stringent gamma criterion was applied. No correlation was found with the gamma passing rates and the DVH-based metrics especially in the ROI with high-dose gradients. Conclusions Delivery quality assurance by using 3DVH and ArcCHECK can provide substantial information through a simple and easy approach, although the accuracy of this system should be judged cautiously. PMID:25807544

  3. Adaptation of eye and hand movements to target displacements of different size.

    PubMed

    Schmitz, Gerd; Bock, Otmar; Grigorova, Valentina; Ilieva, Milena

    2010-06-01

    Previous work has documented that the direction of eye and hand movements can be adaptively modified using the double-step paradigm. Here we report that both motor systems adapt not only to small direction steps (5 degrees gaze angle) but also to large ones (28 degrees gaze angle). However, the magnitude of adaptation did not increase with step size, and the relative magnitude of adaptation therefore decreased from 67% with small steps to 15% with large steps. This decreasing efficiency of adaptation may reflect the participation of directionally selective neural circuits in double-step adaptation. PMID:20424831

  4. Exploration of target molecules for molecular imaging of inflammatory bowel disease

    SciTech Connect

    Higashikawa, Kei; Akada, Naoki; Yagi, Katsuharu; Watanabe, Keiko; Kamino, Shinichiro; Kanayama, Yousuke; Hiromura, Makoto; Enomoto, Shuichi

    2011-07-08

    Highlights: {sup {yields}18}F-FDG PET could discriminate each inflamed area of IBD model mice clearly. {sup {yields}18}F-FDG PET could not discriminate the difference of pathogenic mechanism. {yields} Cytokines and cytokine receptors expression was different by pathogenic mechanism. {yields} Cytokines and cytokine receptors would be new target molecules for IBD imaging. -- Abstract: Molecular imaging technology is a powerful tool for the diagnosis of inflammatory bowel disease (IBD) and the efficacy evaluation of various drug therapies for it. However, it is difficult to elucidate directly the relationships between the responsible molecules and IBD using existing probes. Therefore, the development of an alternative probe that is able to elucidate the pathogenic mechanism and provide information on the appropriate guidelines for treatment is earnestly awaited. In this study, we investigated pathognomonic molecules in the intestines of model mice. The accumulation of fluorine-18 fluorodeoxyglucose ({sup 18}F-FDG) in the inflamed area of the intestines of dextran sulfate sodium (DSS)- or indomethacin (IND)-induced IBD model mice was measured by positron emission tomography (PET) and autoradiography to confirm the inflamed area. The results suggested that the inflammation was selectively induced in the colons of mice by the administration of DSS, whereas it was induced mainly in the ilea and the proximal colons of mice by the administration of IND. To explore attractive target molecules for the molecular imaging of IBD, we evaluated the gene expression levels of cytokines and cytokine receptors in the inflamed area of the intestines of both model mice. We found that the expression levels of cytokines and cytokine receptors were significantly increased during the progression of IBD, whereas the expression levels were decreased as the mucosa began to heal. In particular, the expression levels of these molecules had already changed before the symptoms of IBD appeared. In

  5. Focusing of photomechanical waves with an optical lens for depth-targeted molecular delivery

    NASA Astrophysics Data System (ADS)

    Shimada, Takuichirou; Sato, Shunichi; Kawauchi, Satoko; Ashida, Hiroshi; Terakawa, Mitsuhiro

    2014-02-01

    We have been developing molecular delivery systems based on photomechanical waves (PMWs), which are generated by the irradiation of a laser absorbing material with nanosecond laser pulses. This method enables highly site-specific delivery in the horizontal plane of the tissue. However, targeting in the vertical direction is a remaining challenge. In this study, we developed a novel PMW focusing device for deeper tissue targeting. A commercial optical concave lens and black natural rubber sheet (laser absorber) were attached to the top and bottom end of a cylindrical spacer, respectively, which was filled with water. A laser pulse was transmitted through the lens and water and hit the rubber sheet to induce a plasma, generating a PMW. The PMW was propagated both downward and upward. The downward wave (1st wave) was diffused, while the upward (2nd wave) wave was reflected with the concave surface of the lens and focused at a depth determined by the geometrical parameters. To attenuate the 1st wave, a small-diameter silicon sponge rubber disk was adhered just under the rubber sheet concentrically with the laser axis. With the lens of f = -40 mm, the 2nd wave was focused to a diameter of 5.7 mm at a targeted depth of 20 mm, which was well agreed with the result of calculation by ray tracing. At a laser fluence of 5.1 J/cm2, peak pressure of the PMW reached ~40 MPa at the depth of 20 mm. Under this condition, we examined depth-targeted gene delivery to the rat skin.

  6. Target preparation for milligram sized 14C samples and data evaluation for AMS measurements

    NASA Astrophysics Data System (ADS)

    Andree, Michael; Beer, Jürg; Oeschger, Hans; Bonani, G.; Hofmann, H. J.; Morenzoni, E.; Nessi, M.; Suter, M.; Wölfli, W.

    1984-11-01

    Our preparation technique produces in a glow-discharge an amorphous carbon deposit on a copper substrate. The process starts with 1.6 cm 3 CO 2 STP (900 μg carbon) which is reduced over hot zinc to CO and subsequently cracked in the discharge. The yield of the process is typically 80%. With these targets in the Zürich ion source ion currents up to 20 μA are obtained. The background of samples prepared with this technique is presently around 30 ka (2.5% MODERN). The precision after half an hour measuring time for a modern sample is 0.7% and 2.7% for a three half-lives old sample, including the errors of the background and the NBS oxalic acid measurement. The method we use to correct for the background of the preparation and the accelerator as well as for the fractionation in the accelerator is presented.

  7. Identification of a molecular target of psychosine and its role in globoid cell formation.

    PubMed

    Im, D S; Heise, C E; Nguyen, T; O'Dowd, B F; Lynch, K R

    2001-04-16

    Globoid cell leukodystrophy (GLD) is characterized histopathologically by apoptosis of oligodendrocytes, progressive demyelination, and the existence of large, multinuclear (globoid) cells derived from perivascular microglia. The glycosphingolipid, psychosine (d-galactosyl-beta-1,1' sphingosine), accumulates to micromolar levels in GLD patients who lack the degradative enzyme galactosyl ceramidase. Here we document that an orphan G protein-coupled receptor, T cell death-associated gene 8, is a specific psychosine receptor. Treatment of cultured cells expressing this receptor with psychosine or structurally related glycosphingolipids results in the formation of globoid, multinuclear cells. Our discovery of a molecular target for psychosine suggests a mechanism for the globoid cell histology characteristic of GLD, provides a tool with which to explore the disjunction of mitosis and cytokinesis in cell cultures, and provides a platform for developing a medicinal chemistry for psychosine. PMID:11309421

  8. Small Molecule Activators of the Heat Shock Response: Chemical Properties, Molecular Targets, and Therapeutic Promise

    PubMed Central

    West, James D.; Wang, Yanyu; Morano, Kevin A.

    2012-01-01

    All cells have developed various mechanisms to respond and adapt to a variety of environmental challenges, including stresses that damage cellular proteins. One such response, the heat shock response (HSR), leads to the transcriptional activation of a family of molecular chaperone proteins that promote proper folding or clearance of damaged proteins within the cytosol. In addition to its role in protection against acute insults, the HSR also regulates lifespan and protects against protein misfolding that is associated with degenerative diseases of aging. As a result, identifying pharmacological regulators of the HSR has become an active area of research in recent years. Here, we review progress made in identifying small molecule activators of the HSR, what cellular targets these compounds interact with to drive response activation, and how such molecules may ultimately be employed to delay or reverse protein misfolding events that contribute to a number of diseases. PMID:22799889

  9. Multi-target photoacoustic molecular imaging of cardiovascular inflammatory biomarkers using bioconjugated gold nanorods

    NASA Astrophysics Data System (ADS)

    Ha, S.; Tripathy, S.; Carson, A.; Lavery, L. L.; Zhang, H.; Agarwal, A.; Kotov, N.; Villanueva, F. S.; Kim, K.

    2011-03-01

    Multiple cardiovascular inflammatory biomarkers were simultaneously imaged in vivo using antibody conjugated gold nanorods (GNRs) injected into a mouse model of vascular injury stimulated by a photochemical reaction of Rose Bengal dye to green light. Mixed solutions of ICAM-1 antibody conjugated GNRs (715 nm) and E-selectin antibody conjugated GNRs (800 nm) were injected to bind to their respective inflammatory markers on the luminal surface of the inferior vena cava of a mouse. Photoacoustic intensity was measured by a commercial ultrasound probe synchronized to a pulsed laser (10-18 mJ/cm2) at 715 nm or 800 nm clearly identified the upregulation of targeted biomarkers. Histopathology on the harvested tissues confirmed inflammation. The feasibility of simultaneous photoacoustic molecular imaging of inflammation responses in cardiovascular system using a commercial ultrasound system has been demonstrated in vivo.

  10. Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas.

    PubMed

    Garcia, Michael A; Solomon, David A; Haas-Kogan, Daphne A

    2016-06-01

    The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas (PLGGs), there is significant histologic and genetic diversity within this group. In general, prognosis for PLGGs is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way PLGGs are classified and managed. Here, we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials. PMID:27072750

  11. Targeting the adaptive molecular landscape of castration-resistant prostate cancer

    PubMed Central

    Wyatt, Alexander W; Gleave, Martin E

    2015-01-01

    Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC. PMID:25896606

  12. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  13. Chemopreventive potential of chlorophyllin: a review of the mechanisms of action and molecular targets.

    PubMed

    Nagini, Siddavaram; Palitti, Fabrizio; Natarajan, Adayapalam T

    2015-01-01

    Chlorophyllin (CHL), a water soluble semisynthetic derivative of the ubiquitous plant pigment chlorophyll used as a food additive, is recognized to confer a wide range of health benefits. CHL has been shown to exhibit potent antigenotoxic, anti-oxidant, and anticancer effects. Numerous experimental and epidemiological studies have demonstrated that dietary supple-mentation of CHL lowers the risk of cancer. CHL inhibits cancer initiation and progression by targeting multiple molecules and pathways involved in the metabolism of carcinogens, cell cycle progression, apoptosis evasion, invasion, and angiogenesis. The modulatory effects of CHL on the hallmark capabilities of cancer appear to be mediated via abrogation of key oncogenic signal transduction pathways such as nuclear factor kappa B, Wnt/β-catenin, and phosphatidylinositol-3-kinase/Akt signaling. This review provides insights into the molecular mechanisms of the anticancer effects of dietary CHL. PMID:25650669

  14. Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives

    PubMed Central

    Dhaliwal, Amaninder; Vlachostergios, Panagiotis J; Oikonomou, Katerina G; Moshenyat, Yitzchak

    2015-01-01

    The early detection of colorectal cancer with effective screening is essential for reduction of cancer-specific mortality. The addition of fecal DNA testing in the armamentarium of screening methods already in clinical use launches a new era in the noninvasive part of colorectal cancer screening and emanates from a large number of previous and ongoing clinical investigations and technological advancements. In this review, we discuss the molecular rational and most important genetic alterations hallmarking the early colorectal carcinogenesis process. Also, representative DNA targets-markers and key aspects of their testing at the clinical level in comparison or/and association with other screening methods are described. Finally, a critical view of the strengths and limitations of fecal DNA tests is provided, along with anticipated barriers and suggestions for further exploitation of their use. PMID:26483873

  15. Skin: Major target organ of allergic reactions to small molecular weight compounds

    SciTech Connect

    Merk, Hans F. Baron, Jens M.; Neis, Mark M.; Obrigkeit, Daniela Hoeller; Karlberg, Ann-Therese

    2007-11-01

    Skin is a major target organ for allergic reactions to small molecular weight compounds. Drug allergic reactions may be life-threatening such as in the case of anaphylactic reactions or bullous drug reactions and occur in about 5% of all hospitalized patients. Allergic contact dermatitis has an enormous influence on the social life of the patient because it is the most frequent reason for occupational skin diseases and the treatment and prevention of this disease cost approximately Euro 3 billion per year in Germany. The different proposed pathophysiological pathways leading to a drug eruption are discussed in this paper. All major enzymes which are involved in the metabolism of xenobiotica were shown to be present in skin. Evidence supporting the role of metabolism in the development of drug allergy and allergic contact dermatitis is demonstrated in the example of sulphonamides and fragrances.

  16. Biological activities and potential molecular targets of cucurbitacins: a focus on cancer.

    PubMed

    Chen, Xiuping; Bao, Jiaolin; Guo, Jiajie; Ding, Qian; Lu, Jinjian; Huang, Mingqing; Wang, Yitao

    2012-09-01

    Cucurbitacin and its derivatives (cucurbitacins) are a class of highly oxidized tetracyclic triterpenoids. They are widely distributed in the plant kingdom, where they act as heterologous chemical pheromones that protect plants from external biological insults. Their bioactivities first attracted attention in the 1960s. Documented data demonstrate that cucurbitacins possess strong pharmacological properties, such as antitumor, anti-inflammatory, and hepatoprotective effects, etc. Several molecular targets for cucurbitacins have been discovered, such as fibrous-actin, signal transducer and activator of transcription 3, cyclooxygenase-2, etc. The present study summarizes the achievements of the 50 years of research on cucurbitacins. The aim was to systematically analyze their bioactivities with an emphasis on their anticancer effects. Research and development has shed new insight into the beneficial properties of these compounds. PMID:22561419

  17. Molecular characterisation of cutaneous melanoma: creating a framework for targeted and immune therapies

    PubMed Central

    Rajkumar, Shivshankari; Watson, Ian R

    2016-01-01

    Large-scale genomic analyses of cutaneous melanoma have revealed insights into the aetiology and heterogeneity of this disease, as well as opportunities to further personalise treatment for patients with targeted and immune therapies. Herein, we review the proposed genomic classification of cutaneous melanoma from large-scale next-generation sequencing studies, including the largest integrative analysis of melanoma from The Cancer Genome Atlas (TCGA) Network. We examine studies that have identified molecular features of melanomas linked to immune checkpoint inhibitor response. In addition, we draw attention to low-frequency actionable mutations and highlight frequent non-coding mutations in melanoma where little is known about their biological function that may provide novel avenues for the development of treatment strategies for melanoma patients. PMID:27336610

  18. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

    PubMed Central

    Williams, Jessica A; Manley, Sharon; Ding, Wen-Xing

    2014-01-01

    Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant